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Antidiabetic drugs

Last updated: April 12, 2021

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Antidiabetic drugs (except insulin) are all pharmacological agents that have been approved for hyperglycemic treatment in type 2 diabetes mellitus (DM). If lifestyle modifications (weight loss, dietary modification, and exercise) do not sufficiently reduce HbA1c levels (target level: ∼ 7%), pharmacological treatment with antidiabetic drugs should be initiated. These drugs can be classified according to their mechanism of action as insulinotropic or noninsulinotropic. They are available as monotherapy or combination therapies, with the latter involving two (or, less commonly, three) antidiabetic drugs and/or insulin. The exact treatment algorithms are reviewed in the treatment section of diabetes mellitus. The drug of choice for all patients with type 2 diabetes is metformin. This drug has beneficial effects on glucose metabolism and promotes weight loss or at least weight stabilization. In addition, numerous studies have demonstrated that metformin can reduce mortality and the risk of complications. If metformin is contraindicated, not tolerated, or does not sufficiently control blood glucose levels, another class of antidiabetic drug may be administered. In patients with moderate or severe renal failure or other significant comorbidities, most antidiabetic drugs are not recommended or should be used with caution. Oral antidiabetic drugs are not recommended during pregnancy or breastfeeding.

Classification

Overview of antidiabetic drugs

See “Antihyperglycemic therapy algorithm for type 2 diabetes” for the treatment of type 2 DM with the antidiabetic drugs listed below.

Overview
Class Agents Mechanism of action Side effects Contraindications
Insulinotropic
Sulfonylureas
Meglitinides
  • Nateglinide
  • Repaglinide
Dipeptidyl peptidase-4 (DPP-4) inhibitors
  • Inhibit GLP-1 degradation ↑ glucose-dependent insulin secretion
Glucagon-like peptide-1 (GLP-1) agonists (incretin mimetic drugs)
  • Stimulate the GLP-1 receptor directly
  • Preexisting, symptomatic gastrointestinal motility disorders
Noninsulinotropic
Biguanides
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors
  • Canagliflozin
  • Dapagliflozin
  • Empagliflozin
  • Increase glucose excretion with urine through the inhibition of SGLT-2 in the kidney
Alpha-glucosidase inhibitors
  • Gastrointestinal symptoms (flatulence, diarrhea, feeling of satiety)
Thiazolidinediones
  • Pioglitazone
  • Rosiglitazone
Amylin analogs
  • Pramlintide
  • Decrease glucagon release
  • Slow gastric emptying
  • Increase feeling of satiety

Almost all antidiabetic drugs listed above are oral drugs, except for amylin analogues and GLP-1 analogues, which are injectable.

To remember the important oral antidiabetic drugs, think: “My Pancreas Needs Fitting Treatment!” - Metformin, -gliPs, -gliNs, -gliFs, -gliTs

Common contraindications of antidiabetic agents

Sulfonylureas are associated with the highest risk of hypoglycemia. All other substances do not carry a significant risk of hypoglycemia when used as monotherapy. Combination therapy, particularly with sulfonylurea, significantly increases the risk of hypoglycemia.

Active agent

  • Metformin

Clinical profile

Metformin treatment must be paused prior to the administration of a contrast medium or scheduled surgery to reduce the risk of lactic acidosis!

Because of its favorable risk-benefit ratio, metformin is the drug of choice for monotherapy and combination therapy in all stages of type 2 DM.

Active agents

  • Pioglitazone
  • Rosiglitazone

Clinical profile

Active agents

  • First generation
    • Chlorpropamide
    • Tolbutamide
  • Second generation
    • Glyburide (long-acting agent)
    • Glipizide (short-acting agent)
    • Glimepiride

Clinical profile [6]

Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!

Active agents

  • Repaglinide
  • Nateglinide

Clinical profile

Active agents

  • Exenatide
  • Liraglutide
  • Albiglutide
  • Dulaglutide

Clinical profile [9][10][11]

Active agents

  • Sitagliptin
  • Saxagliptin
  • Linagliptin

Clinical profile [9][13][14]

Active agents

  • Dapagliflozin
  • Empagliflozin
  • Canagliflozin

Clinical profile [15][16]

Active agents

  • Acarbose
  • Miglitol

Clinical profile

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  1. Madiraju et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014; 510 (7506): p.542-546. doi: 10.1038/nature13270 . | Open in Read by QxMD
  2. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2018; 42 (Supplement 1): p.S90-S102. doi: 10.2337/dc19-s009 . | Open in Read by QxMD
  3. Sola et al. State of the art paper Sulfonylureas and their use in clinical practice. Archives of Medical Science. 2015; 4 : p.840-848. doi: 10.5114/aoms.2015.53304 . | Open in Read by QxMD
  4. Triplitt C. Drug Interactions of Medications Commonly Used in Diabetes. Diabetes Spectrum. 2006; 19 (4): p.202-211. doi: 10.2337/diaspect.19.4.202 . | Open in Read by QxMD
  5. Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY. Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets. The Journal of Clinical Endocrinology & Metabolism. 2005; 90 (1): p.501-506. doi: 10.1210/jc.2004-0699 . | Open in Read by QxMD
  6. Armoni M, Kritz N, Harel C, et al. Peroxisome Proliferator-activated Receptor-γ Represses GLUT4 Promoter Activity in Primary Adipocytes, and Rosiglitazone Alleviates This Effect. J Biol Chem. 2003; 278 (33): p.30614-30623. doi: 10.1074/jbc.m304654200 . | Open in Read by QxMD
  7. Astapova O, Leff T. Adiponectin and PPARγ. Elsevier ; 2012 : p. 143-162
  8. Katzung B,Trevor A. Basic and Clinical Pharmacology. McGraw-Hill Education ; 2014
  9. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006; 19 (6): p.612-620.
  10. Dulaglutide. https://www.drugs.com/ppa/dulaglutide.html. Updated: February 23, 2017. Accessed: February 23, 2017.
  11. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. https://www.fda.gov/Drugs/DrugSafety/ucm459579.htm. Updated: August 28, 2015. Accessed: February 23, 2017.
  12. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. https://www.fda.gov/Drugs/DrugSafety/ucm343187.htm. Updated: March 14, 2013. Accessed: February 23, 2017.
  13. DPP-IV Inhibitors. https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_Diabetes_Guide/547042/all/DPP_IV_Inhibitors. Updated: December 3, 2018. Accessed: January 20, 2019.
  14. Highlights of Prescribing Information - Janumet.
  15. Empagliflozin. https://www.drugs.com/ppa/empagliflozin.html. Updated: June 23, 2019. Accessed: September 23, 2019.
  16. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 Inhibitors and the Diabetic Kidney. Diabetes Care. 2016; 39 (Supplement 2): p.S165-S171. doi: 10.2337/dcs15-3006 . | Open in Read by QxMD
  17. Fralick M, Kim SC, Schneeweiss S, Everett BM, Glynn RJ, Patorno E. Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study.. BMJ. 2020; 370 : p.m2812. doi: 10.1136/bmj.m2812 . | Open in Read by QxMD