Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes (17)
Class | Compound(s) | Cellular mechanism(s) | Primary physiological action(s) | Advantages | Disadvantages | Cost* |
---|---|---|---|---|---|---|
Biguanides | • Metformin | Activates AMP-kinase (? other) | • ↓ Hepatic glucose production | • Extensive experience | • Gastrointestinal side effects (diarrhea, abdominal cramping) | Low |
• No hypoglycemia | • Vitamin B12 deficiency | |||||
• ↓ CVD events (UKPDS) | • Contraindications: CKD, acidosis, hypoxia, dehydration, etc. | |||||
• Lactic acidosis risk (rare) | ||||||
Sulfonylureas | 2nd Generation | Closes KATP channels on β-cell plasma membranes | • ↑ Insulin secretion | • Extensive experience | • Hypoglycemia | Low |
• Glyburide/glibenclamide | • ↓ Microvascular risk (UKPDS) | • ↑ Weight | ||||
• Glipizide | ||||||
• Gliclazide† | ||||||
• Glimepiride | ||||||
Meglitinides (glinides) | • Repaglinide | Closes KATP channels on β-cell plasma membranes | • ↑ Insulin secretion | • ↓ Postprandial glucose excursions | • Hypoglycemia | Moderate |
• Nateglinide | • Dosing flexibility | • ↑ Weight | ||||
• Frequent dosing schedule | ||||||
TZDs | • Pioglitazone‡ | Activates the nuclear transcription factor PPAR-γ | • ↑ Insulin sensitivity | • No hypoglycemia | • ↑ Weight | Low |
• Rosiglitazone§ | • Durability | • Edema/heart failure | ||||
• ↑ HDL-C | • Bone fractures | |||||
• ↓ Triglycerides (pioglitazone) | • ↑ LDL-C (rosiglitazone) | |||||
• ? ↓ CVD events (PROactive, pioglitazone) | • ? ↑ MI (meta-analyses, rosiglitazone) | |||||
α-Glucosidase inhibitors | • Acarbose | Inhibits intestinal α-glucosidase | • Slows intestinal carbohydrate digestion/absorption | • No hypoglycemia | • Generally modest A1C efficacy | Low to moderate |
• Miglitol | • ↓ Postprandial glucose excursions | • Gastrointestinal side effects (flatulence, diarrhea) | ||||
• ? ↓ CVD events (STOP-NIDDM) | • Frequent dosing schedule | |||||
• Nonsystemic | ||||||
DPP-4 inhibitors | • Sitagliptin | Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations | • ↑ Insulin secretion (glucose dependent) | • No hypoglycemia | • Angioedema/urticaria and other immune-mediated dermatological effects | High |
• Vildagliptin† | • ↓ Glucagon secretion (glucose dependent) | • Well tolerated | • ? Acute pancreatitis | |||
• Saxagliptin | • ? ↑ Heart failure hospitalizations | |||||
• Linagliptin | ||||||
• Alogliptin | ||||||
Bile acid sequestrants | • Colesevelam | Binds bile acids in intestinal tract, increasing hepatic bile acid production | • ? ↓ Hepatic glucose production | • No hypoglycemia | • Generally modest A1C efficacy | High |
• ? ↑ Incretin levels | • ↓ LDL-C | • Constipation | ||||
• ↑ Triglycerides | ||||||
• May ↓ absorption of other medications | ||||||
Dopamine-2 agonists | • Bromocriptine (quick release)§ | Activates dopaminergic receptors | • Modulates hypothalamic regulation of metabolism | • No hypoglycemia | • Generally modest A1C efficacy | High |
• ↑ Insulin sensitivity | • ? ↓ CVD events (Cycloset Safety Trial) | • Dizziness/syncope | ||||
• Nausea | ||||||
• Fatigue | ||||||
• Rhinitis | ||||||
SGLT2 inhibitors | • Canagliflozin | Inhibits SGLT2 in the proximal nephron | • Blocks glucose reabsorption by the kidney, increasing glucosuria | • No hypoglycemia | • Genitourinary infections | High |
• Dapagliflozin‡ | • ↓ Weight | • Polyuria | ||||
• Empagliflozin | • ↓ Blood pressure | • Volume depletion/hypotension/ dizziness | ||||
• Effective at all stages of type 2 diabetes | • ↑ LDL-C | |||||
• Associated with lower CVD event rate and mortality in patients with CVD (EMPA-REG OUTCOME) | • ↑ Creatinine (transient) | |||||
• DKA, urinary tract infections leading to urosepsis, pyelonephritis | ||||||
GLP-1 receptor agonists | • Exenatide | Activates GLP-1 receptors | • ↑ Insulin secretion (glucose dependent) | • No hypoglycemia | • Gastrointestinal side effects (nausea/vomiting/diarrhea) | High |
• Exenatide extended release | • ↓ Glucagon secretion (glucose dependent) | • ↓ Weight | • ↑ Heart rate | |||
• Liraglutide | • Slows gastric emptying | • ↓ Postprandial glucose excursions | • ? Acute pancreatitis | |||
• Albiglutide | • ↑ Satiety | • ↓ Some cardiovascular risk factors | • C-cell hyperplasia/medullary thyroid tumors in animals | |||
• Lixisenatide† | • Injectable | |||||
• Dulaglutide | • Training requirements | |||||
Amylin mimetics | • Pramlintide§ | Activates amylin receptors | • ↓ Glucagon secretion | • ↓ Postprandial glucose excursions | • Generally modest A1C efficacy | High |
• Slows gastric emptying | • ↓ Weight | • Gastrointestinal side effects (nausea/vomiting) | ||||
• ↑ Satiety | • Hypoglycemia unless insulin dose is simultaneously reduced | |||||
• Injectable | ||||||
• Frequent dosing schedule | ||||||
• Training requirements | ||||||
Insulins | • Rapid-acting analogs | Activates insulin receptors | • ↑ Glucose disposal | • Nearly universal response | • Hypoglycemia | Moderate to high# |
- Lispro | ||||||
- Aspart | ||||||
- Glulisine | ||||||
- Inhaled insulin | ||||||
• Short-acting | • ↓ Hepatic glucose production | • Theoretically unlimited efficacy | • Weight gain | |||
- Human Regular | ||||||
• Intermediate-acting | • Suppresses ketogenesis | • ↓ Microvascular risk (UKPDS) | • ? Mitogenic effects | |||
- Human NPH | ||||||
• Basal insulin analogs | • Training requirements | |||||
- Glargine | ||||||
- Detemir | ||||||
- Degludec† | ||||||
• Premixed (several types) | • Patient reluctance | |||||
• Injectable (except inhaled insulin) | ||||||
• Pulmonary toxicity (inhaled insulin) |
CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (31); GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MI, myocardial infarction; PPAR-γ, peroxisome proliferator–activated receptor γ; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events (32); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (33); TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (34,35). Cycloset trial of quick-release bromocriptine (36).
↵* Cost is based on lowest-priced member of the class (see ref. 17).
↵† Not licensed in the U.S.
↵‡ Initial concerns regarding bladder cancer risk are decreasing after subsequent study.
↵§ Not licensed in Europe for type 2 diabetes.
↵# Cost is highly dependent on type/brand (analogs > human insulins) and dosage. Adapted with permission from Inzucchi et al. (17).