Antidiabetic drugs

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

• Insulinotropic agents
  • Stimulate the secretion of insulin from pancreatic β cells
    • Glucose-dependent (GLP-1 agonists, DPP-4 inhibitors): Insulin secretion is stimulated by elevated blood glucose levels (postprandially).
    • Glucose-independent (sulfonylurea, meglitinides): Insulin is secreted regardless of the blood glucose level, even if blood glucose levels are low → risk of hypoglycemia
  • Depend on residual β-cell function
• Noninsulinotropic agents
  • Effective in patients with nonfunctional β cells
  • Not dependent on residual insulin production
  • Agents: biguanides (metformin), SGLT-2 inhibitors, thiazolidinediones, α-glucosidase inhibitors, amylin analogues

Overview

See “Antihyperglycemic treatment of diabetes mellitus” for details on the treatment of type 2 DM with the antidiabetic drugs listed below.

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

• Type 1 diabetes mellitus: Patients require insulin therapy (see principles of insulin therapy).
• Pregnancy and breastfeeding (see also gestational diabetes)
  • All antidiabetic agents are contraindicated.
  • Antidiabetic drugs should be substituted with human insulin as early as possible (ideally prior to the pregnancy).
• Renal failure
  • Chronic kidney disease is by far the most relevant contraindication; it significantly limits the possibilities of antidiabetic treatment regimens.
  • Antidiabetic drugs that may be administered if GFR < 30 mL/min include DPP-4 inhibitors, incretin mimetic drugs, meglitinides, and thiazolidinediones.
• Morbidity and surgery
  • Major surgery performed under general anesthesia
  • Acute conditions requiring hospitalization (infections, organ failure)
  • Elective procedures associated with an increased risk of hypoglycemia (periods of fasting, irregular food intake)

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

• Mechanism of action: enhances the effect of insulin
  • Reduction in insulin resistance via modification of glucose metabolic pathways
    • Inhibits mitochondrial glycerophosphate dehydrogenase (mGPD) → ↓ hepatic gluconeogenesis and intestinal glucose absorption ^[7]
    • Increases peripheral insulin sensitivity → ↑ peripheral glucose uptake and glycolysis
  • Lowers postprandial and fasting blood glucose levels
  • Reduces LDL, increases HDL
• Indications: drug of choice in all patients with type 2 diabetes
• Clinical characteristics ^[8]
  • Glycemic efficacy: lowers HbA1c by 1.2–2% over 3 months
  • Weight loss (often desired) or weight stabilization
  • No risk of hypoglycemia
  • Beneficial effect on dyslipidemia
  • Reduces the risk of macroangiopathic complications in patients with diabetes
  • Must be paused prior to surgery
  • Cost-effective
• Important side effects
  • Metformin-associated lactic acidosis
    • Incidence: ∼ 8 cases/100,000 patient years
    • High-risk groups
      • Elderly individuals
      • Patients with renal insufficiency or CHF
    • Clinical features: frequently nonspecific
      • Gastrointestinal symptoms: nausea, vomiting, diarrhea, abdominal pain, flatulence
      • Severe symptoms: muscle cramps, hyperventilation, apathy, disorientation, coma
    • Diagnostics
      • ↑ Serum lactate
      • Arterial blood gas: metabolic acidosis and anion gap
    • Treatment: Discontinue metformin and treat acidosis.
  • Vitamin B₁₂ deficiency
  • Metallic taste in the mouth (dysgeusia)
• Contraindications
  • Renal failure (if creatinine clearance < 30 mL/min)
  • Intravenous iodinated contrast medium
  • Heart failure (NYHA III and IV), respiratory failure, shock, sepsis
  • Alcoholism
  • Severe liver failure
  • Chronic pancreatitis, starvation ketosis, ketoacidosis, sepsis
• Important interactions: sulfonylureas

