Diabetes Mellitus Type 2 in Adults
Synopsis
Key Points
Type 2 diabetes mellitus is a metabolic disease in which hyperglycemia results from insulin resistance and reduced insulin; it accounts for 90% to 95% of cases of diabetes in adults [1]
Most cases are diagnosed with laboratory tests during routine screening or incidentally during another illness
Diagnosis is confirmed by fasting plasma glucose level of 126 mg/dL (7 mmol/L) or higher, 2-hour oral glucose tolerance test result of 200 mg/dL (11.1 mmol/L) or higher, hemoglobin A1C level of 6.5% or higher, and/or random plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher in presence of classic signs and symptoms of hyperglycemia (eg, polyuria, polydipsia, polyphagia, unexplained weight loss, weakness, blurred vision) [2]
Therapeutic lifestyle modifications (eg, diet, exercise, weight loss) are the cornerstone of therapy; pharmacotherapy is added to reach glycemic targets
Acute glycemic complications include hypoglycemia and hyperglycemic hyperosmolar state
Chronic microvascular complications are prevented by strict glycemic control; role of glycemic control in macrovascular disease prevention is complex
Mortality rate is 1.5 times higher for patients with type 2 diabetes than for general population, largely owing to cardiovascular complications [3]
Urgent Action
Severe hypoglycemia and hyperglycemic hyperosmolar state are life-threatening complications of type 2 diabetes and must be treated emergently
Pitfalls
Type 2 diabetes can be undiagnosed for many years owing to gradual development of hyperglycemia over time
Treating common comorbidities of diabetes mellitus often leads to polypharmacy; medication regimens and dosages may need to be adjusted as the disease progresses and cardiovascular function and renal function decline [4]
Terminology
Clinical Clarification
Diabetes mellitus type 2 is a chronic, heterogeneous metabolic disorder that manifests as hyperglycemia and is characterized by impaired insulin secretion, insulin resistance, and increased hepatic glucose production [1]
Most cases begin in adulthood, and type 2 accounts for 90% to 95% of cases of diabetes in adults
Overt hyperglycemia of type 2 diabetes results from a combination of underlying insulin resistance and progressive pancreatic β-cell dysfunction, ultimately leading to defects in insulin secretion
Prediabetes is impaired fasting glucose level and/or impaired glucose tolerance, indicating a state of increased risk for development of diabetes
Classification
General classification scheme for diabetes mellitus [1]
Type 1
Type 1A: immune mediated
Type 1B: idiopathic
Type 2
Accounts for 90% to 95% of cases of diabetes in adults [1]
Type 2 diabetes is not subclassified further
Gestational diabetes
Other specific types of diabetes due to other less common causes
Genetic defects of β-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Endocrinopathies
Drug- or chemical-induced diabetes
Posttransplantation diabetes
Cystic fibrosis–related diabetes
Infections
Uncommon forms of immune-mediated diabetes (eg, stiff man syndrome)
Other unusual genetic syndromes associated with diabetes (eg, Down syndrome, Klinefelter syndrome)
Diagnosis
Clinical Presentation
History
Most patients are initially asymptomatic, then identified through routine screening or by an incidental finding on laboratory tests in context of another illness
Type 2 diabetes can be undiagnosed for many years owing to gradual development of hyperglycemia over time
Symptoms develop as hyperglycemia worsens, including:
Polyuria
Polydipsia
Polyphagia
Unexplained weight loss
Weakness
Blurred vision
Patients with known, established type 2 diabetes often relate a history of hypertension, dyslipidemia, or cardiovascular disease
History of frequent infections (eg, candidiasis, urinary tract infections) or slow-healing wounds (eg, foot ulcers) suggests poor metabolic control
Physical examination
Overweight or obese body habitus in approximately 80% of patients [5]
Signs of insulin resistance
Increased abdominal adiposity
Acanthosis nigricans (cutaneous velvety hyperpigmented patches most prominent in intertriginous areas) when insulin resistance is extreme
Elevated blood pressure (common) [6]
Patients found to have blood pressure of 140/90 mm Hg or higher should have blood pressure confirmed with multiple readings, including measurements on a separate day, to diagnose hypertension
Patients with blood pressure of 180/110 mm Hg or higher and known cardiovascular disease can receive hypertension diagnosis in a single visit
Signs of complications in long-standing and/or poorly controlled disease:
Microaneurysms, exudates, and/or macular edema on funduscopic examination
Decreased lower extremity sensation, pedal pulses, and/or reflexes
Foot ulcers, deformities, or wounds on inspection
Heart rate variability on deep inspiration, position change, and/or Valsalva maneuver
Causes and Risk Factors
Causes
Multifactorial pathogenesis in which metabolic, behavioral, lifestyle, and environmental factors precipitate disease in genetically predisposed persons [7]
Combination of insulin resistance, increased hepatic gluconeogenesis, and relative defects in insulin secretion promote metabolic dysfunction
Overweight or obese body habitus is a major factor contributing to insulin resistance, which is a precursor to development of glucose intolerance and diabetes
Hypercaloric diet and sedentary lifestyle also increase insulin resistance
Hyperglycemia develops when progressive impairments in insulin secretion render pancreatic β cells unable to maintain euglycemia
Strong hereditary component contributes to manifestation of the disease, with complex polygenic inheritance pattern underlying most cases
Risk factors and/or associations
Age
Incidence increases with age, owing in part to age-related reduced glucose tolerance but also to reduced physical activity and increased adiposity
Sex
Females with history of the following are at greater risk for diabetes:
Polycystic ovary syndrome
Delivery of an infant weighing more than 4 kg
Previous diagnosis of gestational diabetes
Genetics
Most cases of type 2 diabetes have a complex multifactorial polygenic basis, with more than 100 loci identified as contributing to higher risk [8]
Most genes identified by genome-wide association studies individually confer modest risk of diabetes; when combined, they enable development and progression of the disease
Single-nucleotide polymorphisms within the following set of genes are robustly associated with type 2 diabetes: TCF7L2, GCK, HNF1B, WFS1, KCNJ11, PPARG, and IRS1 [8]
Presence of multiple at-risk polymorphisms in a patient substantially increases risk of developing diabetes
Genetic risk for type 2 diabetes is largely expressed in setting of environmental factors such as obesity and sedentary lifestyle
Ethnicity/race
Increased prevalence in Black, Latino, American Indian, Pacific Islander, and Asian American populations [1]
There is heterogeneity in prevalence of diabetes among Asian American subgroups, with highest rates in South Asian people (17.2 cases per 1000 person-years) and lowest rates among Vietnamese (4.6 cases per 1000 person-years) [9]
Other risk factors/associations
Risk factors
Prediabetes (hemoglobin A1C level 5.7% to 6.4%; 5-fold elevated risk) [10]
Overweight or obesity (2-fold elevated risk if overweight; risk rises proportionately with higher class of obesity) [5]
Sedentary lifestyle
Medications that worsen glucose tolerance or exacerbate hyperglycemia, such as: [1]
Glucocorticoids
Thiazide diuretics
Atypical antipsychotics
HIV medications
Statin therapy [11]
May increase risk for type 2 diabetes in patients already at high risk for type 2 diabetes
Sleep disorders (eg, obstructive sleep apnea, chronic sleep deprivation, night shift work schedule) in conjunction with glucose intolerance
Diagnostic Procedures
Primary diagnostic tools
Elements of history and physical examination findings can suggest the disorder, but biochemical parameters are essential for diagnosis
Laboratory confirmation of diabetes mellitus can be achieved with any of the following: [1][12]
Fasting plasma glucose measurement of at least 126 mg/dL (7 mmol/L)
Random glucose measurement of at least 200 mg/dL (11.1 mmol/L) when symptoms of hyperglycemia (eg, polyuria, polydipsia, polyphagia) are present
2-hour glucose measurement of at least 200 mg/dL (11.1 mmol/L) from an oral glucose tolerance test
Hemoglobin A1C measurement of at least 6.5%
Confirmation of diagnosis requires 2 of the above abnormal test results unless accompanied by clear clinical diagnosis of hyperglycemia [1]
Condition of prediabetes is met with 1 or both of the following states, or with hemoglobin A1C testing: [1]
Impaired fasting glucose level: fasting glucose value of 100 to 125 mg/dL (5.6-6.9 mmol/L)
Impaired glucose tolerance: 2-hour post–oral glucose tolerance test value of 140 to 199 mg/dL (7.8-11 mmol/L)
Hemoglobin A1C level: 5.7% to 6.4%
Additional clinical or laboratory tests to assess comorbidities and complications at time of diagnosis [13]
Measure the following:
Blood pressure
Comprehensive metabolic panel (includes electrolytes, renal and liver function)
Fasting lipid panel
Urinary albumin excretion
Refer for baseline dilated eye examination
Obtain resting ECG for patients with hypertension or suspected cardiovascular disease [14]
For older adult patients with diabetes, assess osteoporosis risk factors and obtain fracture history; recommend measurement of bone mineral density if appropriate for patient's age and sex
Refer patients with symptoms suggestive of obstructive sleep apnea (eg, excessive daytime sleepiness, snoring, witnessed apnea) for screening for sleep apnea [15]
Consider measurement of early morning serum testosterone level in males with diabetes and signs and symptoms of hypogonadism (eg, decreased libido, erectile dysfunction)
For patients with elevated liver enzyme levels, obtain liver ultrasonography and evaluate for presence of nonalcoholic steatohepatitis and liver fibrosis
Laboratory
Fasting glucose measurement [1]
Convenient, inexpensive measurement; however, levels can fluctuate [7]
Fasting requires no caloric intake for at least 8 hours; in absence of unequivocal hyperglycemia, repeated testing is required to confirm
Diagnostic thresholds are as follows:
Fasting glucose reference range: less than 100 mg/dL (less than 5.6 mmol/L)
Impaired fasting glucose level: 100 to 125 mg/dL (5.6-6.9 mmol/L)
Diabetes mellitus: 126 mg/dL (7 mmol/L) or higher
In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis
Random glucose measurement [1]
Diagnostic threshold is 200 mg/dL (11.1 mmol/L) or higher when signs or symptoms of hyperglycemia are present
In absence of unequivocal signs or symptoms of hyperglycemia, repeated testing is required to confirm
Hemoglobin A1C level [1]
Hemoglobin A1C level is the best measure of chronic glycemia and closely correlates with complications [7]
Less biologic variability compared with glucose-based tests
Diagnostic threshold
Diabetes mellitus: 6.5% or greater
In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis
Prediabetes: suggested by 5.7% to 6.4% (requires confirmatory fasting plasma glucose measurement or oral glucose tolerance test result for definitive diagnosis)
Accuracy is reduced in certain conditions:
Hemoglobinopathies (eg, sickle cell anemia, thalassemias, spherocytosis)
Iron deficiency
Hemolytic anemia
Chronic kidney disease
Severe hepatic disease
Severe renal disease
HIV treated with certain medications
Pregnancy and postpartum period
Erythropoietin therapy
Recent blood loss or transfusion
Less accurate for Black patients (hemoglobin A1C measurement is higher than in White patients despite similar glucose levels) [18]
Oral glucose tolerance test [1]
Sensitive as a metabolic test; however, inconvenient and time-consuming for patient [7]
Performed 2 hours after oral ingestion of 75 g of glucose dissolved in water
Ensure patient has had adequate carbohydrate intake (at least 150 g/day) for 3 days before testing
Diagnostic threshold for 2-hour glucose measurements:
Glucose tolerance reference range: less than 140 mg/dL (less than 7.8 mmol/L)
Impaired glucose tolerance level: 140 to 199 mg/dL (7.8-11.1 mmol/L)
Diabetes mellitus: 200 mg/dL (11.1 mmol/L) or higher
In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis
Pancreatic autoantibody testing [1]
Aids in classification when uncertainty exists about type 1 versus type 2 diabetes but not routinely indicated for most patients
Autoantibodies include those against insulin, glutamic acid decarboxylase 2, certain islet cell antigens, zinc transporter 8, and protein tyrosine phosphatase receptor type N
Results are negative for most patients with type 2 diabetes
C-peptide level
Normal or elevated C-peptide level is usually indicative of type 2 diabetes, whereas low or completely absent C-peptide level is indicative of type 1 diabetes [19]
Can be low in setting of glucotoxicity; may be most helpful when delayed until several months after metabolic control has been established
Additional laboratory tests recommended at diagnosis to screen for associated diseases and complications include: [13]
Fasting lipid panel
Renal function tests for nephropathy
Estimated GFR
Urine albumin to creatinine ratio
Liver function tests
Differential Diagnosis
Most common
Type 1 diabetes
Often presents overtly rather than through screening, with moderate to severe hyperglycemia and accompanying symptoms of polyuria, polydipsia, polyphagia, and unexplained weight loss
Typically (although not always) distinguished by: [20]
Younger age at onset (younger than 40 years)
BMI within reference range
History of ketoacidosis
Diagnosis is confirmed by positive pancreatic autoantibodies (against insulin, glutamic acid decarboxylase 2, certain islet cell antigens, zinc transporter 8, and protein tyrosine phosphatase receptor type N)
Diabetes insipidus
Spectrum of diseases that display hypotonic polyuria and inability to concentrate urine owing to inadequate secretion of or impaired renal responsiveness to arginine vasopressin
Presenting symptoms of polyuria, polydipsia, and nocturia overlap with those of diabetes mellitus when the latter is associated with symptomatic hyperglycemia
Diagnosis is suggested by 24-hour urine volume greater than 3 L and low urinary osmolality; definitive diagnosis requires water deprivation test[21]
Most easily differentiated from diabetes mellitus on basis of laboratory testing (ie, plasma glucose level, oral glucose tolerance test, or hemoglobin A1C level)
Monogenic diabetes/maturity-onset diabetes of youth [22][23]
Autosomal dominant disorders that cause β-cell dysfunction and impaired insulin secretion, with onset of hyperglycemia at young age (younger than 25 years)
Features include young age at presentation and strong family history of diabetes, without typical features of type 2 diabetes (eg, nonobese, low-risk ethnic group)
Other clinical situations that may suggest monogenic diabetes include: [24]
Mild fasting hyperglycemia that is stable and easy to control over long term
Gestational diabetes in females without typical risk factors
BMI within reference range at onset without ketosis or pancreatic antibodies
Unusual sensitivity to low-dose sulfonylureas or meglitinides
Can be formally differentiated from type 2 diabetes by genetic testing, most commonly with identification of mutations in HNF1A gene (HNF1 homeobox A) or GCK gene (glucokinase) [25]
Medication-induced diabetes [26]
Drugs promoting hyperglycemia may also induce type 2 diabetes in a genetically susceptible person [27]
Common triggers include:
Glucocorticoids
Thiazide diuretics
Atypical antipsychotics
Statins
Calcineurin inhibitors
Identified by temporal association of hyperglycemia that develops after inciting drug is used
