Table 8.2

Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes

ClassCompound(s)Cellular mechanism(s)Primary physiological action(s)Renal dosing recommendations (6366)*
Biguanides• MetforminActivates AMP kinase (? other)↓ Hepatic glucose production
  • No dose adjustment if eGFR >45;

  • do not initiate OR assess risk/benefit if currently on metformin if eGFR 30–45;

  • discontinue if eGFR <30

Sulfonylureas (2nd generation)• GlyburideCloses KATP channels on β-cell plasma membranes↑ Insulin secretion• Avoid use in patients with renal impairment
• Glipizide• Initiate conservatively at 2.5 mg daily to avoid hypoglycemia
• Glimepiride• Initiate conservatively at 1 mg daily to avoid hypoglycemia
Meglitinides (glinides)• RepaglinideCloses KATP channels on β-cell plasma membranes↑ Insulin secretion• Initiate conservatively at 0.5 mg with meals if eGFR <30
• Nateglinide• Initiate conservatively at 60 mg with meals if eGFR <30
Thiazolidinediones• PioglitazoneActivates the nuclear transcription factor PPAR-γ↑ Insulin sensitivity• No dose adjustment required
• Rosiglitazone§• No dose adjustment required
α-Glucosidase inhibitors• AcarboseInhibits intestinal α-glucosidaseSlows intestinal carbohydrate digestion/absorption• Avoid if eGFR <30
• Miglitol• Avoid if eGFR <25
DPP-4 inhibitors• SitagliptinInhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations
  • ↑ Insulin secretion (glucose dependent);

  • ↓ Glucagon secretion (glucose dependent)

  • 100 mg daily if eGFR >50;

  • 50 mg daily if eGFR 30–50;

  • 25 mg daily if eGFR <30

• Saxagliptin
  • 5 mg daily if eGFR >50;

  • 2.5 mg daily if eGFR ≤50

• Linagliptin• No dose adjustment required
• Alogliptin
  • 25 mg daily if eGFR >60;

  • 12.5 mg daily if eGFR 30–60;

  • 6.25 mg daily if eGFR <30

Bile acid sequestrants• ColesevelamBinds bile acids in intestinal tract, increasing hepatic bile acid production
  • ? ↓ Hepatic glucose production;

  • ? ↑ Incretin levels

• No specific dose adjustment recommended by manufacturer
Dopamine-2 agonists• Bromocriptine (quick release)§Activates dopaminergic receptors
  • Modulates hypothalamic regulation of metabolism;

  • ↑ Insulin sensitivity

• No specific dose adjustment recommended by manufacturer
SGLT2 inhibitors• CanagliflozinInhibits SGLT2 in the proximal nephronBlocks glucose reabsorption by the kidney, increasing glucosuria
  • No dose adjustment required if eGFR ≥60;

  • 100 mg daily if eGFR 45–59;

  • avoid use and discontinue in patients with eGFR persistently <45

• Dapagliflozin
  • Avoid initiating if eGFR <60;

  • not recommended with eGFR 30–60;

  • contraindicated with eGFR <30

• Empagliflozin• Contraindicated with eGFR <30
GLP-1 receptor agonists• ExenatideActivates GLP-1 receptors
  • ↑ Insulin secretion (glucose dependent)

  • ↓ Glucagon secretion (glucose dependent);

  • Slows gastric emptying;

  • ↑ Satiety

• Not recommended with eGFR <30
• Exenatide extended release• Not recommended with eGFR <30
• Liraglutide• No specific dose adjustment recommended by the manufacturer; limited experience in patients with severe renal impairment
• Albiglutide• No dose adjustment required for eGFR 15–89 per manufacturer; limited experience in patients with severe renal impairment
• Lixisenatide
  • No dose adjustment required for eGFR 60–89;

  • no dose adjustment required for eGFR 30–59, but patients should be monitored for adverse effects and changes in kidney function;

  • clinical experience is limited with eGFR 15–29; patients should be monitored for adverse effects and changes in kidney function;

  • avoid if eGFR <15

• Dulaglutide• No specific dose adjustment recommended by the manufacturer; limited experience in patients with severe renal impairment
Amylin mimetics• Pramlintide§Activates amylin receptors
  • ↓ Glucagon secretion;

  • Slows gastric emptying;

  • ↑ Satiety

• No specific dose adjustment recommended by manufacturer
Insulins• Rapid-acting analogsActivates insulin receptors
  • ↑ Glucose disposal;

  • ↓ Hepatic glucose production;

  • Suppresses ketogenesis

• Lower insulin doses required with a decrease in eGFR; titrate per clinical response
Lispro
Aspart
Glulisine
Inhaled insulin
• Short-acting analogs
Human Regular
• Intermediate-acting analogs
Human NPH
• Basal insulin analogs
Glargine
Detemir
Degludec
• Premixed insulin products
NPH/Regular 70/30
70/30 aspart mix
75/25 lispro mix
50/50 lispro mix
  • *eGFR is given in mL/min/1.73 m2.

  • § Not licensed in Europe for type 2 diabetes.

  • GIP, glucose-dependent insulinotropic peptide; PPAR-γ, peroxisome proliferator–activated receptor γ.