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Tuesday, August 19, 2025

Antidiabetic agents


Introduction

Antidiabetic agents are pharmacologic therapies used in the management of diabetes mellitus, a metabolic disorder characterized by chronic hyperglycemia due to defects in insulin secretion, insulin action, or both.

  • Type 1 Diabetes Mellitus (T1DM): Requires exogenous insulin replacement.

  • Type 2 Diabetes Mellitus (T2DM): Managed with oral and injectable agents targeting multiple pathophysiologic defects (insulin resistance, β-cell dysfunction, excessive hepatic glucose output, altered incretin response).

The goal of antidiabetic therapy is to achieve and maintain optimal glycemic control (HbA1c targets), prevent acute complications (hypoglycemia, ketoacidosis), and reduce long-term microvascular and macrovascular complications.

Classification of Antidiabetic Agents

1. Insulins

  • Mechanism: Replaces or supplements endogenous insulin; facilitates glucose uptake in muscle and fat, inhibits hepatic glucose production.

  • Generic Types:

    • Rapid-acting: insulin aspart, lispro, glulisine.

    • Short-acting: regular insulin.

    • Intermediate-acting: NPH insulin.

    • Long-acting: insulin glargine, detemir, degludec.

    • Premixed formulations: biphasic combinations (e.g., aspart + protamine aspart).

  • Uses: All patients with T1DM, many with advanced T2DM, diabetic ketoacidosis, perioperative/critical illness glycemic control.

  • Adverse Effects: Hypoglycemia, weight gain, lipohypertrophy.

2. Biguanides

  • Mechanism: Reduce hepatic gluconeogenesis, increase insulin sensitivity, enhance peripheral glucose uptake.

  • Generic Name: metformin.

  • Uses: First-line therapy for T2DM (unless contraindicated).

  • Adverse Effects: GI upset, lactic acidosis (rare), vitamin B12 deficiency (long-term).

  • Contraindications: Severe renal impairment (eGFR <30 mL/min), advanced heart failure, hepatic insufficiency.

3. Sulfonylureas (Insulin Secretagogues)

  • Mechanism: Stimulate pancreatic β-cells to release insulin by inhibiting KATP channels.

  • Generics: glibenclamide (glyburide), glipizide, gliclazide, glimepiride.

  • Uses: T2DM uncontrolled with metformin.

  • Adverse Effects: Hypoglycemia, weight gain.

  • Contraindications: T1DM, pregnancy, renal/hepatic failure.

4. Meglitinides (Glinides)

  • Mechanism: Short-acting insulin secretagogues, act on β-cell KATP channels.

  • Generics: repaglinide, nateglinide.

  • Uses: Postprandial hyperglycemia control in T2DM.

  • Adverse Effects: Hypoglycemia (less than sulfonylureas), weight gain.

5. Thiazolidinediones (TZDs)

  • Mechanism: PPAR-γ agonists → increase insulin sensitivity in adipose tissue, muscle, and liver.

  • Generics: pioglitazone, rosiglitazone.

  • Uses: T2DM, especially with insulin resistance.

  • Adverse Effects: Fluid retention, weight gain, heart failure exacerbation, increased fracture risk, bladder cancer (pioglitazone – debated).

  • Contraindications: Heart failure (NYHA class III–IV), active liver disease.

6. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

  • Mechanism: Inhibit degradation of incretin hormones (GLP-1, GIP) → enhance insulin release, suppress glucagon.

  • Generics: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin.

  • Uses: T2DM, often combined with metformin.

  • Adverse Effects: Nasopharyngitis, headache, rare pancreatitis, joint pain.

  • Advantages: Weight neutral, low risk of hypoglycemia.

7. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

  • Mechanism: Mimic GLP-1, stimulating glucose-dependent insulin release, delaying gastric emptying, reducing appetite.

  • Generics: exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide.

  • Uses: T2DM, especially in obese patients; liraglutide/semaglutide also approved for weight management.

  • Adverse Effects: GI upset (nausea, vomiting), pancreatitis (rare).

  • Advantages: Weight loss, cardiovascular benefit (liraglutide, semaglutide, dulaglutide).

  • Contraindications: Medullary thyroid carcinoma, multiple endocrine neoplasia type 2 (MEN2).

8. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

  • Mechanism: Inhibit renal glucose reabsorption → glycosuria, reduced plasma glucose.

  • Generics: dapagliflozin, empagliflozin, canagliflozin, ertugliflozin.

  • Uses: T2DM with cardiovascular disease, heart failure, or chronic kidney disease.

  • Adverse Effects: Genital mycotic infections, polyuria, volume depletion, rare euglycemic ketoacidosis, Fournier’s gangrene (rare).

  • Advantages: CV and renal protection, modest weight loss, BP reduction.

9. Alpha-Glucosidase Inhibitors

  • Mechanism: Delay carbohydrate digestion/absorption by inhibiting intestinal brush-border enzymes.

  • Generics: acarbose, miglitol, voglibose.

  • Uses: Postprandial hyperglycemia, adjunct therapy.

  • Adverse Effects: Flatulence, diarrhea, abdominal discomfort.

  • Contraindications: Inflammatory bowel disease, intestinal obstruction.

10. Amylin Analogues

  • Mechanism: Analog of amylin, slows gastric emptying, suppresses glucagon, promotes satiety.

  • Generic: pramlintide.

  • Uses: Adjunct in T1DM and insulin-treated T2DM.

  • Adverse Effects: Hypoglycemia (when combined with insulin), nausea.

11. Bile Acid Sequestrants (Antihyperglycemic Effect)

  • Mechanism: Unknown; possibly decreases hepatic glucose production.

  • Generic: colesevelam.

  • Uses: T2DM (adjunct), dyslipidemia.

  • Adverse Effects: Constipation, bloating, drug-binding interactions.

12. Dopamine-2 Agonists

  • Mechanism: Reset hypothalamic circadian rhythms → improve insulin sensitivity.

  • Generic: bromocriptine (quick-release formulation).

  • Uses: T2DM (rarely used today).

  • Adverse Effects: Nausea, dizziness, hypotension.

Contraindications (Summary by Class)

  • Metformin: Severe renal dysfunction, lactic acidosis risk.

  • Sulfonylureas/Meglitinides: Hypoglycemia risk, caution in elderly.

  • TZDs: Heart failure, active liver disease.

  • DPP-4 inhibitors: Hypersensitivity, pancreatitis (caution).

  • GLP-1 agonists: History of thyroid C-cell tumors, MEN2.

  • SGLT2 inhibitors: Severe renal impairment, recurrent UTIs, ketoacidosis risk.

  • Alpha-glucosidase inhibitors: Chronic GI disease.

  • Insulin: Risk of hypoglycemia (use with monitoring).

Clinical Considerations

  1. First-line therapy: Metformin remains standard in T2DM unless contraindicated.

  2. Dual therapy: If HbA1c remains above goal after 3 months of monotherapy, add another agent. Choice depends on comorbidities:

    • ASCVD: SGLT2 inhibitor or GLP-1 receptor agonist with proven CV benefit.

    • Heart failure or CKD: SGLT2 inhibitor preferred.

    • Obesity: GLP-1 receptor agonist or SGLT2 inhibitor.

    • Cost constraints: Sulfonylurea or TZD.

  3. Insulin initiation: Recommended when HbA1c ≥10%, fasting plasma glucose ≥300 mg/dL, or patient is symptomatic.

  4. Avoid combinations with overlapping mechanisms: e.g., sulfonylurea + meglitinide (both secretagogues).

  5. Fixed-dose combinations (FDCs): Improve adherence but reduce dosing flexibility.



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