Resolution of hyperglycemia after discontinuation of introduced medication confirms medication-induced diabetes
However, when it is not practical to discontinue medication, hyperglycemia is treated with pharmacotherapy as needed
Endocrinopathies
Some rare neuroendocrine tumors secrete or cause secretion of hormones that antagonize insulin action or reduce insulin secretion, leading to hyperglycemia
Cushing syndrome, acromegaly, glucagonoma, and pheochromocytomas are associated with glucose intolerance, and a subset of people with such conditions develop overt type 2 diabetes during course of disease
Treatment
Goals
Aim for optimal glycemic control
Glycemic targets differ among professional organizations; however, all organizations agree that target goals should be individualized [28]
For recent-onset type 2 diabetes mellitus in nonpregnant females without cardiovascular disease, normal (or near-normal) glycemia is the goal to prevent or delay progression of micro- and macrovascular complications
Hemoglobin A1C targets
American Diabetes Association recommends target hemoglobin A1C level of less than 7% as appropriate for most nonpregnant adults; lower level may be acceptable if it can be achieved safely without significant hypoglycemia [30]
American Association of Clinical Endocrinologists recommends target hemoglobin A1C level of 6.5% for most nonpregnant adults if it can be achieved safely [29]
Less stringent hemoglobin A1C goals (eg, 7%-8%) are appropriate for select patients with: [29][30][31]
History of severe hypoglycemia
Limited life expectancy
Advanced microvascular or macrovascular complications
Extensive comorbid conditions (including renal and liver failure)
Long-standing diabetes in which glycemic goal is difficult to attain
Self-monitoring of blood glucose level: targets
Ambulatory glucose profile targets (continuous glucose monitoring)
Inpatient glucose targets vary by setting
Glucose target level between 140 and 180 mg/dL is recommended for most critically and noncritically ill patients [33]
Glucose target level between 110 and 140 mg/dL may be appropriate for select individual patients (eg, those who have undergone cardiac surgery or have history of stroke or acute ischemic cardiac events) provided that target levels can be achieved without significant hypoglycemia [33]
Control cardiovascular risk factors
Blood pressure goals
American Diabetes Association, American Association of Clinical Endocrinologists, and American College of Cardiology/American Heart Association guidelines recommend blood pressure target of lower than 130/80 mm Hg for most patients [6][29][34]
Individualization of blood pressure targets is emphasized in all guidelines, with consideration of other factors (eg, age, presence of kidney disease and/or coronary artery disease)
Blood pressure threshold of lower than 140/80 is recommended during pregnancy [35]
Lipid goals
American Diabetes Association recommends reducing LDL-C levels as follows: [6]
By 50% or more from baseline or to a level of less than 70 mg/dL in patients with 1 or more atherosclerotic cardiovascular disease risk factors
To less than 55 mg/dL in patients with established atherosclerotic cardiovascular disease
American Association of Clinical Endocrinologists does specify numeric LDL-C goals according to degree of atherosclerotic cardiovascular disease risk [29][38]
High risk
For patients with diabetes and no atherosclerotic cardiovascular disease or major cardiovascular risk factors:
LDL-C goal is less than 100 mg/dL
Non–HDL-C goal is less than 130 mg/dL
Very high risk
For patients with diabetes and at least 1 additional major atherosclerotic cardiovascular disease risk factor (eg, hypertension, family history, low HDL-C level, smoking):
LDL-C goal is less than 70 mg/dL
Non–HDL-C goal is less than 100 mg/dL
Extreme risk
For patients with diabetes and a prior atherosclerotic cardiovascular disease event or chronic kidney disease stage 3 or 4:
LDL-C goal is less than 55 mg/dL
Non–HDL-C goal is less than 80 mg/dL
Disposition
Admission criteria [39]
DKA [40]
Plasma glucose level greater than 250 mg/dL
Arterial pH less than 7.3
Serum bicarbonate level less than 15 mEq/L
Moderate ketonuria and/or ketonemia
Volume depletion
Acute kidney injury
Hyperglycemic hyperosmolar state [41]
Plasma glucose level greater than 600 mg/dL
Elevated serum osmolality greater than 320 mmol/kg
Altered mental status
Hypoglycemia with neuroglycopenia [39]
Blood glucose level less than 50 mg/dL refractory to treatment
Coma, seizures, or altered behavior due to hypoglycemia
Uncontrolled diabetes [39]
Hyperglycemia with volume depletion
Persistent hyperglycemia associated with metabolic deterioration
Hemoglobin A1C level that is 100% or more above upper reference limit
Recurrent fasting plasma glucose level greater than 300 mg/dL, refractory to outpatient treatment
Frequent episodes of hypoglycemia with blood glucose level less than 50 mg/dL, refractory to outpatient treatment
Metabolic instability as evidenced by frequent swings between fasting hyperglycemia and hypoglycemia
Recurrent DKA not precipitated by infection or injury
Severe psychosocial issues that cause uncontrolled diabetes that cannot be managed in community
Criteria for ICU admission
Critical illness and mental obtundation as with DKA or hyperosmolar hyperglycemic state [42]
Need for IV insulin infusion
Recommendations for specialist referral
Certified diabetes educator for diabetes self-management education and ongoing support
Registered dietitian for medical nutrition therapy
Ophthalmologist for dilated eye examination
Endocrinologist for: [7]
Uncertain diagnosis
Teaching and supervising insulin therapy
Treatment of labile glycemia (eg, recurrent hypoglycemia, persistent hyperglycemia, ketoacidosis)
When complexity of care exceeds capacity of primary care setting
Nephrologist for:
Persistent proteinuria
Decreased GFR
Labile blood pressure
Hyperkalemia
Cardiologist for associated cardiovascular disease management
Podiatrist for:
Orthotic footwear
Prevention or treatment of diabetic foot ulcers
Dentist for periodontal examination
Mental health specialist for:
Depression
Self-harm
Blatant disregard for self-care
Severe anxiety
Diabetes-related distress
Cognitive impairment
Treatment Options
Comprehensive diabetes management encompasses several components, including:
Therapeutic lifestyle changes
Pharmacotherapy
Glucose monitoring
Diabetes education
Strategies to reduce cardiovascular risk factors
All patients should engage in lifestyle modifications directed at weight loss and increased physical activity [43]
Such interventions improve measures of glycemia and cardiovascular risk factors and reduce need for medications in established type 2 diabetes
General guidance on pharmacologic therapy
Patients with established or subclinical cardiovascular disease or chronic kidney disease should receive an agent (with or without metformin) that has proven cardiovascular or renal protective benefits (eg, sodium-glucose cotransporter-2 inhibitor or GLP-1 receptor agonist) [44]
Insulin may be the preferred agent for glucose lowering (at least initially) in setting of severe hyperglycemia (hemoglobin A1C level greater than 10%), particularly: [44]
When associated with weight loss or ketosis
During hospitalization, surgery, or acute illness
For underweight patients
All glucose-lowering medications have advantages and disadvantages that require consideration, both within and between classes, including factors such as: [43][44]
Efficacy (ability to lower hemoglobin A1C level to less than 7% or absolute reduction in hemoglobin A1C level)
Macro- and/or microvascular disease risk reduction (specifically cardiovascular and renal protection)
Durability
Safety and adverse effects (particularly with respect to hypoglycemia, renal effects, and effect on body weight)
Tolerability
Patient acceptance (particularly with respect to route of administration and dosing schedules)
Clinicians are encouraged to evaluate and compare categories of antihyperglycemic agents using patient-oriented STEPS (safety, tolerability, effectiveness, price, and simplicity of use) criteria [46]
Antihyperglycemic medications
Biguanides
Guidelines and experts universally agree that metformin, a biguanide, is the preferred first line agent in the absence of contraindications or intolerance
Decreases hepatic glucose production and increases glucose uptake in muscle tissue
May be continued as other agents are added
Low risk for hypoglycemia with long-lasting antihyperglycemic effect
May benefit cardiovascular health [47]
Can be used in patients with renal impairment provided estimated GFR is 30 mL/minute/1.73 m² or more though dosage adjustment is necessary when estimated GFR is less than 45 mL/min/1.73 m² (for some patients, required when estimated GFR is 45-59 mL/minute/1.73 m²) [49]
May cause adverse gastrointestinal effects (eg, cramping, diarrhea) and vitamin B₁₂ deficiency; monitor vitamin B₁₂ levels
Choice of alternative first line therapy should be patient centered and may include 1 of the following drug classes: [2][44]
Sodium-glucose cotransporter-2 inhibitors
Guidelines favor canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin based on cardiovascular and/or renal protective effects [2]
Increase urinary excretion of glucose
Favored over sulfonylureas as an add-on to metformin therapy in terms of cardiovascular mortality, hemoglobin A1C lowering, weight reduction, systolic blood pressure reduction, and heart rate response [43]
Low risk of hypoglycemia
Class-wide clinical benefits in addition to improved glycemic control include reduced risk of hospitalization due to heart failure (for patients with and without existing cardiovascular disease), reduced risk of major cardiovascular events for patients with atherosclerotic cardiovascular disease or chronic kidney disease, and improved renal outcomes for patients with kidney disease [50][51][52]
May cause dehydration, hypotension, minimal increases in LDL-C level, weight loss, urinary tract infections, fungal genital tract infections, bone loss, and fractures
Glucagon-like peptide-1 (GLP-1) receptor agonists
Semaglutide is the only agent available as both oral and injectable glucagon-like peptide-1 receptor agonist; all others (dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide) are injectable
Increase glucose-dependent insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase satiety
Low risk of hypoglycemia
Frequently cause adverse gastrointestinal effects (eg, nausea, vomiting, diarrhea) and weight loss
Contraindicated for patients with personal or family history of medullary thyroid carcinoma or patients with multiple endocrine neoplasia type 2
Use with caution for patients with a history of pancreatitis; discontinue if pancreatitis develops
Dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonists (ie, tirzepatide)
Activate both the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors to increase insulin secretion and decrease glucagon levels in a glucose-dependent manner
High glycemic efficacy and low risk of hypoglycemia
Slows gastric emptying and increases satiety
SURPASS-CVOT study is underway to evaluate long-term cardiovascular outcomes of tirzepatide compared with dulaglutide [53]
May cause adverse gastrointestinal effects (nausea, vomiting, diarrhea); associated with weight loss
Sulfonylureas
Class includes glimepiride, glipizide, and glyburide
Stimulate insulin secretion
Risk of hypoglycemia present, especially in the setting of concomitant renal insufficiency
Retrospective data suggest a possible cardiovascular risk with use of this class of drugs, compared with metformin [54]
May cause weight gain, and efficacy may decrease after several years of treatment
Dipeptidyl peptidase 4 (DPP-4) inhibitors
Class includes alogliptin, linagliptin, saxagliptin, and sitagliptin
Increase glucose-dependent insulin secretion and decrease glucagon secretion
Low risk of hypoglycemia
Neutral effect on risk of myocardial infarction or stroke but increased risk of hospitalization for heart failure; use with caution for patients with concurrent heart failure [55]
May cause upper respiratory tract infections, pancreatitis, or immune-related dermatologic effects (eg, angioedema, urticaria)
Comparison with other oral agents [43]
Favored over sulfonylureas in terms of long-term all-cause mortality, long-term cardiovascular mortality, and cardiovascular morbidity
Favored over pioglitazone in terms of short-term cardiovascular morbidity
Favored over sulfonylureas or thiazolidinediones for weight control
Inferior to metformin and sulfonylureas for hemoglobin A1C reduction
Dose adjustment (except for linagliptin) is needed for patients with chronic kidney disease
Thiazolidinediones
Pioglitizone is only thiazolidinedione mentioned in recent guidelines, with rosiglitizone use limited due to boxed warnings [2]
Increase glucose uptake by fat and muscle tissue and decrease hepatic glucose production
Low risk of hypoglycemia
Contraindicated for patients with New York Heart Association class 3 and 4 heart failure
May cause weight gain, fluid retention, peripheral edema, bone loss, and fractures
Useful for patients with nonalcoholic steatohepatitis
Safe for patients with renal insufficiency and renal failure
Whether pioglitazone increases risk of bladder cancer is controversial [58]
Less commonly used classes of drugs (eg, α-glucosidase inhibitors, bile acid sequestrants [colesevelam], dopamine agonists [bromocriptine]) may be considered, but these agents have very modest glucose-lowering effects, more bothersome adverse effects, and are typically considered adjunct therapies
α-Glucosidase inhibitors
Class includes acarbose and migilitol
Slow carbohydrate digestion and absorption from the intestines
Low risk of hypoglycemia
May cause adverse gastrointestinal effects (eg, flatulence, diarrhea) and are typically considered weight neutral
Meglitinides
Class includes nateglinide and repaglinide
Increase insulin secretion
Moderate risk of hypoglycemia
No clear evidence to support a cardiovascular benefit [61]
May cause weight gain
May cause dizziness, diarrhea, and upper respiratory tract infections
Bile acid sequestrant (eg, colesevelam)
May cause constipation
Decrease hepatic glucose production and increase incretin levels
Low risk of hypoglycemia
Lower LDL-C level
Central acting dopamine-2 agonists (eg, bromocriptine)
Decrease postprandial glucose due to suppression of hepatic glucose production [62]
Low risk of hypoglycemia
May improve cardiovascular health
May cause nausea, orthostatic hypotension, fatigue, or rhinitis
Contraindicated for patients taking antipsychotic medications
Amylin mimetic/analogue (eg, pramlintide)
Decreases glucagon secretion, slow gastric emptying, and increase satiety
Low risk of hypoglycemia
Neutral cardiovascular effects [63]
May cause adverse gastrointestinal effects (eg, nausea, vomiting) and weight loss
Dual therapy
An initial combination regimen including agents targeting cardiorenal risk reduction is indicated for patients with established or high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease [2]
Also consider initial combination therapy for the following patients: [44]
Those with high hemoglobin A1C level at diagnosis (ie, greater than 8.5%)
Those aged younger than 40 years with type 2 diabetes
Otherwise, add second oral or noninsulin injectable if hemoglobin A1C target level is not achieved or maintained over 3 months of monotherapy
Dual therapy regimens usually include metformin plus another agent
Individualization of therapy is encouraged based on drug-specific effects and patient factors
For patients with or at high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, addition of a drug proven to reduce major cardiovascular events, cardiovascular mortality, or both is recommended [2][44][51]
Glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitors reduce risk of cardiovascular mortality and all-cause mortality for patients with established cardiovascular disease [52]
Glucagon-like peptide-1 receptor agonists are also likely to reduce risk of fatal and nonfatal stroke and atrial fibrillation [64]
Sodium-glucose cotransporter-2 inhibitors also reduce risk of hospitalization for heart failure, slow progression of chronic kidney disease, and reduce risk of end-stage renal disease [52][66]
Associated with a lower risk of incident atrial fibrillation compared to glucagon-like peptide-1 receptor agonists in a large cohort study, though prior meta-analyses had conflicting results [67]
Can be used for patients older than 18 years with atherosclerotic cardiovascular disease or high risk for atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease [51][68][69]
Ertugliflozin reduced hospitalization for heart failure but did not significantly reduce major cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) [74]
For patients without atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, consider a combination of metformin and another agent to address individual glycemic and weight goals [2][69]
Greatest efficacy for lowering blood glucose:
Dulaglutide (high dose), semaglutide, tirzepatide, basal insulin
Other agents with high efficacy for glucose lowering include other glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, and thiazolidinediones
Glucagon-like peptide-1 receptor agonist and basal insulin were modestly more effective than a sulfonylurea and a dipeptidyl-peptidase IV inhibitor in achieving and maintaining target hemoglobin A1C levels in a comparative effectiveness trial evaluating second line medication for patients with low risk of cardiovascular or kidney disease [75]
Greatest efficacy for weight loss:
Semaglutide and tirzepatide
Other agents with high efficacy for weight loss include dulaglutide and liraglutide
Add a third oral or noninsulin injectable if hemoglobin A1C target is not achieved after approximately 3 months of dual therapy (triple therapy usually includes metformin plus 2 other agents from separate drug classes)
A glucagon-like peptide-1 receptor agonist or dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist is recommended before initiation of basal insulin, if patient is not already taking one
Addition of insulin rather than a third noninsulin agent is preferable in patients who are already taking 2 oral antihyperglycemic agents and have hemoglobin A1C greater than 9% or symptomatic hyperglycemia [29]
Insulin therapy [77]
Treatment with insulin becomes necessary if therapy with 2 or more oral agents or noninsulin injectable drugs fails to maintain adequate glycemic control
Other indications for insulin include: [2]
Severe hyperglycemia (as indicated by fasting plasma glucose levels of 300 mg/dL [16.7 mmol/L] or higher)
Hemoglobin A1C levels greater than 10%
Symptoms of hyperglycemia
Evidence of ongoing catabolism (weight loss)
Aim is to create a near-normal glycemic profile while minimizing weight gain and avoiding hypoglycemia
As initial therapy, addition of once-daily basal insulin is often sufficient unless patient is markedly hyperglycemic and/or symptomatic; it also provides relatively uniform coverage over a 24-hour period
After start of basal insulin, further therapy can consist of addition of either a glucagon-like peptide-1 receptor agonist (if not already started) or prandial insulin (in incremental doses)
Prandial insulin is more effective than simply increasing basal insulin doses further and lowers hemoglobin A1C levels with less weight gain and less hypoglycemia compared with increasing basal insulin doses
Insulin regimens are highly individualized and based on patient age, duration of diabetes, comorbidities, and risk of hypoglycemia
Barriers with insulin
Hypoglycemia is the major limiting factor and may occur as a result of multiple issues (eg, decreased caloric intake, delayed meals, mismatches between insulin injections and meals, alcohol intake, exercise, use of other medications, kidney disease)
Weight gain is a frequent valid concern; average weight gain after 1 year is approximately 1.75 kg for a person starting insulin [81]
Selection of basal insulin [82]
Both isophane insulin suspension and basal insulin analogues are capable of lowering hemoglobin A1C level to a similar extent, but insulin analogues have the advantages of less frequent and severe hypoglycemia and reduced weight gain, and they provide basal coverage for up to 24 hours or longer with a single injection
Basal analogue duration of action (longer to shorter): degludec, longest; glargine, long; detemir, shortest
Long-acting insulin analogues are preferable for patients on basal insulin therapy who are at high risk for hypoglycemia [83]
Concentrated long-acting insulin analogues [82]
Insulin glargine U-300
Glargine formulation with smaller injection volume, prolonged insulin activity, and efficacy similar to that of glargine U-100
Available in a prefilled pen calibrated for the higher concentration, so no dose conversion calculations are required
Lower rates of nocturnal hypoglycemia compared directly with insulin glargine U-100 and insulin detemir [84]
Insulin degludec U-200
Degludec formulation with smaller injection volume and efficacy similar to that of U-100 basal analogues
Available in a prefilled pen also calibrated for the higher concentration
Ability to lower hemoglobin A1C level is similar to that of glargine with lower rates of hypoglycemia [85]
Alternative insulin options
Short-acting (regular), intermediate-acting (neutral protamine Hagedorn insulin, that is, isophane insulin suspension), and premixed insulins are less expensive but also less effective for postprandial blood glucose excursions [77]
Regular insulin is available in 2 concentrations: 100 units/mL and 500 units/mL. It is essential that clinicians and patients ensure that the correct concentration of regular insulin is used
Concentrated regular insulin, U-500 (500 units/mL) [86]
Available form of insulin for those patients requiring more than 200 units/day
Total daily dose is given as 2 to 4 injections per day, typically administered 30 to 60 minutes before meals
Works as both a basal and a bolus insulin
Always use a conversion chart when administering doses from the Humulin R U-500 vial with U-100 insulin syringes or 1-mL tuberculin syringes; no dose conversion is required with the Humulin R U-500 KwikPen
Premixed insulin combinations (50/50, 70/30, 80/20)
Contains both long acting and short or neutral (regular) acting insulin in a fixed concentration
Increased rate of hypoglycemia and inferior glycemic control versus basal insulin alone [87]
Basal insulin/glucagon-like peptide-1 receptor agonist combination
More potent (in lowering of hemoglobin A1C level) than all comparators, including insulin degludec, insulin glargine, liraglutide and placebo
Major advantage of this combination is its ability to minimize weight gain with insulin therapy; disadvantage is limited dosing flexibility [82]
Fixed-ratio combination of insulin plus glucagon-like peptide-1 receptor agonist
Insulin glargine; lixisenatide (Soliqua, LixiLan)
Formulation contains insulin glargine, 100 units/mL and lixisenatide, 33 mcg/mL, so that each dosing unit increment contains 1 unit of insulin glargine with 0.33 mcg of lixisenatide up to a maximum daily dose of 60 units of insulin glargine with 20 mcg of lixisenatide
Very potent hemoglobin A1C effect: during treatment in clinical trials, hemoglobin A1C level is lowered an average of 0.5% more versus use of insulin glargine alone [88]
Insulin degludec; liraglutide (Xultophy, IDegLira)
Formulation contains insulin degludec,100 units/mL, and liraglutide, 3.6 mg/mL, so that each dosing unit increment contains 1 unit of insulin degludec with 0.036 mg of liraglutide up to a maximum dose of 50 units of insulin degludec with 1.8 mg of liraglutide
Self-monitoring of blood glucose level [89][90]
Provides profile of daily glycemic fluctuations that reflect meals, physical activity, and actions of specific insulin components
Routine glucose monitoring may be of limited clinical benefit for patients with type 2 diabetes not taking insulin
However, can provide insight into impact of nutrition, physical activity, and medication management on glucose levels and may be useful during intercurrent illness or hypoglycemic episodes
Usually performed via glucometer testing of fingerstick blood of patients with type 2 diabetes
Use of continuous glucose monitoring devices is now the standard of care for most patients with type 1 diabetes, but among insulin-treated patients with type 2 diabetes, it is usually reserved for those experiencing severe nocturnal hypoglycemia or hypoglycemia unawareness
Bariatric surgery
Highly effective for attaining significant and durable weight loss by patients with obesity; improves glycemic control and reduces cardiovascular risk factors for patients with type 2 diabetes who are unable to achieve lasting weight loss and improvement in glycemic control with nonsurgical measures [91]
Rate of resolution for diabetes (defined as becoming nondiabetic with normal hemoglobin A1C level without medications) after bariatric surgery is approximately 78% [92]
Management of comorbidities
Treatment of hypertension and dyslipidemia is as important as achievement of glycemic control in type 2 diabetes to reduce risk of complications [55][95]
ACE inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension and diabetic nephropathy
Statins are recommended as first line therapy for treatment of dyslipidemia in most patients with type 2 diabetes
Drug therapy
Oral agents
Biguanides
Metformin immediate-release
Metformin Hydrochloride Oral tablet; Adults: 500 mg PO twice daily or 850 mg PO once daily, initially. May increase dose by 500 mg/week or 850 mg every 2 weeks if needed. Doses more than 2,000 mg/day may be better tolerated in 3 divided doses. Max: 2,550 mg/day. Use doses more than 1,000 mg/day with caution in older adults.
Metformin extended-release
Metformin Hydrochloride Oral tablet, extended-release; Adults: 500 mg PO once daily, initially. May increase dose by 500 mg/week if needed. Max: 2,000 mg/day; may consider 1,000 mg PO twice daily if glycemic control is not achieved with 2,000 mg PO once daily. Use doses more than 1,000 mg/day with caution in older adults.
Sodium-glucose cotransporter-2 inhibitors
Canagliflozin
Canagliflozin Oral tablet; Adults: 100 mg PO once daily, initially. May increase dose to 300 mg PO once daily if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Dapagliflozin
Dapagliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase the dose to 10 mg PO once daily if needed.
Empagliflozin
Empagliflozin Oral tablet; Adults: 10 mg PO once daily, initially. May increase the dose to 25 mg PO once daily if additional glycemic control is needed.
Ertugliflozin
Ertugliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 15 mg PO once daily if needed.
Glucagon-like peptide-1 receptor agonists
Semaglutide
Semaglutide Oral tablet; Adults: 3 mg PO once daily for 30 days, then 7 mg PO once daily. May increase the dose to 14 mg PO once daily after at least 30 days on 7 mg/day if additional glycemic control is needed.
Sulfonylureas
Glimepiride
Glimepiride Oral tablet; Adults: 1 or 2 mg PO once daily, initially. May increase dose by 1 or 2 mg/day every 1 to 2 weeks if needed. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glimepiride Oral tablet; Older Adults: 1 mg PO once daily, initially. May increase dose by 1 or 2 mg/day every 1 to 2 weeks if needed; a conservative titration scheme is recommended. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glipizide immediate-release
Glipizide Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glipizide Oral tablet; Older Adults: 2.5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed; a conservative titration scheme is recommended. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glipizide extended-release
Glipizide Oral tablet, extended-release; Adults: 5 mg PO once daily, initially. Adjust dose based on glycemic control if needed. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glipizide Oral tablet, extended-release; Older Adults: 2.5 mg PO once daily, initially. Adjust dose based on glycemic control if needed. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glyburide
Glyburide Oral tablet; Adults: 2.5 to 5 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glyburide Oral tablet; Older Adults: 1.25 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed; a conservative titration scheme is recommended. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Dipeptidyl-peptidase IV inhibitors
Alogliptin
Alogliptin Oral tablet; Adults: 25 mg PO once daily.
Linagliptin
Linagliptin Oral tablet; Adults: 5 mg PO once daily.
Saxagliptin
Saxagliptin Oral tablet; Adults: 2.5 or 5 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Sitagliptin
Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily.
Thiazolidinediones
Pioglitazone
Pioglitazone Hydrochloride Oral tablet; Adults: 15 or 30 mg PO once daily, initially. May increase dose by 15 mg/day based on HbA1c if needed. Max: 45 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions
Rosiglitazone
Rosiglitazone Maleate Oral tablet; Adults: 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 weeks if needed. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
α-Glucosidase inhibitors
Acarbose
Acarbose Oral tablet; Adults weighing more than 60 kg: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily and then 100 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Acarbose Oral tablet; Adults weighing 60 kg or less: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 50 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Miglitol
Miglitol Oral tablet; Adults: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose after 4 to 8 weeks to 50 mg PO 3 times daily for 3 months and then 100 mg PO 3 times daily based on HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Meglitinides
Nateglinide
Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily, or 60 mg PO 3 times daily for patients who are near glycemic goal when treatment is initiated.
Repaglinide
Repaglinide Oral tablet; Adults: 0.5 mg PO before each meal for patients whose HbA1c is less than 8% and 1 or 2 mg PO before each meal for patients whose HbA1c is 8% or more. May double the dose after at least 1 week if needed. Usual dose range: 0.5 to 4 mg PO before each meal. Max: 4 mg/dose and 16 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Bile acid sequestrants [96]
Colesevelam hydrochloride
Colesevelam Hydrochloride Oral tablet; Adults: 1.875 g PO twice daily or 3.75 g PO once daily.
Central acting dopamine-2 agonists
Bromocriptine mesylate
Bromocriptine Mesylate Oral tablet [Diabetic Therapy]; Adults: 0.8 mg PO once daily in the morning within 2 hours of waking, initially. May increase dose by 0.8 mg/day every 7 days if needed. Usual dose: 1.6 to 4.8 mg/day. Max: 4.8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Noninsulin injectables
Glucagon-like peptide-1 receptor agonists
Dulaglutide
Dulaglutide Solution for injection; Adults: 0.75 mg subcutaneously once weekly, initially. After 4 weeks, may increase to 1.5 mg subcutaneously once weekly for additional glycemic control. If additional glycemic control is needed, increase the dose in 1.5 mg increments after at least 4 weeks on the current dose. Max: 4.5 mg/week.
Exenatide immediate-release
Exenatide Solution for injection; Adults: 5 mcg subcutaneously twice daily, initially. May increase the dose to 10 mcg subcutaneously twice daily after 1 month if additional glycemic control is needed.