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

• Mechanism of action: : activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type in the nucleus) → ↑ transcription of genes involved in glucose and lipid metabolism → ↑ levels of adipokines such as adiponectin and insulin sensitivity → ↑ storage of fatty acids in adipocytes, ↓ products of lipid metabolism (e.g., free fatty acids) → ↓ free fatty acids in circulation → ↑ glucose utilization and ↓ hepatic glucose production
• Indications: may be considered as monotherapy in patients with severe renal failure and/or contraindications for insulin therapy
• Clinical characteristics ^[9][10]
  • Glycemic efficacy: lowers HbA1c by 1% in 3 months
  • Favorable effect on lipid metabolism: ↓ triglyceride, ↓ LDL, ↑ HDL
  • No risk of hypoglycemia
  • Onset of action is delayed by several weeks.
• Important side effects ^[11]
  • ↑ Risk of heart failure
  • ↑ Risk of bone fractures (osteoporosis)
  • Fluid retention and edema
  • Weight gain
  • Rosiglitazone: ↑ risk of cardiovascular complications like cardiac infarction or death
• Contraindications
  • Congestive heart failure (NYHA III or IV)
  • Liver failure
  • Pioglitazone: history of bladder cancer or active bladder cancer; macrohematuria of unknown origin

Active agents

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

Clinical profile ^[12]

• Mechanism of action
  • Block ATP-sensitive potassium channels of the pancreatic β cells → depolarization of the cell membrane → calcium influx → insulin secretion
  • Extrapancreatic effect: ↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity
• Indications
  • Patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine
  • Generally not frequently used
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 1.2% over 3 months
  • Low cost
• Important side effects
  • Life-threatening hypoglycemia; increased risk under the following circumstances:
    • Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole) ^[13]
    • Patients with renal failure
    • Decreased carbohydrate intake (diets or periods of fasting)
    • Elevated glucose utilization (e.g., unaccustomed physical activity)
    • Sulfonylurea overdose
  • Alcohol intolerance (first-generation agents): disulfiram-like reaction
  • Weight gain
  • Hematological changes: granulocytopenia, hemolytic anemia
  • Allergic skin reactions
  • Sulfonylureas are associated with more cardiovascular (macrovascular) complications than metformin.
  • β-cell apoptosis: Studies suggest that sulfonylureas induce β-cell apoptosis in human islet cells. ^[14]
• Contraindications
  • Beta blockers (can mask hypoglycemic symptoms while lowering serum glucose levels)
  • Severe cardiovascular comorbidity
  • Obesity
  • Sulfonamide allergy (particularly long-acting substances)
  • Severe liver and kidney failure

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

• Mechanism of action (similar mechanism of action to that of sulfonylureas)
  • Blockage of ATP-sensitive potassium channels of the pancreatic beta cells → depolarization of the cell membrane → calcium influx → insulin secretion
  • Meglitinides should be taken shortly before meals.
• Indications: : particularly suitable for patients with postprandial peaks in blood glucose levels, but overall rarely prescribed
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 0.75% over 3 months
  • Tolerated well by patients with chronic kidney disease
  • More expensive than sulfonylureas
• Important side effects
  • Life-threatening hypoglycemia, especially in patients with renal failure (less of a risk than with sulfonylureas)
  • Weight gain
  • Hepatotoxicity (rare)
• Contraindications: severe liver failure
• Interactions: sulfonylureas

Active agents

• Exenatide
• Liraglutide
• Albiglutide
• Dulaglutide

Clinical profile ^[15][16][17]

• Mechanism of action
  • Incretin effect: food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effect
  • Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → ↑ insulin secretion, ↓ glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight)
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 0.5–1.5% over 3 months
  • Subcutaneous injection
  • Weight loss (may be wanted)
  • No risk of hypoglycemia
• Side effects
  • Gastrointestinal symptoms
    • Nausea, vomiting
    • Strong feeling of satiety (often desired)
    • Pancreatitis; and potentially pancreatic cancer ^[18]
  • Potential risk of medullary thyroid cancer (MTC): further investigation required
• Contraindications
  • Preexisting symptomatic gastrointestinal motility disorders
  • Chronic pancreatitis or a family history of pancreatic tumors
  • Personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2)

Active agents

• Sitagliptin
• Saxagliptin
• Linagliptin

Clinical profile ^[15][19][20]

