Table 1

Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes

ClassCompound(s)Cellular mechanism(s)Primary physiological action(s)AdvantagesDisadvantagesCost*
Biguanides• MetforminActivates AMP-kinase  (? other)• ↓ Hepatic glucose production• Extensive experience• Gastrointestinal side effects (diarrhea, abdominal cramping)Low
• No hypoglycemia• Lactic acidosis risk (rare)
• ↓ CVD events (UKPDS)• Vitamin B12 deficiency
• Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc.
Sulfonylureas2nd GenerationCloses KATP channels on  β-cell plasma membranes• ↑ Insulin secretion• Extensive experience• HypoglycemiaLow
• Glyburide/glibenclamide• ↓ Microvascular risk (UKPDS)• ↑ Weight
• Glipizide• ? Blunts myocardial ischemic preconditioning
• Gliclazide• Low durability
• Glimepiride
Meglitinides (glinides)• RepaglinideCloses KATP channels on  β-cell plasma membranes• ↑ Insulin secretion• ↓Postprandial glucose excursions• HypoglycemiaModerate
• Nateglinide• Dosing flexibility• ↑ Weight
• ? Blunts myocardial ischemic preconditioning
• Frequent dosing schedule
TZDs• PioglitazoneActivates the nuclear  transcription factor PPAR-γ• ↑ Insulin sensitivity• No hypoglycemia• ↑ WeightLow
• 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• AcarboseInhibits intestinal  α-glucosidase• Slows intestinal carbohydrate digestion/absorption• No hypoglycemia• Generally modest HbA1c efficacyModerate
• Miglitol• ↓Postprandial glucose excursions
• ? ↓ CVD events (STOP-NIDDM)• Gastrointestinal side effects (flatulence, diarrhea)
• Nonsystemic• Frequent dosing schedule
DPP-4 inhibitors• SitagliptinInhibits DPP-4 activity,  increasing postprandial  active incretin (GLP-1, GIP) concentrations• ↑ Insulin secretion (glucose-dependent)• No hypoglycemia• Angioedema/urticaria and other immune-mediated dermatological effectsHigh
• Vildagliptin• ↓ Glucagon secretion (glucose-dependent)• Well tolerated• ? Acute pancreatitis
• Saxagliptin
• Linagliptin• ? ↑ Heart failure hospitalizations
• Alogliptin
Bile acid sequestrants• ColesevelamBinds bile acids in  intestinal tract, increasing  hepatic bile acid  production• ? ↓ Hepatic glucose production• No hypoglycemia• Generally modest HbA1c efficacyHigh
• ? ↑ 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 HbA1c efficacyHigh
• Dizziness/syncope
• ↑ Insulin sensitivity• ? ↓ CVD events (Cycloset Safety Trial)• Nausea
• Fatigue
• Rhinitis
SGLT2 inhibitors• CanagliflozinInhibits SGLT2 in the proximal nephron• Blocks glucose reabsorption  by the kidney, increasing  glucosuria• No hypoglycemia• Genitourinary infectionsHigh
• Dapagliflozin• ↓ Weight• Polyuria
• Empagliflozin• Volume depletion/hypotension/dizziness
• ↓ Blood pressure• ↑ LDL-C
• Effective at all stages of T2DM• ↑ Creatinine (transient)
GLP-1 receptor agonists• ExenatideActivates GLP-1 receptors• ↑ Insulin secretion (glucose-dependent)• No hypoglycemia• Gastrointestinal side effects (nausea/ vomiting/diarrhea)High
• Exenatide extended release• ↓ Glucagon secretion (glucose-dependent)• ↑ Heart rate
• Liraglutide• ↓ Weight• ? Acute pancreatitis
• Albiglutide• Slows gastric emptying• ↓ Postprandial glucose excursions• C-cell hyperplasia/medullary thyroid  tumors in animals
• Lixisenatide• ↑ Satiety• ↓ Some cardiovascular risk factors• Injectable
• Dulaglutide• Training requirements
Amylin mimetics• Pramlintide§Activates amylin receptors• ↓ Glucagon secretion• ↓ Postprandial glucose excursions• Generally modest HbA1c efficacyHigh
• ↑ Satiety• ↓ Weight• Gastrointestinal side effects (nausea/ vomiting)
• Hypoglycemia unless insulin dose is simultaneously reduced
• Slows gastric emptying• Injectable
• Frequent dosing schedule
• Training requirements
Insulins• Rapid-acting analogsActivates insulin receptors• ↑ Glucose disposal• Nearly universal response• HypoglycemiaVariable#
 - Lispro
 - Aspart
 - Glulisine
• Short-acting
 - Human Regular
• Intermediate-acting• Weight gain
 - Human NPH
• Basal insulin analogs• ↓ Hepatic glucose production• ↓ Microvascular risk (UKPDS)• ? Mitogenic effects
 - Glargine• Injectable
 - Detemir• Training requirements
 - Degludec• Other• Theoretically unlimited efficacy• Patient reluctance
• Premixed (several types)
  • CVD, cardiovascular disease; 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 (26); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (60); T2DM, type 2 diabetes mellitus; UKPDS, UK Prospective Diabetes Study (4,61). Cycloset trial of quick-release bromocriptine (62).

  • * Cost is based on lowest-priced member of the class (see Supplementary Data).

  • 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.