Exenatide extended-release
Exenatide Suspension for injection, Extended Release; Adults: 2 mg subcutaneously once weekly.
Liraglutide
Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase the dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
Lixisenatide
Lixisenatide Solution for injection; Adults: 10 mcg subcutaneously once daily for 14 days, then 20 mcg subcutaneously once daily.
Semaglutide
Semaglutide Solution for injection; Adults: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg subcutaneously once weekly, initially. May increase the dose to 1 mg subcutaneously once weekly after 4 weeks on 0.5 mg/week and 2 mg subcutaneously once weekly after 4 weeks on 1 mg/week if additional glycemic control is needed.
Dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonists [97]
Tirzepatide injection
Tirzepatide Solution for injection; Adults: 2.5 mg subcutaneously once weekly for 4 weeks, then 5 mg subcutaneously once weekly, initially. May increase dose by 2.5 mg/week after at least 4 weeks if needed. Max: 15 mg/week.
Amylin mimetic/analogues
Pramlintide
Pramlintide Acetate Solution for injection; Adults: 60 mcg subcutaneously immediately before each major meal. May increase dose to 120 mcg/dose when no clinically significant nausea has occurred for at least 3 days. Max: 120 mcg/dose. If significant nausea persists at 120 mcg/dose, decrease dose to 60 mcg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Insulin
Initial strategy is to start with a single daily injection of a long-acting basal insulin analogue and add prandial control if necessary (basal-bolus strategy) [77]
Step 1: start basal insulin analogue (eg, glargine, detemir, degludec)
If hemoglobin A1C level is less than 8%, start with 0.1 to 0.2 units/kg/day (or 10 units/day)
If hemoglobin A1C level is greater than 8%, start with 0.2 to 0.3 units/kg/day
Step 2: titrate insulin approximately every 2 to 3 days until glycemic targets are reached (usually fasting blood glucose level is less than 110 mg/dL)
If fixed regimen is used, increase by 2 units per day
If adjustable regimen is used, titration is based on fasting blood glucose level
If fasting blood glucose level is greater than 180 mg/dL, add 4 units
If fasting blood glucose level is between 140 and 180 mg/dL, add 2 units
If fasting blood glucose level is between 110 and 139 mg/dL, add 1 unit
Step 3: monitor for hypoglycemia
If blood glucose level is less than 70 mg/dL, reduce basal insulin by 10% to 20%
If blood glucose level is less than 40 mg/dL, reduce basal insulin by 20% to 40%
Long-acting (basal) insulins
Insulin degludec
Insulin Degludec Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Insulin detemir
Insulin Detemir (Recombinant) Solution for injection; Adults: 10 units subcutaneously once daily or divided twice daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily or divided twice daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Insulin glargine
Insulin Glargine Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/dose subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Short-acting (prandial) insulin
Intensification of insulin regimens
If the basal insulin regimen accomplishes fasting and preprandial blood glucose targets, but hemoglobin A1C level is still above target, modify the insulin regimen to cover postprandial blood glucose excursions using rapid-acting analogues (eg, lispro, aspart, glulisine)
Various stepwise approaches may be used to start prandial insulin
Weight based, given at each meal [29]
Calculate total daily dose of insulin: 0.3 to 0.5 units/kg/day
Half of the total units are given as basal insulin and half are given as prandial insulin, divided equally among the 3 meals
Titrate every 2 to 3 days to reach glycemic targets
Increase total daily dose by 2 units/day or prandial 10% to 20% depending on type of regimen and severity of blood glucose elevation
1 prandial dose added, given before largest meal of day [77]
Start with an initial dose of 2 to 4 units, increased by 1 to 2 units every 3 days if glucose level at the next meal is not within the goal range (typically 70-130 mg/dL)
Add prandial doses to the second and third meals at 8- to 12-week intervals if hemoglobin A1C targets are not met
Titration of prandial insulin
On an ongoing basis, prandial doses can be fixed or adjusted for meal size using carbohydrate counting
Fixed prandial doses have the advantage of being simple and easier to adhere to; an individualized algorithm can be created to provide guidance on how to adjust doses based on preprandial blood glucose levels [99]
Doses based on carbohydrate content of meals have the advantage of allowing flexibility with meal content, but this method is more complex
Prandial doses may be increased by 1 to 2 units once or twice weekly until targets (which are usually based on the fasting blood glucose level at subsequent meals) are reached [30]
Consider decreasing basal insulin dose if significant increases are made to the prandial insulin dose, particularly to evening meal dose [2]
Insulin aspart
Insulin Aspart (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 5 to 10 minutes before the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Insulin glulisine
Insulin Glulisine Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 15 minutes before or within 20 minutes after starting the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Insulin lispro
Insulin Lispro Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 15 minutes before or immediately after the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Alternative insulin options
Isophane insulin suspension
Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Regular insulin 100 units/mL
Insulin Regular (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily approximately 30 minutes before the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
Premixed insulin (50/50, 70/30, 80/20)
Insulin Aspart (Recombinant), Insulin Aspart Protamine (Recombinant) Suspension for injection; Adults: 10 to 12 units subcutaneously once daily, initially. Increase dose by 2 units once or twice weekly to achieve target blood glucose without hypoglycemia; reduce dose by 2 units if hypoglycemia of undetermined cause occurs. Consider dividing the dose twice daily if the dose reaches 40 to 50 units/day.
Insulin Lispro Protamine (NPL), Insulin Lispro Suspension for injection; Adults: 10 to 12 units subcutaneously once daily, initially. Increase dose by 2 units once or twice weekly to achieve target blood glucose without hypoglycemia; reduce dose by 2 units if hypoglycemia of undetermined cause occurs. Consider dividing the dose twice daily if the dose reaches 40 to 50 units/day.
Insulin Regular (Recombinant), Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 10 to 12 units subcutaneously once daily, initially. Increase dose by 2 units once or twice weekly to achieve target blood glucose without hypoglycemia; reduce dose by 2 units if hypoglycemia of undetermined cause occurs. Consider dividing the dose twice daily if the dose reaches 40 to 50 units/day.
| Type of insulin | Names | Time of action: onset, peak, and duration of effects | Comments |
|---|---|---|---|
| Basal | NPH | Onset: 2-4 hours Peak: 4-10 hours Duration: 10-18 hours | Variable action profile; can mix with rapid-acting insulins. NPH available as 100 unit/mL |
| Basal analog | Glargine | Onset: 1.5 hours Peak: none Duration: 24 hours | Glargine available as 100 unit/mL as well as concentrated 300 unit/mL |
| Detemir | Onset: 1-3 hours Peak: 6-8 hours Duration: 18-20 hours | Basal analog insulins provide similar hemoglobin A1C levels, better evening glucose levels, and less hypoglycemia compared to NPH. Determir available as 100 unit/mL | |
| Degludec | Onset: 1 hour Peak: 12 hours Duration: more than 42 hours | Ultra-long-acting, once-daily basal analog with peakless activity. Degludec available as 100 unit/mL and 200 unit/mL | |
| Bolus regular | Humulin R | Onset: 30 minutes Peak: 1.5-3.5 hours Duration: 5-7 hours | Longer duration compared to rapid-acting analogs makes regular insulin useful in gastroparesis. Available as 100 unit/mL |
| Bolus regular U-500 insulin | Humulin R U500 | Onset: 30 minutes Peak: 1.5-3.5 hours Duration: 5-7 hours | Use for insulin-resistant patients who need more than 200 total units per day, given 3 times per day. Available as 500 unit/mL |
| Bolus rapid-acting analog | Lispro, aspart, glulisine | Onset: 5-15 minutes Peak: 0.5-2 hours Duration: 3-5 hours | Rapid-acting analog insulin provides better control of postprandial glucose levels and less hypoglycemia compared with regular insulin; may be taken during or after meals. Lispro available as 100 unit/mL and 200 unit/mL. Aspart and glulisine available as 100 unit/mL |
| Premixed insulin (50/50, 70/30, 75/25, 80/20) | Humalog 75/25 or 50/50 mix, Novolog 70/30 mix, Novolin 70/30, Humulin 70/30 | Onset: 5-15 minutes Peak: 0.5-2 hours Duration: 3-5 hours | Titration of both basal and prandial must occur simultaneously; compared with use of basal insulin or basal bolus insulin regimens, there is an increased rate of hypoglycemia with inferior achievement of glycemic goals |
Nondrug and supportive care
Therapeutic lifestyle modifications [29][100]
Medical nutrition therapy [101]
Counseling and education sessions for development of an individualized eating plan according to metabolic needs of individual patient, preferably provided by a registered dietitian [102]
Incorporates weight loss goals, caloric needs, and distribution of macronutrients [102]
Addresses lifestyle, preferences, eating patterns, culture, and comorbidities of individual patient
Capable of reducing hemoglobin A1C level by 1% to 2% [102]
Various eating patterns (eg, paleolithic, low-carbohydrate, high-protein, vegetarian, nut-enriched diets; DASH diet [Dietary Approaches to Stop Hypertension]; Mediterranean diet ) have beneficial effects on weight loss, glycemic control, and cardiovascular risk [105][93][100]
Intermittent fasting or time-restricted eating may be feasible for achieving weight loss for some patients [100]
General recommendations consist of: [106][107]
Emphasizing nutrient-dense foods in appropriate portion sizes
Consuming fruits, nonstarchy vegetables, and low-fat dairy products
Limiting added sugars
Substituting healthy fats for saturated and trans fats
Minimizing consumption of red and processed meats, sodium, sugar-sweetened beverages, and refined grains
Avoiding highly processed foods
Part of medical nutrition involves instruction in how to use carbohydrate, fat, and protein counting for patients who have advanced to flexible insulin therapy
Macronutrient consideration [100]
Ideal distribution of calories among carbohydrates, fats, and proteins for patients with type 2 diabetes to optimize glycemic control is unknown
Individualize macronutrient distribution based on dietary reference intake recommendations for healthy eating, metabolic goals, and total caloric needs [102]
Carbohydrates
Evidence is insufficient to support a specific amount of carbohydrate intake for all people with diabetes
Monitoring carbohydrate intake, by carbohydrate counting or experience-based estimation, is an especially important strategy for patients who use insulin [102]
Certain sources of carbohydrates are preferred over others for patients with type 2 diabetes
Whole grains, vegetables, fruits, legumes, and dairy products are foods that are higher in fiber and lower in glycemic load
These sources are preferable over others, especially those containing sugars
Reduce consumption of sugar-sweetened and nonnutritive sweetened beverages; encourage water as an alternative
Fats
Recommended total fat intake is equal to 20% to 35% of total calories (same as for general population) [100]
Emphasize consumption of healthy fats (eg, long-chain ω-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid) from food sources (eg, fish, nuts, avocados)
Limit consumption of saturated fats (eg, those from full-fat dairy, red meat, and tropical oils) and trans fats
Proteins
Emphasize sources of protein that are low in saturated fat (eg, fish, egg whites, beans); avoid processed meats
Ideal amount of protein intake
Usual protein intake: 15% to 20% of total energy [100]
For patients without diabetic nephropathy, evidence is inconclusive regarding ideal amount of protein intake for optimizing glycemic control or reducing cardiovascular risk [108]
Therefore, protein intake should approximate recommended daily allowance for general population (0.8 g/kg body weight)
For people with diabetic nephropathy (either micro- or macroalbuminuria), dietary protein restriction is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or course of GFR decline
For patients with non–dialysis-dependent diabetic kidney disease, recommended daily dietary protein intake is the same as that for general population (0.8 g/kg body weight)
For patients receiving dialysis, consider higher levels of dietary protein intake
Micronutrients [107]
Routine supplementation is not recommended because no clear evidence of benefit exists for patients with diabetes who do not have underlying deficiencies
Healthy diet can usually provide sufficient micronutrients
Alcohol [100]
Should be consumed in moderation, if at all (1 or fewer drinks per day for females, 2 or fewer drinks per day for males)
Ingestion of alcohol increases risk of delayed hypoglycemia, especially for patients who use insulin or insulin secretagogues
Physical activity
Increased physical activity and exercise improve glycemic control, lipid levels, blood pressure, and insulin sensitivity and lower risk of cardiovascular disease and mortality [93]
Prescribe exercise program with individualized goals [110]
Begin exercise slowly and gradually build up
Goal duration for optimal health benefit is at least 150 minutes of moderate-intensity (50%-70% of maximum heart rate) aerobic exercise per week, spread out over at least 3 days per week; avoid more than 2 consecutive days without exercise
Encourage balance, strength, and flexibility training at least 2 days per week in addition to aerobic training
Participation in both resistance and aerobic training is associated with reduction in hemoglobin A1C level [111]
Participation in high-intensity interval training is associated with improved insulin sensitivity and reduction in hemoglobin A1C level[112]
High-intensity resistance exercise training has greater beneficial effect than low- to moderate-intensity resistance training
Insulin dosing may need to be modified with exercise to prevent hypoglycemia
Pre-exercise medical clearance is unnecessary for patients before beginning low- or moderate-intensity physical activity not exceeding demands of brisk walking, unless symptoms of cardiovascular disease or microvascular complications are present [110]
Pre-exercise medical clearance is recommended for patients who are currently sedentary and will undertake exercise that is more intense than brisk walking and for those with signs or symptoms of cardiovascular disease, long duration of diabetes, older age, or diabetes-related complications [110]
American College of Sports Medicine exercise preparticipation health screening guidelines focus on assessing: [114]
Patient's current level of physical activity
Presence of signs or symptoms and/or known cardiovascular, metabolic, or renal disease
Desired exercise intensity
Weight management
Patients who are overweight and patients with obesity with type 2 diabetes require at least 5% weight loss to improve glycemic control, lipid levels, and blood pressure [100]
Aiming for more intensive weight loss (eg, 15%) may yield greater benefits and may be an appropriate goal for some patients
Primary approach to weight management is through lifestyle modification, which includes:
Dietary change focused on caloric restriction
Increased energy expenditure through physical activity
Behavioral modification (monitoring of food, exercise, and weight)
Intensive lifestyle interventions (eg, targeting weight reduction through caloric restriction and increased physical activity) are effective for modest weight loss (3%-5%) [115]