• Mechanism of action: indirectly increase the endogenous incretin effect by inhibiting the DPP-4 that breaks down GLP-1 → ↑ insulin secretion, ↓ glucagon secretion, delayed gastric emptying
• Indications: See “Antihyperglycemic therapy algorithm for type 2 diabetes.”
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 0.5–0.75% over 3 months
  • No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously because insulin release is glucose-dependent
  • Usually no weight changes
• Important side effects
  • Gastrointestinal symptoms: diarrhea, constipation (milder than in GLP-1 agonist exposure)
  • Arthralgia
  • ↑ Feeling of satiety (often favorable) due to delayed gastric emptying
  • Nasopharyngitis and upper respiratory tract infection
  • Urinary infections (mild)
  • ↑ Risk of pancreatitis
  • Worsening renal function, acute renal failure
  • Headaches, dizziness
• Contraindications
  • Liver failure
  • Renal failure
  • Hypersensitivity

Active agents

• Dapagliflozin
• Empagliflozin
• Canagliflozin

Clinical profile ^[21][22]

• Mechanism of action: reversible inhibition of SGLT-2 in the proximal tubule of the kidney → ↓ glucose reabsorption in the proximal convoluted tubule of the kidney → glycosuria and polyuria
• Indications: especially in young patients with treatment-compliant type 2 DM without significant renal failure
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 0.6% over 3 months
  • Promotes weight loss
  • ↓ Blood pressure
  • ↓ Risk of cardiovascular mortality in patients with type 2 DM and cardiovascular disease
• Important side effects
  • Urinary tract infections, genital infections (vulvovaginal candidiasis, balanitis) due to glucosuria
  • Dehydration → weight loss, orthostatic hypotension
  • Severe diabetic ketoacidosis
  • ↑ Risk of lower limb amputation: Studies suggest a small increase in amputation rates under canagliflozin treatment. ^[23]
  • Studies indicate a carcinogenic effect (breast cancer, bladder cancer)
• Contraindications
  • Chronic kidney disease: If GFR decreases, drug efficacy decreases and adverse effects increase.
  • Recurrent urinary tract infections (e.g., in patients with anatomical or functional anomalies of the urinary tract)

Active agents

• Acarbose
• Miglitol

Clinical profile

• Mechanism of action
  • Inhibit alpha-glucosidase (a brush border enzyme expressed by intestinal epithelial cells) → delayed and ↓ intestinal glucose absorption and ↓ carbohydrate breakdown, resulting in ↓ hyperglycemia after food ingestion
  • Particularly effective in controlling postprandial blood glucose levels
  • The undigested carbohydrates reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas.
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 0.8% over 3 months
  • No risk of hypoglycemia
• Important side effects: gastrointestinal symptoms (flatulence, bloating, abdominal discomfort, diarrhea)
• Contraindications
  • Severe renal failure
  • Inflammatory bowel disease
  • Conditions associated with malabsorption

• One-Minute Telegram 18-2021-3/3: New monoclonal antibody helps to reduce body fat in patients with type 2 diabetes

• One-Minute Telegram 10-2020-2/3: Positive effects of SGLT2 inhibitors in patients with heart failure regardless of diabetes status

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1. ONGLYZA (saxagliptin) tablets, for oral use.
2. BYETTA® (exenatide) Injection.
3. FARXIGA (dapagliflozin) tablets, for oral use.
4. PRECOSE® (acarbose tablets).
5. ACTOS (pioglitazone hydrochloride) tablets for oral use.
6. SYMLIN® (pramlintide acetate) injection for subcutaneous use.
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. Astapova O, Leff T. Adiponectin and PPARγ. Elsevier ; 2012 : p. 143-162
14. Katzung B,Trevor A. Basic and Clinical Pharmacology. McGraw-Hill Education ; 2014
15. 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.
16. Dulaglutide. https://www.drugs.com/ppa/dulaglutide.html. Updated: February 23, 2017. Accessed: February 23, 2017.
17. 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.
18. 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.
19. 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.
20. Highlights of Prescribing Information - Janumet.
21. Empagliflozin. https://www.drugs.com/ppa/empagliflozin.html. Updated: June 23, 2019. Accessed: September 23, 2019.
22. 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
23. 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