Table 7.1

Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes (17)

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• Vitamin B12 deficiency
• ↓ CVD events (UKPDS)• Contraindications: CKD, acidosis, hypoxia, dehydration, etc.
• Lactic acidosis risk (rare)
Sulfonylureas2nd GenerationCloses KATP channels on β-cell plasma membranes• ↑ Insulin secretion• Extensive experience• HypoglycemiaLow
• Glyburide/glibenclamide• ↓ Microvascular risk (UKPDS)• ↑ Weight
• Glipizide
• Gliclazide
• Glimepiride
Meglitinides (glinides)• RepaglinideCloses KATP channels on β-cell plasma membranes• ↑ Insulin secretion• ↓ Postprandial glucose excursions• HypoglycemiaModerate
• Nateglinide• Dosing flexibility• ↑ Weight
• 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 A1C efficacyLow to moderate
• Miglitol• ↓ Postprandial glucose excursions• Gastrointestinal side effects (flatulence, diarrhea)
• ? ↓ CVD events (STOP-NIDDM)• Frequent dosing schedule
• Nonsystemic
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• ? ↑ Heart failure hospitalizations
• Linagliptin
• Alogliptin
Bile acid sequestrants• ColesevelamBinds bile acids in intestinal tract, increasing hepatic bile acid production• ? ↓ Hepatic glucose production• No hypoglycemia• Generally modest A1C 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 A1C efficacyHigh
• ↑ Insulin sensitivity• ? ↓ CVD events (Cycloset Safety Trial)• Dizziness/syncope
• 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• ↓ 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• ExenatideActivates 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 efficacyHigh
• 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 analogsActivates insulin receptors• ↑ Glucose disposal• Nearly universal response• HypoglycemiaModerate 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).