Weight loss achieved through lifestyle modification decreases cardiovascular risk factors, although available data do not demonstrate that this translates into reduction in cardiovascular events [117]
However, maintaining this weight loss in conjunction with a high level of physical activity was associated with a lower risk of the composite cardiovascular outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina) [118]
Pharmacotherapy can be considered when lifestyle interventions do not achieve desired goals [91]
Minimally invasive approaches (eg, implanted gastric balloons) are rarely used for patients with diabetes
Oral hydrogel that mimics space-occupying effect of implantable gastric balloons has been approved for long-term use by patients with BMI greater than 25 kg/m² and demonstrated improved weight loss outcomes in a subgroup of patients with prediabetes or diabetes [91]
Bariatric surgery may be considered for patients whose BMI remains greater than 30 kg/m² despite lifestyle modifications and/or pharmacologic treatment [119]
Achieves greater improvement in glycemic control and reduction of cardiovascular risk factors for patients with obesity and type 2 diabetes compared with lifestyle and pharmacologic interventions [93]
Diabetes self-management education and support [100]
Ongoing processes of facilitating knowledge, skill, and ability necessary for patient to participate in diabetes self-care
Focus is on helping patients make informed self-management decisions
Core educational topics include: [120]
Diabetes disease process and treatment options
Incorporating nutritional changes and physical activity into lifestyle
Monitoring blood glucose level, then interpreting and using results for day-to-day management decisions
Using medications safely for greatest effectiveness
Blood glucose monitoring
Self-monitoring of blood glucose [90]
Point-of-care testing technology in which a small volume of capillary blood is placed on a test strip and inserted into a glucometer, providing a real-time digital display of blood glucose level
Rationale for blood glucose monitoring, regardless of insulin use, is to encourage patients to play a more active role in their diabetes management and to maximize efficacy and safety of glucose-lowering therapies
Patient uses glucose data to make immediate decisions regarding coordination of insulin dosing with food intake and physical activity
Instruct patients to record and store blood glucose data so that it may be reviewed by clinicians to assist in drug therapy titration
Glucose data are trended and analyzed by health care professional to tailor treatment plan
If decline in bedtime to morning glucose level is more than 55 mg/dL (3.1 mmol/L), this suggests an excessive basal insulin dose [90]
Overnight rise in glucose levels may indicate need to increase basal insulin dose
Recommended regimen for blood glucose testing depends on medication regimen [90]
If using multiple daily injections of insulin, test glucose level before meals, at bedtime, and (if needed) periodically in the middle of the night
If using basal insulin only, without prandial doses, test glucose level in the morning when fasting and at bedtime
If using noninsulin medications:
Home glucose monitoring may be helpful when altering diet, physical activity, and/or medications
Use self-monitoring only when patients and/or caregivers have knowledge, skills, and willingness to incorporate glucose monitoring and any therapeutic adjustments into their diabetes care plan
If using an insulin secretagogue (eg, sulfonylurea, meglitinide), test fasting blood glucose level once daily and periodically at other times to confirm effectiveness of therapy and detect possible hypoglycemia
If using medications with low risk of hypoglycemia, test at least weekly; initial daily testing at meals and bedtime may be helpful for patient understanding of effects of medical nutrition therapy and lifestyle modifications on glucose levels
If using lifestyle therapy only, daily testing is not recommended; initial daily testing at meals and bedtime may be helpful for patient understanding of effects of medical nutrition therapy and lifestyle modifications on glucose levels
More frequent monitoring is required for:
Frequent hypoglycemia
Recurrent episodes of severe or nocturnal hypoglycemia
Persistently elevated hemoglobin A1C level
Continuous glucose monitoring [29][121]
Testing technology uses a catheter with a glucose oxidase sensor, which is placed subcutaneously to measure and record interstitial glucose levels
Downloadable metrics from devices (eg, time in range, glycemic variability, patterns of hypoglycemia and hyperglycemia) are used to make adjustments to the insulin regimen
Personal-use continuous devices, which patients own and use over the long term, display glucose data in real time so that patient can make immediate or retrospective adjustments to diabetes management
Professional-use devices are used on a short-term basis (eg, 72 hours) to assess glycemic patterns for therapeutic decision-making by a health care professional
Short-term, intermittent, real-time continuous glucose monitoring is appropriate for persons who use basal insulin alone and have hemoglobin A1C levels above 7% [122]
Traditionally used by patients with type 1 diabetes because evidence has shown benefit in this population
However, current expert opinion holds that continuous glucose monitoring is likely to assist other patients, regardless of diabetes type [123]
Offer to all patients who use multiple daily insulin injections who are capable of using the devices, particularly those with higher risk of hypoglycemia or hypoglycemia unawareness [29]
Can also be offered to patients on basal insulin who are capable of using devices safely
Small trial conducted in insulin-treated patients with type 2 diabetes showed significant reduction in hemoglobin A1C level for patients using a continuous glucose monitoring device versus self-monitoring of blood glucose level [124][125]
Based on this, continuous glucose monitoring is recommended as an option to improve glycemic control in patients with type 2 diabetes who are treated with basal-bolus insulin therapy [126]
Contraindication: physical or cognitive impairment precluding ability to effectively use the technology
Smoking cessation [100]
Smokers (and those exposed to secondhand tobacco smoke) with type 2 diabetes are at greater risk for microvascular complications of diabetes, cardiovascular disease, and sudden death
Offer counseling and/or medications to assist with cessation
Encourage avoidance of tobacco smoke for those who have been exposed
Immunizations [13]
The following immunizations are highly recommended for adult patients with diabetes: [127]
COVID-19 vaccine series according to CDC recommendations
Annual influenza vaccine with inactive or recombinant vaccine; live attenuated influenza vaccine should not be given
Pneumococcal vaccine series according to CDC recommendations
Patients aged 19 to 64 years should be vaccinated with PCV15 or PCV20 (15-valent or 20-valent pnemococcal conjugate vaccine) or PPSV23 (23-valent polysaccharide vaccine) as per CDC recommendations
Patients aged 65 years or older should receive either PCV20 or PPSV23 as per CDC recommendations
Hepatitis B vaccine (2- or 3-dose series) for patients aged younger than 60 years; consider for those aged 60 years and older based on individual patient risk and projected immune response
HPV vaccine for adults aged 26 years and younger; consider for adults aged 27 through 45 years based on shared decision making
Zoster vaccine for adults aged 50 years and older (2-dose Shingrix, even if previously vaccinated)
Tetanus, diphtheria, pertussis booster every 10 years
Respiratory syncytial virus vaccine in adults aged 60 years and older
Procedures
Continuous subcutaneous insulin infusion (insulin pump) therapy [128][129]
General explanation
Mechanically driven insulin delivery technology in which a catheter is placed subcutaneously to provide a continuous infusion of short-acting insulin
Provided as a preset basal rate with operator-driven periodic boluses
Most often used for patients with type 1 diabetes, but some patients with type 2 diabetes (particularly those with insulinopenia) can benefit with very modest improvements in glycemic control [130]
A sensor-augmented pump is a continuous subcutaneous insulin infusion device combined with a continuous glucose monitoring feature [129]
A pump with threshold suspension functionality temporarily halts delivery of insulin when interstitial glucose levels fall below a set threshold
A system is available that integrates an insulin pump and continuous glucose monitor and uses an algorithm to determine insulin needs based on sensor values without requiring intervention from user
Indication
Intensively managed insulin-treated patients with type 2 diabetes can be considered for insulin pump therapy under the following sets of circumstances:
Absolute insulin deficiency, as confirmed with undetectable C-peptide level [128]
Good adherence to monitoring and dosing insulin, yet poor glycemic control despite multiple interventions (eg, oral agent insulin, glucagon-like peptide-1 receptor agonist); currently administers 4 or more insulin injections daily [122]
Contraindications
Physical or cognitive impairment precluding the rigors of insulin pump therapy during initiation and maintenance [128]
Inability to manage complexity of therapy, which can require:
Carbohydrate counting
Calculating insulin bolus and correction doses
Adjusting basal settings
Complications
Unrecognized pump malfunction can lead to hyperglycemia
Interpretation of results
Overall, use of insulin pump therapy in place of multiple daily injections of insulin does not lead to better glycemic control in patients with type 2 diabetes on basis of achieving lower hemoglobin A1C level [128]
May decrease overall insulin requirements in insulin-treated patients with type 2 diabetes [128]
Bariatric surgery
General explanation
Comprises a set of surgical procedures performed in persons with obesity to achieve and sustain substantial weight loss
Most common bariatric procedures include:
Roux-en-Y gastric bypass
Laparoscopic adjustable gastric banding
Vertical sleeve gastrectomy
Biliopancreatic diversion with duodenal switch
Most bariatric surgical procedures are performed through a laparoscopic approach; only rarely is open surgery necessary
Weight loss and diabetes resolution are greatest for biliopancreatic diversion with duodenal switch, followed by gastric bypass; least success is achieved by banding procedures [92]
Postoperative improvements in metabolic control occur rapidly and are out of proportion to weight loss
Indication
Second Diabetes Surgery Summit recommends bariatric surgery for patients who have type 2 diabetes and any of the following: [119]
Class III obesity (BMI of 40 kg/m² or greater), regardless of level of glycemic control or complexity of glucose-lowering regimens
Class II obesity (BMI of 35-39.9 kg/m²) with inadequately controlled hyperglycemia despite lifestyle modification and optimal medical therapy
Class I obesity (BMI of 30-34.9 kg/m²) with inadequately controlled hyperglycemia despite optimal medical therapy with either oral or injectable medications (including insulin) [131]
BMI thresholds are adjusted down by 2.5 kg/m² for patients of Asian ethnicity
Contraindications
Absolute
Diseases associated with poor long-term life expectancy
Poor myocardial reserve
Significant chronic obstructive pulmonary disease or respiratory dysfunction
Uncontrolled or untreated major depression or other psychiatric illnesses
Active substance use/misuse
Severe portal hypertension
Relative
History of nonadherence to medical care
Borderline personality disorder or bipolar disease
Moderate portal hypertension
Complications [132]
All bariatric procedures
Mortality rates are typically 0.1% to 0.5% for laparoscopic procedures and 2% for open procedures
Thromboembolism
Staple line leak
Stomach ulcer
Internal hernia
Gallstones
Nutritional deficiencies
Nephrolithiasis
Bone loss
Biliopancreatic diversion procedure
Associated with highest perioperative complication rate
Additional complications of hypoalbuminemia, fat malabsorption, and liver dysfunction
Interpretation of results
Data suggest erosion of diabetes remission over time; more than 35% to 50% of patients who initially achieve remission of diabetes eventually experience recurrence [91]
Median disease-free period after Roux-en-Y gastric bypass is approximately 8 years, and most patients continue to have substantially improved glycemia level for at least 5 to 15 years [91]
With or without diabetes relapse, most patients who undergo surgery maintain substantial improvement of glycemic control from baseline for at least 5 years and up to 15 years [133]
Analysis of 11 trials comparing surgery with lifestyle modifications or pharmacotherapy for patients with diabetes shows median hemoglobin A1C reduction of 2% for surgery and 0.5% for conventional therapies [119]
Microvascular complications of nephropathy, neuropathy, and retinopathy appear to be reduced, but definitive proof awaits results of studies in progress [135]
Major complication rate is approximately 5% and reoperation rate is approximately 8% [134]
Comorbidities
Hypertension
Affects most patients with type 2 diabetes and greatly increases risk of micro- and macrovascular complications
Treatment of hypertension reduces cardiovascular events and microvascular complications; however, specific blood pressure goal for patients with diabetes has been uncertain; suggested targets vary by professional society [6][93][136][137]
American Diabetes Association, American College of Cardiology/American Heart Association, and others generally recommend target blood pressure less than 130/80 mm Hg for patients with diabetes [6][34]
Individualize treatment but do not target to less than 120/80 mm Hg, as this is associated with adverse events
Association of British Clinical Diabetologists and Renal Association UK recommend the following blood pressure targets: [109]
Less than 140/90 mm Hg in patients with urine albumin to creatinine ratio less than 3 mg/mmol (less than 26.55 mg/g)
Less than 130/80 mm Hg in those with urine albumin to creatinine ratio greater than 3 mg/mmol (greater than 26.55 mg/g)
In older adults, pharmacologic therapy to achieve treatment goals of less than 130/70 mm Hg is not recommended; treating to lower systolic blood pressure below 130 mm Hg has not been shown to improve cardiovascular outcomes, and treating to lower diastolic blood pressure below 70 mm Hg has been associated with higher mortality [138]
Association of British Clinical Diabetologists and Renal Association UK recommend blood pressure targets of no lower than 150/90 mm Hg in patients aged 75 years or older [109]
Treatment
Advise all patients with blood pressure greater than 120/80 mm Hg to undertake lifestyle changes for reducing blood pressure, such as: [6]
Weight loss, if patient is overweight or has obesity
DASH diet or DASH-like diet, which includes reduced sodium and increased potassium intake
Moderation of alcohol intake
Increased physical activity
Start pharmacotherapy in addition to lifestyle changes for patients with blood pressure higher than 130/80 mm Hg [6]
For patients with diabetes and hypertension but without albuminuria for whom cardiovascular disease prevention is the primary goal, any of the following drug classes may be considered:
ACE inhibitor
Angiotensin receptor blocker
Thiazide diuretic
Dihydropyridine calcium channel blocker
For patients with hypertension, diabetes, and early-stage heart failure, treatment with a thiazide-type diuretic or an ACE inhibitor is more effective than treatment with a calcium channel blocker in preventing progression to symptomatic heart failure [139]
For patients with diabetes, albuminuria, and hypertension, start either an ACE inhibitor or an angiotensin receptor blocker, but not both; titrate to maximum tolerated dose [109]
Multidrug therapy (ie, thiazide diuretic and ACE inhibitor/angiotensin receptor blocker at maximal doses) is often required to achieve blood pressure targets
If blood pressure is 150/90 mm Hg or higher, start pharmacotherapy with 2 agents in addition to lifestyle modifications [6]
Dyslipidemia
Patients with type 2 diabetes have a specific type of dyslipidemia that promotes atherosclerosis and contributes to elevated risk of atherosclerotic cardiovascular disease [140]
Lack of consensus exists among medical societies regarding use of numeric lipid goals
American Heart Association does not specify a numeric LDL-C goal [141]
American Association of Clinical Endocrinologists recommends the following LDL-C goals: [29][38]
For patients with diabetes and no atherosclerotic cardiovascular disease or major risk factors: less than 100 mg/dL
For patients with diabetes and at least 1 other major risk factor: less than 70 mg/dL
For patients with diabetes with established atherosclerotic cardiovascular disease: less than 55 mg/dL
Lifestyle modifications to address dyslipidemia are recommended for all patients with diabetes, regardless of whether pharmacotherapy is used, including: [140]
Medical nutrition therapy (low saturated fat, low trans fat, low cholesterol, increased ω-3 fatty acids, increased fiber)
Weight loss if necessary
Increased physical activity
Smoking cessation
Intensify lifestyle modifications and optimize glycemic control for patients with triglyceride levels of 150 mg/dL or greater and/or HDL-C levels lower than 40 mg/dL (for males) or lower than 50 mg/dL (for females) [6]
Pharmacotherapy for treatment of dyslipidemia
Statin therapy is first line drug therapy for patients with dyslipidemia; type of therapy is adjusted based on assessment of cardiovascular risk and age
Moderate-intensity statin therapy is indicated for adults aged 40 to 75 years with diabetes mellitus without atherosclerotic cardiovascular disease
High-intensity statin therapy to reduce LDL-C level by at least 50% of baseline and to target LDL-C goal of less than 70 mg/dL is indicated for adults aged 40 to 75 years who are at higher risk (1 or more atherosclerotic cardiovascular disease risk factors) [6]
Addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor to maximum tolerated statin therapy is reasonable for these patients, especially if multiple atherosclerotic cardiovascular disease risk factors and an LDL-C level of 70 mg/dL or greater are present
High-intensity statin therapy to target an LDL-C reduction of at least 50% from baseline and an LDL-C goal of less than 55 mg/dL is recommended for patients with diabetes and atherosclerotic cardiovascular disease [6]
Addition of ezetimibe or a PCSK9 inhibitor is recommended if goals are not achieved on maximum tolerated statin therapy
Initiation of statin therapy may be reasonable for adults aged 20 to 39 years with diabetes and additional atherosclerotic cardiovascular disease risk factors [6]
Patients who are intolerant of statin therapy who require cholesterol-lowering therapy can be treated with bempedoic acid or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy with monoclonal antibody treatment or inclisiran siRNA [6]
Chronic kidney disease [143]
Drug therapy is challenging owing to potential for various adverse effects (eg, lactic acidosis, hypoglycemia) [144]
Contraindications and dose adjustments exist for all medication classes and should be reviewed for patients with chronic kidney disease stages 2 to 5
Treatment with an ACE inhibitor or an angiotensin receptor blocker is recommended for patients with albuminuria (urine albumin-creatinine ratio 30 mg/g creatinine or greater) and/or eGFR less than 60 mL/min/1.73 m² to prevent the progression of kidney disease and reduce cardiovascular events [66]
Glycemic control is based on a combination of metformin and sodium-glucose cotransporter-2 inhibitors for most patients [145]
Metformin
Discontinue when estimated GFR falls below 30 mL/minute/1.73 m²
Sodium-glucose cotransporter-2 inhibitors
Recommended in addition to angiotensin receptor blocker or ACE inhibitor to reduce chronic kidney disease progression, all-cause mortality, cardiovascular mortality, and hospitalization for heart failure for patients with estimated GFR of 20 mL/minute/1.73 m² or greater and urinary albumin-creatinine ratio of 200 mg/g or greater [66][146]
May also be beneficial for patients with urinary albumin-creatinine ratio ranging from normal to 200 mg/g
Can be continued even if estimated GFR falls below 20 mL/minute/1.73 m², unless it is not tolerated or kidney replacement therapy is initiated [49]
Glucagon-like peptide-1 receptor agonists
Recommended for patients who have not achieved glycemic targets despite use of metformin and a sodium-glucose cotransporter-2 inhibitor (or who are unable to use those medications) [49]
Dulaglutide, liraglutide, and semaglutide may be used in all stages of renal impairment
Exenatide immediate release is not recommended when estimated GFR is less than 30 mL/minute/1.73 m²; exenatide extended release is not recommended when estimated GFR is less than 45 mL/minute/1.73 m²
Lixisenatide is not recommended when estimated GFR is less than 15 mL/minute/1.73 m²
Dipeptidyl-peptidase IV inhibitor
Can be used in all stages of renal impairment
All require dosage adjustment, except linagliptin
Sulfonylureas
Undesirable to use this class in general, particularly glipizide, owing to risk of hypoglycemia
Most sulfonylureas are contraindicated for patients with stage 4 chronic kidney disease
Meglitinides
May be used in stage 3 to 5 chronic kidney disease but require careful dose adjustments
Thiazolidinediones
Only pioglitazone is advisable owing to safety concerns with other agents in this class [143]
Do not use pioglitazone for patients with end-stage renal disease requiring hemodialysis
Dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonists
Can be used in all stages of renal impairment
Use of tirzepatide is associated with nausea, vomiting, and diarrhea, which may lead to dehydration. This dehydration has resulted in acute kidney injury
Coronary artery disease
Use American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk calculator to assess 10-year atherosclerotic cardiovascular disease risk and to guide therapy
Promote lifestyle modifications to reduce cardiovascular risk, including: [37][93]
Smoking cessation
Maintaining body weight within reference range
Regular physical activity
Consumption of a balanced diet replete with fruits and vegetables, low in saturated fat and sodium, and enriched with whole grains
Most patients with coronary artery disease should be treated with metformin plus a drug proven to reduce major cardiovascular events and/or cardiovascular mortality [51]
Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to reduce risk of all-cause and cardiovascular mortality and major cardiovascular events for patients with established atherosclerotic cardiovascular disease or multiple risk factors for atherosclerotic cardiovascular disease [146]
Glucagon-like peptide-1 receptor agonists also reduce risk of nonfatal stroke
Sodium–glucose cotransporter-2 inhibitors also reduce risk of hospitalization for heart failure and composite of significant decline in estimated GFR, progression to end-stage kidney disease, or kidney death
Strongest evidence for cardiovascular benefit has been demonstrated with liraglutide, dulaglutide, semaglutide, empagliflozin, dapagliflozin, and canagliflozin [51]
Combined therapy with a sodium–glucose cotransporter-2 inhibitor with a glucagon-like peptide-1 receptor agonist may be considered for additive reduction in the risk of cardiovascular events [6]
Treat risk factors (eg, hypertension, dyslipidemia)
Antiplatelet therapy with low-dose aspirin is recommended for secondary prevention of coronary artery disease for patients with history of cardiovascular disease and may be considered for primary prevention for patients at increased risk of cardiovascular events [6]
Benefits of aspirin for primary prevention of cardiovascular disease in patients with type 2 diabetes need to be weighed carefully against risks of bleeding [93]
Not generally recommended for adults aged older than 70 years or those aged younger than 50 years with no other risk factors for atherosclerotic cardiovascular disease
Addition of low-dose anticoagulation to antiplatelet therapy may be an option for high-risk patients with diabetes [93]
An ACE inhibitor or angiotensin receptor blocker is recommended for patients with known cardiovascular disease [6]
Obtain resting ECG for patients with hypertension or suspected cardiovascular disease [14]
Routine screening for coronary artery disease is not recommended for asymptomatic patients [6]
Exercise ECG may be considered for cardiovascular risk assessment for patients with cardiac symptoms or abnormal resting ECG [6]
Coronary artery calcium measurement may be considered for patients aged 40 years or older [6]
Congestive heart failure
Sodium-glucose cotransporter-2 inhibitors are recommended for patients with clinical heart failure [44][139][147]
Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin have been shown to: [146][148]
Reduce risk of heart failure hospitalizations for patients with type 2 diabetes mellitus when left ventricular ejection fraction is greater than 40%
Reduce all-cause mortality, cardiovascular mortality, and hospitalization for heart failure when left ventricular ejection fraction is 40% or less
If additional glycemic control is needed, use glucagon-like peptide-1 receptor agonists, metformin, or both; insulin may also be used [139]
Thiazolidinediones and dipeptidyl-peptidase IV inhibitors are not recommended for patients with heart failure [139]
Obesity
Base diagnosis of obesity on overall assessment of the following: [91]
Adipose tissue mass (BMI used as a general guide)
Adipose distribution (using anthropometric measurements such as waist circumference, waist-to-hip circumference ratio, or waist-to-height ratio), or
Functional, health, or well-being consequences
Obesity (BMI of 30 kg/m² or greater) and overweight status (BMI of 25-30 kg/m²) are associated with insulin resistance [149]
Abdominal adiposity (waist circumference greater than 102 cm in males and greater than 88 cm in females) is also associated with insulin resistance [29]
Efforts to achieve modest and sustained weight loss are a priority
Sustained weight loss of 3% to 5% results in clinically meaningful reductions in triglyceride levels, fasting blood glucose level (20 mg/dL), and hemoglobin A1C level (0.2%-0.3%) [115]
Greater amounts of weight loss will: [115]
Further reduce hemoglobin A1C level (0.6%-1%)
Reduce blood pressure (approximately 3 mm Hg)
Improve LDL-C and HDL-C levels
Reduce need for medications to control blood pressure, blood glucose level, and lipid levels
First line therapy is lifestyle modification to achieve weight loss of 5% or more; greater weight loss (10% or more) has disease-modifying effects [91]
Consists of reduced-calorie diet in conjunction with physical activity and behavioral therapy
Individual counseling sessions occur frequently (16 or more in 6 months) with goal of producing a 500- to 750-kcal/day energy deficit
Prescribe long-term (1 year or longer) comprehensive weight maintenance programs for patients who achieve short-term weight loss goals
Use of very-low-calorie diets (800 kcal/day or less) and total meal replacements are reserved for patients for whom careful medical monitoring is possible
Second line therapy is pharmacotherapy, which is indicated for a person who has diabetes and BMI of 27 kg/m² or greater [115]
Preferred pharmacotherapy agents are a glucagon-like peptide-1 receptor agonist or dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist with greater weight loss efficacy (ie, semaglutide or tirzepatide) [91]
Other FDA-approved medications for treatment of obesity include liraglutide, phentermine, orlistat, phentermine-topiramate extended-release, and naltrexone-bupropion [91]
Reassess medications for comorbid conditions and minimize those that cause weight gain, including atypical antipsychotics, antidepressants, glucocorticoids, anticonvulsants, antihistamines, and anticholinergics [91]
Select a regimen for diabetes management to include drugs that have favorable effects on body weight where possible [91]
Diabetes medication classes associated with weight gain include:
Sulfonylureas
Meglitinides
Thiazolidinediones
Insulin
Diabetes medication classes that promote modest weight loss include:
Biguanides
Glucagon-like peptide-1 receptor agonists
Sodium-glucose cotransporter-2 inhibitors
Dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists
Amylin mimetics
Diabetes medication classes that are weight neutral include dipeptidyl-peptidase IV inhibitors
Bariatric surgery is a recommended option to treat type 2 diabetes in patients with: [91]
BMI of 40 kg/m² or greater (37.5 kg/m² or greater in Asian American patients)
BMI of 35 to 39.9 kg/m² (32.5-37.4 kg/m² in Asian American patients) if unable to achieve durable weight loss and reduction in comorbidities (including hyperglycemia) with nonsurgical methods
Bariatric surgery may also be considered for patients with BMI of 30 to 34.9 kg/m² (27.5-32.4 kg/m² in Asian American patients) if unable to achieve durable weight loss and reduction in comorbidities (including hyperglycemia) with nonsurgical methods [91]
Metabolic dysfunction-associated steatotic liver disease (new terminology for nonalcoholic fatty liver disease) [13]
Excess of fat in the liver (steatosis) in patients with at least 1 cardiometabolic risk factor, and not resulting from excessive alcohol consumption or other secondary causes
Type 2 diabetes is a risk factor for development of the disease [150]
Spectrum of the disease ranges from metabolic dysfunction– associated steatotic liver disease (formerly nonalcoholic fatty liver disease) to metabolic dysfunction-associated steatohepatitis (nonalcoholic steatohepatitis) to cirrhosis [151]
It is estimated that more than 70% of patients with type 2 diabetes have evidence of nonalcoholic fatty liver disease, and more than 50% have steatohepatitis
Noninvasive screening for nonalcoholic fatty liver disease with clinically significant hepatic fibrosis and risk stratification for future cirrhosis are recommended for patients with type 2 diabetes [150]
Initially determine risk based on FIB-4 (fibrosis-4) index, which is derived from age, ALT, AST, and platelets; patients with an indeterminate or high FIB-4 score should then have liver stiffness measurement with transient elastography or blood biomarker ELF (enhanced liver fibrosis) scoring [13]
Refer patients with indeterminate results or high risk for significant liver fibrosis to a gastroenterologist or hepatologist for further workup and long-term management
No specific treatments exist for nonalcoholic steatohepatitis, so medications should be chosen based on efficacy in treating hyperglycemia and obesity, especially if significant fibrosis exists [152]
Pioglitazone or glucagon-like peptide-1 receptor agonists are preferred treatments for hyperglycemia in patients with type 2 diabetes and biopsy-proven nonalcoholic steatohepatitis or high risk for nonalcoholic fatty liver disease with clinically significant liver fibrosis on noninvasive tests [13]
Pioglitazone reduces nonalcoholic fatty liver disease activity and resolves nonalcoholic steatohepatitis in approximately half of treated patients [153]
Glucagon-like peptide-1 receptor agonists are also effective in treating steatohepatitis and may slow fibrosis progression; can be used as adjunctive therapy with lifestyle interventions for weight loss
Other glucose-lowering agents may be continued as needed for glycemic control; however, they have either failed to reduce steatohepatitis in studies (metformin) or have not been studied with regard to liver histologic end points (sulfonylureas, glitinides, dipeptidyl peptidase 4 inhibitors, or acarbose) [13]
Insulin therapy is preferred for treatment of hyperglycemia in adults with type 2 diabetes and decompensated cirrhosis [13]
Obstructive sleep apnea
Associated with obesity (particularly central obesity), male sex, and older age
Affects approximately 58% to 77% of patients with type 2 diabetes and 86% of those with both diabetes and obesity [29]
Increases risk for heart disease owing to increased insulin resistance, hyperglycemia, hypertension, dyslipidemia, and inflammation
Assess sleep pattern and duration in all patients with type 2 diabetes [154]
Treat with weight loss, CPAP, adjustable airway pressure devices, oral appliances, and/or surgery
Treatment of sleep apnea improves quality of life and positively affects blood pressure
Liver failure and cirrhosis
Treatment of diabetes in these patients is complex because many diabetes drugs can promote hypoglycemia and lactic acidosis [155]
In most cases, insulin therapy, including insulin analogues, is the safest choice [13]
Oral diabetes medications are contraindicated for patients with advanced liver diseases who have cirrhosis, ascites, or encephalopathy [156]
Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to be safe for patients with liver disease [155]
Dipeptidyl-peptidase IV inhibitors appear to be safe for use by patients with liver cirrhosis [155]
Osteoporosis
Use thiazolidinediones and the sodium-glucose cotransporter-2 inhibitor canagliflozin with caution
HIV
Risk of developing diabetes is increased with treatment with some protease inhibitors and nucleoside reverse transcriptase inhibitors [13]
Psychosocial disorders [158]
Depression
Highly prevalent in patients with type 2 diabetes; 20% to 25% of patients with diabetes are affected by depression [159]
Associated with increased risk of myocardial infarction and mortality
Depression and diabetes-related distress are associated with poor self-care, nonadherence, and poor glycemic control
Refer to mental health specialist for assessment and treatment [100]
Anxiety
Anxiety over aspects of the disease or diabetes care (eg, complications, injections, hypoglycemia) is common and can lead to maladaptive behavior (eg, avoidance, withdrawal, excessive repetitive habits) [100]
Fears of hypoglycemia can lead to self-relaxing of glycemic goals and reducing intensity of measures to treat the disease
Refer patients to diabetes education for blood glucose awareness training or to mental health specialist for more severe forms of anxiety
Diabetes-related distress is the experience of people who become overly burdened by the ongoing behavioral demands of managing the disease [159]
Refer such patients to diabetes education or to mental health specialist if areas of diabetes care are adversely impacted
Special populations
Older adults [160]
Older adults with type 2 diabetes have higher rates of premature death, disability, and comorbidities than their counterparts without diabetes
Geriatric syndromes are also more common in older adults with type 2 diabetes
Cognitive impairment
Polypharmacy
Urinary incontinence
Falls (with associated fractures)
Chronic pain
Glucose targets for older adults with type 2 diabetes depend on comorbidities, complications, life expectancy, and functional status; in general, the healthier the patient, the more aggressive the glycemic target [160]
In healthy older adults (few comorbidities, fully functional)
Hemoglobin A1C level: 7% to less than 7.5%
Fasting blood glucose level: 90 to 150 mg/dL
Bedtime blood glucose level: 100 to 180 mg/dL
In somewhat unhealthy older adults (multiple comorbidities, some functional or cognitive impairment)
Hemoglobin A1C level: 7.5% to less than 8%
Fasting blood glucose level: 100 to 150 mg/dL
Bedtime blood glucose level: 150 to 180 mg/dL
In very unhealthy older adults (eg, in long-term care; with end-stage chronic illness, significant physical impairment, moderate to severe dementia)
Hemoglobin A1C level: 8% to less than 8.5%
Fasting blood glucose level: 100 to 180 mg/dL
Bedtime blood glucose level: 110 to 250 mg/dL
Lifestyle modifications are a cornerstone of treatment for older adults with diabetes as for other ages [162]
Intensive lifestyle modification results in greater reductions in hemoglobin A1C level and weight but increased incidence of mild hypoglycemic episodes in older adults
Metformin is the first line agent for treatment of type 2 diabetes in older adults [163]
Dipeptidyl-peptidase IV inhibitors are also a safe and easy-to-use option for older patients [164]
Medications to improve cardiovascular and renal outcomes (sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists) are also beneficial for older adult patients; age alone should not be an obstacle to treatment [44]
Older adults with type 2 diabetes are at increased risk for hypoglycemia owing to decreased insulin level and increased renal insufficiency [160][163]
Require closer monitoring when treated with medications that can cause hypoglycemia; consider continuous glucose monitoring for those on multiple daily doses of insulin
Pregnant patients
Manage patients with preexisting type 2 diabetes who are planning a pregnancy or who become pregnant in a multidisciplinary care setting, if available
Some medications commonly used for both diabetes and its complications are teratogenic and should be discontinued before conception or during pregnancy, including:
Statins
ACE inhibitors
Angiotensin receptor blockers
Most noninsulin glucose-lowering medications
Although preconception and first trimester exposure to these medications was not associated with an increased frequency of congenital anomalies in a global population-based cohort study, their use should continue to be avoided in pregnancy until there are more data [165]
Insulin is the preferred medication for managing glycemia during pregnancy [29][35]
Long-term safety profile is superior compared with noninsulin agents
Insulin can easily be titrated to match changing insulin demand in pregnancy
First-trimester insulin requirements are typically lower, whereas second- and third-trimester requirements are typically higher owing to increasing insulin resistance
Metformin is considered to be a relatively safe alternative to insulin during pregnancy [29]
Glucose targets for pregnant patients with pregestational type 2 diabetes are more aggressive than for general population of patients with type 2 diabetes [29]
Preprandial, bedtime, and overnight (ie, fasting) glucose levels: 60 to 95 mg/dL
1-hour postprandial blood glucose level: 110 to 140 mg/dL
2-hour postprandial blood glucose level: 100 to 120 mg/dL
Target hemoglobin A1C level of less than 6% or lower only if this can be achieved without significant hypoglycemia; target can be less than 7% if necessary to prevent hypoglycemia [29]
Pregnant patients with type 2 diabetes are more likely to be overweight or have obesity
Suggested weight gain for a pregnant patient with overweight and diabetes is 15 to 25 pounds
Suggested weight gain for a pregnant patient with obesity and diabetes is 10 to 20 pounds
In pregnancy complicated by preexisting type 2 diabetes and hypertension, blood pressure targets and treatment may differ from those of prepregnancy care [35]
Blood pressure threshold for initiation or titration of therapy of 140/90 mm Hg is recommended to reduce adverse pregnancy outcomes without compromising fetal growth [35]
Safe antihypertensive drugs to use in pregnancy include methyldopa, nifedipine, labetalol, diltiazem, clonidine, and prazosin [35]
Because diabetes is associated with increased risk of preeclampsia, prescribe low-dose aspirin during second and third trimesters to reduce risk [35]
Doses of 100 to 150 mg/day are recommended; however, a dose of 162 mg/day (ie, 2 81-mg tablets, which is the low-dose aspirin available in the United States) may be acceptable
Aspirin doses of less than 100 mg are not effective in reducing risk of preeclampsia [35]
Hospitalized patients
Scheduled insulin therapy is recommended for most hospitalized patients with hyperglycemia (with or without known type 2 diabetes) [166]
Either a dipeptidyl-peptidase IV inhibitor with correction insulin or scheduled insulin therapy may be given to selected well-managed patients with mild hyperglycemia hospitalized for a noncritical illness [166]
Initiation or continuation of a sodium-glucose cotransporter-2 inhibitor is recommended for patients hospitalized with heart failure after recovery from the acute illness if there are no contraindications [33]
Avoid in severe illness, ketonemia or ketonuria, and during prolonged fasting and surgical procedures
Inpatient glucose targets vary per setting and circumstance [33]
Initiate insulin therapy for hospitalized patients with persistent hyperglycemia of 180 mg/dL or greater (checked on 2 occasions)
Maintain glucose level between 140 and 180 mg/dL in most critically and noncritically ill patients
More stringent glucose targets between 110 and 140 mg/dL may be appropriate for select patients (eg, those who had previous cardiac surgery, stroke, or acute ischemic cardiac events), provided that target can be achieved without significant hypoglycemia
Target range of 100 to 180 mg/dL may be acceptable in noncritically ill patients
Glucose levels greater than 250 mg/dL may be acceptable in terminally ill patients with short life expectancy
ICU
Administer IV insulin infusions using validated written or computerized protocols (where available) that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose
Non-ICU
A basal plus bolus correction insulin regimen is the preferred treatment for patients who are not critically ill with poor oral intake or those who have NPO status. An insulin regimen with basal, nutritional, and correction components is optimal for patients with good nutritional intake
Perioperative care
Stop sodium-glucose cotransporter-2 inhibitors 3 to 4 days before surgery [33]
Withhold metformin on the day of surgery, and withhold all other oral hypoglycemic drugs beginning on the morning of surgery [33]
Use regular insulin or rapid-acting insulin analogues to correct higher glycemic excursions
Resume oral medications 1 to 2 days before discharge, when possible
Enteral/parenteral feedings [33]
Give insulin in portions designated as basal, nutritional, and correctional
Dosing can be determined by preadmission basal insulin dose
Neutral protamine Hagedorn–based or basal bolus regimens are recommended for patients receiving enteral nutrition [166]
Tube feedings: use 1 unit of insulin for 10 to 15 g of carbohydrate
Enteral bolus feeding: give 1 unit of regular or immediate-acting insulin per 10 to 15 g of carbohydrate before feeding
Continuous peripheral or central parenteral delivery: add 1 unit of regular insulin per 10 g of dextrose
Administer correctional doses, based on point-of-care blood glucose measurements, every 6 hours in all cases using regular insulin or an immediate-acting insulin
Continuous enteral or parenteral feeding results in a constant postprandial state; attempting to reduce blood glucose levels to below 140 mg/dL greatly increases risk of hypoglycemia
Avoid iatrogenic hypoglycemia (less than 70 mg/dL) [33]
Inpatient hypoglycemia is associated with higher complication rates and greater mortality
Triggers include:
Emesis
Reduced oral intake
Reduction in glucocorticoid doses
Misalignment between administration of rapid-acting insulin and meals
Interruption of change in enteral/parenteral feedings
New NPO status
Hemoglobin A1C level at admission can predict risk for in-hospital hypoglycemia for older patients; levels less than 7% are associated with highest rate of hypoglycemic episodes [168]
Monitoring
Periodic evaluation of several clinical and laboratory parameters is part of ongoing comprehensive management of type 2 diabetes
Glycemic control
Acute (day-to-day) control
Capillary blood glucose measurements performed by patient, obtained via glucometer
Self-monitoring of blood glucose level is suggested for patients using insulin
Frequency of blood glucose monitoring is individualized and determined by:
Glucose lability
Frequency of hypoglycemia
Presence of hypoglycemia unawareness
Insulin requirements
Review patient records of self-monitored blood glucose levels every 3 months
Long-term control [13]
Hemoglobin A1C level provides a 2- to 3-month estimation of glycemia, although it does not provide a measure of glycemic variability or hypoglycemia
Measure hemoglobin A1C level every 3 months until it is stable or goals are met
With evaluation of hemoglobin A1C levels, it is appropriate to revise treatment strategies on basis of changes in general health, patient preferences, and life expectancy that alter balance of benefits and harms [31]
Consider de-escalation of therapy (by reducing dosage or number of drugs) for patients who reach hemoglobin A1C target less than 6.5% [31]
Discrepancy between preprandial self-monitored blood glucose levels and hemoglobin A1C level can be caused by high postprandial blood glucose levels
Lifestyle and behavior [13]
Inquire at least annually about eating patterns and weight; advise or refer to dietitian as needed
Inquire at least annually about sleep patterns and physical activity; advise on optimal sleep duration and engagement in exercise
Discourage tobacco use and advise limited alcohol intake
Medications
Biguanides
Metformin
Obtain serum creatinine level, GFR, and vitamin B₁₂ levels annually, at a minimum
Before starting, estimated GFR should be greater than 45 mL/minute/1.73 m²; patient may remain on metformin until estimated GFR falls to 30 mL/minute/1.73 m², when it must be stopped
Dipeptidyl-peptidase IV inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, dual glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 receptor agonists
Before starting, measure baseline renal function, and recheck periodically throughout therapy
Monitoring of comorbidities
Hypertension [6]
Monitor blood pressure at each office visit (3-4 times annually at a minimum)
If ACE inhibitors, angiotensin receptor blockers, or diuretics are used, monitor estimated GFR and serum levels of creatinine and potassium within 7 to14 days after initiation of treatment and regularly thereafter
Dyslipidemia [6]
Monitor lipid profile at time of first diagnosis and periodically thereafter; every 5 years if patient is aged younger than 40 years, or more frequently if indicated
Once patient is using lipid-lowering therapy, measuring lipid profile may be considered on an individual basis to monitor adherence and efficacy; check lipid levels 4 to 12 weeks after initiating therapy or changing dose
Obesity
Calculate and document BMI at each patient encounter
Psychosocial issues
Screen for depression, anxiety, and disordered eating at least annually [13]
Consider assessment for cognitive impairment in older adults
Surveillance for complications
Retinopathy [171]
Refer to retinal specialist for initial dilated eye examination at time of diagnosis
Dilated eye examination every 2 years if no evidence of retinopathy exists for 1 or more annual eye examinations
Dilated eye examination annually if any level of retinopathy is present
Nephropathy [66]
Measure both urine albumin-creatinine ratio and creatinine clearance/estimated GFR annually; if urinary albumin over 30 mg/g of creatinine and/or estimated GFR is less than 60 mL/minute/1.73 m², measure every 6 months
Refer to nephrologist for further management if GFR is less than 30 mL/minute/1.73 m²
Neuropathy [171]
Assess all patients for peripheral neuropathy at time of diagnosis and at least annually thereafter
Assessment includes:
Thorough history
10-g monofilament testing
At least 1 of the following tests: pinprick, temperature, or vibration sensation
Hypoglycemia
Inquire about timing of episodes, awareness, frequency, and potential causes
Cognitive impairment
Screen annually for early detection of cognitive impairment in adults aged 65 years or older [163]
Heart failure
Measure natriuretic peptide or high-sensitivity cardiac troponin at least annually to identify early-stage heart failure and determine risk for progression to symptomatic heart failure [139]
Osteoporosis and fractures [13]
In people with type 2 diabetes, in the absence of other comorbidities, perform bone mineral density screening using DXA at least 5 years after diagnosis of diabetes
Reassess in high-risk patients aged older than 65 years and younger patients with multiple risk factors every 2 to 3 years
Peripheral arterial disease [6]
Screen with ankle-brachial index testing in asymptomatic patients aged 50 years and older and in patients of any age with microvascular disease in any location, foot complications, or end-organ damage due to diabetes
Also consider screening for individuals with diabetes for 10 or more years
Low testosterone (males) [13]
Consider screening with a morning serum testosterone level in men with symptoms or signs of hypogonadism, such as decreased sexual desire or erectile dysfunction
Complications and Prognosis
Complications
Acute
Hypoglycemia
Common treatment-related complication of diabetes caused by imbalance among food intake, physical activity, pharmacologic effects, organ function, and counterregulation with glucagon and/or epinephrine
Hypoglycemia thresholds: [30][172]
Hypoglycemia below 70 mg/dL is low enough to require fast-acting carbohydrate and adjustment of insulin doses
Hypoglycemia below 54 mg/dL indicates serious, clinically important hypoglycemia
Any hypoglycemia (no specific threshold) that causes cognitive impairment and requires external assistance for recovery is considered severe
Treatment for alert and conscious patient consists of:
Consumption of glucose (eg, juice, soft drink, milk, glucose tablet)
Reassessment of blood glucose level after 15 minutes
Repeated glucose intake if blood glucose level remains low
Confused or unconscious patients should receive an injection of glucagon subcutaneously or intramuscularly from medical personnel or a trained family member/caregiver and then be referred for emergency medical care
If untreated, hypoglycemia can lead to loss of consciousness, seizure, coma, and death
Severe or frequent hypoglycemia is associated with cognitive decline in older adults, increased risk for cardiovascular events, and increased mortality
Hyperglycemic hyperosmolar state [173]
Presents with altered mental status, profound dehydration, and hyperglycemia without ketoacidosis
Signs and symptoms include polyuria, polydipsia, polyphagia, weight loss, and weakness
Patients have marked hypovolemia, blood glucose level greater than 600 mg/dL, and serum osmolality level greater than 320 mOsm/kg, without significant ketonemia or acidosis [174]
Occurs more frequently than DKA in patients with type 2 diabetes because insulin production is sufficient to prevent ketoacidosis but insufficient to prevent severe hyperglycemia with accompanying dehydration; onset is slower than that of DKA
Relatively high mortality rate owing to higher incidence in older patients with comorbidities and severe dehydration
Treatment aims to gradually replace fluid losses, correct hyperglycemia, and reduce osmolality [174]
Treat with fluid resuscitation, insulin infusion, electrolyte replacement, and correction of precipitating factors [174]
DKA [173]
Seldom occurs spontaneously in patients with type 2 diabetes, but on rare occasions can occur in association with illness or infection; onset is abrupt
Presents with biochemical triad of hyperglycemia, ketonemia, and metabolic acidosis
Signs and symptoms include polyuria, polydipsia, polyphagia, weight loss, weakness, abdominal pain, nausea, vomiting, Kussmaul respirations, acetone breath, and blood glucose level greater than 250 mg/dL [41]
Treat with fluid resuscitation, insulin infusion, electrolyte replacement, and correction of precipitating factors (including discontinuation of sodium-glucose cotransporter-2 inhibitors, if relevant) [175]
Chronic
Cardiovascular disease
Major macrovascular complication of type 2 diabetes
Sodium-glucose cotransporter-2 inhibitors are recommended to reduce the risk of cardiovascular death or hospitalization for heart failure among patients with symptomatic heart failure, established atherosclerotic cardiovascular disease, and in patients with chronic kidney disease [177]
Glucagon-like peptide-1 receptor agonists also reduce the risk of cardiovascular mortality, myocardial infarction, and stroke among patients with type 2 diabetes [178]
Antiplatelet therapy with low-dose aspirin, statin therapy, and aggressive blood pressure and glycemic control is recommended; also consider addition of an ACE inhibitor
Impact of strict glycemic control on reducing risk of cardiovascular disease in type 2 diabetes is uncertain owing to mixed results from clinical trials
Composite analysis of trials of intensive glycemic control suggests that glucose lowering has an overall modest reduction in major cardiovascular disease outcomes, which likely emerge after many years of intensive therapy and strict control [183]
The concept of cardiovascular-kidney-metabolic (CKM) syndrome has been defined by the American Heart Association to encapsulate the complex relationship between diabetes, chronic kidney disease, and congestive heart failure and atherosclerotic cardiovascular disease [184]
Stages of CKM [184]
Stage 0: No CKM risk factors (overweight/obesity, metabolic risk factors, chronic kidney disease, or subclinical/clinical cardiovascular disease)
Stage 1: Overweight/obesity, abdominal obesity, or dysfunctional adipose tissue, without the presence of other metabolic risk factors or chronic kidney disease
Stage 2: Metabolic risk factors (hypertriglyceridemia [135 mg/dL or greater], hypertension, metabolic syndrome, diabetes) or chronic kidney disease
Stage 3: Subclinical atherosclerotic cardiovascular disease (based on coronary artery calcification, coronary catheterization/CT angiography) or subclinical heart failure (based on cardiac biomarkers or echocardiography) along with excess or dysfunctional adiposity, other metabolic risk factors, or chronic kidney disease
Stage 4: Clinical cardiovascular disease (coronary heart disease, heart failure, stroke, peripheral artery disease, or atrial fibrillation) along with excess or dysfunctional adiposity, other metabolic risk factors, or chronic kidney disease; further subclassified according to presence of kidney failure
Increasing CKM stage is associated with higher absolute risk of both atherosclerotic cardiovascular disease and heart failure
The recently developed PREVENT model predicts risk of total cardiovascular disease (a composite of congestive heart failure and atherosclerotic cardiovascular disease) among the general population of individuals without cardiovascular disease at baseline [185][186][187]
Equation includes traditional cardiovascular disease risk factors and kidney function (eGFR) as predictors along with urine albumin-creatinine ratio and/or hemoglobin A1c (in individuals with chronic kidney disease and/or diabetes at baseline) and social deprivation index when available
Peripheral vascular disease [6]
Atherosclerotic occlusive disease of medium and small vessels of lower extremities; initially characterized by intermittent claudication
Progression to limb-threatening ischemia is characterized by pain at rest, tissue loss, and gangrene
Major cause of lower extremity amputations
Presence of peripheral vascular disease is indicative of systemic vascular disease (eg, coronary, renal, cerebral) and is an associated risk for myocardial infarction, cerebral vascular events, and death
Treatment focuses on smoking cessation, exercise therapy, foot care, glycemic control, control of dyslipidemia and hypertension, antiplatelet therapy, and symptom control with pentoxifylline or cilostazol
Retinopathy
Present in 25% to 45% of patients with type 2 diabetes; leading cause of blindness in adults [29]
Begin annual assessment for diabetic retinopathy at time of type 2 diabetes diagnosis
Diabetic retinopathy includes macular edema, nonproliferative diabetic retinopathy, and proliferative diabetic retinopathy
Progression of diabetic retinopathy may be slowed with aggressive blood pressure, lipid, and glycemic control
Treatment may include laser photocoagulation therapy and anti–vascular endothelial growth factor therapy
Nephropathy
Present in 40% of patients with diabetes; causes approximately 50% of end-stage renal disease cases [29]
Begin annual assessment for diabetic nephropathy at time of type 2 diabetes diagnosis; include assessment of urinary albumin-creatinine ratio and serum creatinine level for estimated GFR [66]
Progression of diabetic nephropathy may be slowed with aggressive control of blood pressure, lipids, and glycemia [138]
Treatment with an ACE inhibitor or an angiotensin receptor blocker is recommended for a urinary albumin-creatinine ratio greater than 30 mg/g creatinine [66][138]
Both drug classes have dual effects of controlling blood pressure and slowing progression of kidney damage
Avoid combined use of an ACE inhibitor and an angiotensin receptor blocker, owing to higher risks of hyperkalemia and acute kidney injury [188]
Addition of a sodium-glucose cotransporter-2 inhibitor (in addition to maximally titrated angiotensin receptor blocker or ACE inhibitor) is recommended if urinary albumin-creatinine ratio is 200 mg/g or greater and estimated GFR is 20 mL/minute/1.73 m² or greater [49][66]
May also be considered for patients with urinary albumin-creatinine ratio between normal and 200 mg/g
A nonsteroidal mineralocorticoid receptor antagonist (finerenone) can also reduce chronic kidney disease progression and cardiovascular events in patients at increased risk for these outcomes [49][66][139][145]
Owing to risk of hyperkalemia, use for patients with consistently normal serum potassium concentration and monitor serum potassium level regularly after initiation [145]
Supportive care measures are also important components of care (eg, maintaining a low-protein/low-fat diet, engaging in physical exercise, reducing alcohol consumption, and smoking cessation)
Neuropathy [66]
Affects approximately 50% of patients with diabetes [29]
Begin annual neurologic assessment at time of type 2 diabetes diagnosis
Encompasses an array of heterogeneous conditions; most common are diabetic peripheral neuropathy and autonomic neuropathy
Diabetic peripheral neuropathy
Signs and symptoms include decreased sensation, pain, paresthesia, decreased reflexes, decreased pulses, abnormalities in foot structure, impaired skin integrity, and decreased skin temperature; occurs primarily in feet, legs, and ankles
Large fiber neuropathies cause ataxia and increase risk of falls; management consists of physical therapy, orthotics, tendon lengthening, casting, and/or surgery
Small fiber neuropathies may be diagnosed with punch biopsy; management consists of measures to protect feet (eg, prevention of heat injury, padded socks, daily inspection, skin emollients)
Autonomic neuropathy
Signs and symptoms vary by system affected
Cardiovascular autonomic neuropathy: orthostatic hypotension; exercise intolerance; resting tachycardia; and heart rate variability on Valsalva maneuver, deep inspiration, or position change
Gastrointestinal autonomic neuropathy: gastroparesis, constipation, fecal incontinence, nausea, vomiting, and erratic glucose control
Genitourinary autonomic neuropathy: erectile dysfunction; vaginal dryness; nocturia; and urinary frequency, urgency, retention, or incontinence
Vasomotor autonomic neuropathy: anhidrosis, hyperhidrosis, heat intolerance, impaired visceral sensation, hypoglycemic unawareness
Cardiovascular autonomic neuropathy is significant as a risk factor for cardiovascular mortality
Optimizing glycemic control, blood pressure, and lipid levels can slow progression of neuropathy in people with type 2 diabetes [171]
Painful neuropathy may be treated with: [171]
Tricyclic antidepressants
Selective serotonin reuptake inhibitors
Selective norepinephrine reuptake inhibitors
Gabapentinoids
Sodium channel blockers
Treatment of autonomic neuropathy depends on system affected and is aimed at symptom management
Other complications
Osteoporosis and fractures
Cognitive impairment and dementia
Low testosterone
Prognosis
Mortality rate for adults with diabetes (any type) is approximately 1.5 times higher than that for general population, largely owing to cardiovascular events [3]
People with type 2 diabetes have excess mortality compared with general population [189]
For each increase of 1 percentage point in hemoglobin A1C level, corresponding average increase in risk of 12% for all-cause mortality and 14% for cardiovascular mortality exists [189]
Excess mortality in type 2 diabetes appears to be greater with worsening glycemic control, severe renal complications, and impaired renal function [189]
Intensive glycemic control resulting in hemoglobin A1C level less than 7% is associated with 25% reduction in risk of microvascular complications (eg, retinopathy, nephropathy, neuropathy); intensive glycemic control does not have as great an effect on cardiovascular complications [190]
Some patients with diabetes experience sustained metabolic improvement, either spontaneously or after medical interventions, which can persist after withdrawal of glucose-lowering medication [191]
Remission is defined as hemoglobin A1C level less than 6.5% at least 3 months after cessation of glucose-lowering pharmacotherapy
Patients in remission should undergo testing at least yearly thereafter and continue routine monitoring for potential complications of diabetes
Screening and Prevention
Screening
At-risk populations
Consider screening of the following asymptomatic adults at any age: [1][29]
Patients who are overweight (BMI of 25 kg/m² or greater, or 23 kg/m² or greater in Asian American individuals) who have 1 or more additional risk factors, such as:
First-degree relative with diabetes
High-risk race or ethnicity (eg, Black, Latino, American Indian, Pacific Islander, Asian American)
Physical inactivity
Hypertension (blood pressure 140/90 mm Hg or higher or currently on therapy for hypertension)
Dyslipidemia (HDL-C level less than 35 mg/dL and/or triglyceride level greater than 250 mg/dL)
Polycystic ovary syndrome
Conditions associated with insulin resistance (eg, metabolic syndrome, nonalcoholic fatty liver disease, acanthosis nigricans)
Long-term use of glucocorticoids
Antipsychotic therapy for patients with severe bipolar disorder or schizophrenia
Sleep disorders in conjunction with glucose intolerance (eg, obstructive sleep apnea, chronic sleep deprivation, night shift work schedule)
History of cardiovascular disease
Patients with hemoglobin A1C level of 5.7% or greater, impaired glucose tolerance, or impaired fasting glucose level on previous testing
Patients with HIV
Patients with past diagnosis of gestational diabetes
Screen all other asymptomatic patients beginning at age 35 years
If results of initial screening are normal, repeat testing at least every 3 years [1]
Consider more frequent testing depending on initial results and risk status; for example:
Test patients with prediabetes annually
Test patients with history of gestational diabetes at least every 3 years
Monitor glucose status regularly in patients at high risk of developing type 2 diabetes who are on statin therapy [11]
Screening tests
Screening tests are similar to diagnostic testing and include any of the following: [1]
Fasting plasma glucose level
Oral glucose tolerance test
Hemoglobin A1C level
Prevention
For patients with impaired glucose tolerance, type 2 diabetes can be delayed or prevented through lifestyle modification and pharmacologic interventions targeting risk factors of obesity and sedentary activity [192][193][194]
Lifestyle modification includes:
Pharmacotherapy for weight management may be considered [11]
Pharmacologic therapy can minimize progression of hyperglycemia and reduce cardiovascular risk
Metformin, acarbose, and thiazolidinediones have been shown to be effective in slowing progression from impaired glucose tolerance to type 2 diabetes[196]
Metformin has the strongest evidence base and safety record as pharmacologic therapy for diabetes prevention [197][198]
Consider for patients with prediabetes, especially those aged 25 to 59 years with BMI greater than 35 kg/m², higher fasting plasma glucose (eg, 110 mg/dL or greater), and higher hemoglobin A1C level (eg, 6.0% or higher), and females with history of gestational diabetes [11]
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