Drugs for diabetic mellitus

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"diabetes mellitus" AND "antidiabetic drugs" AND management

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Drugs for Diabetes Mellitus

Antidiabetic drugs are broadly divided into insulin and non-insulin agents (oral + injectable). The choice depends on diabetes type, degree of hyperglycemia, comorbidities (especially CV disease, HF, CKD), and individual patient factors.

1. INSULIN

Insulin is the primary treatment for Type 1 DM and is also used in Type 2 DM when oral agents fail or in hospitalized/critically ill patients.

Insulin Preparations by Duration of Action

Type	Examples	Onset	Peak	Duration
Rapid-acting	Lispro, Aspart, Glulisine	5-15 min	30-90 min	3-5 h
Short-acting (Regular)	Regular insulin	30-45 min	2-4 h	5-8 h
Intermediate-acting	NPH (Isophane)	2-4 h	4-10 h	10-16 h
Long-acting	Glargine, Detemir, Degludec	1-2 h	Peakless	20-24 h

Key points:

Rapid-acting analogues (lispro, aspart, glulisine): Inject 15 min before a meal. Lower postprandial hypoglycemia risk vs. regular insulin. They dissociate into monomers rapidly, enabling fast absorption. - Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 1050
Regular insulin: Must be injected 30-45 min before meals. The only form suitable for IV infusion (100 units/mL). - Goodman & Gilman, p. 1050
NPH insulin: Cloudy suspension with zinc and protamine; usually given once or twice daily with short-acting insulin.
Insulin glargine: Clear solution (pH 4.0), forms a precipitate at subcutaneous neutral pH giving prolonged "peakless" action. Cannot be mixed with other insulins. - Goodman & Gilman, p. 1051
Insulin detemir: Binds albumin at injection site, contributing to its prolonged action.

Hospitalized patients: Insulin is the cornerstone; target glucose 140-180 mg/dL for most, 110-140 mg/dL for some critically ill patients. Sliding-scale-only regimens are less effective than scheduled basal-bolus regimens. - Goodman & Gilman, p. 1053

2. INSULIN SECRETAGOGUES

A. Sulfonylureas (2nd Generation preferred)

Drugs: Glimepiride, Glipizide, Glyburide (glibenclamide)

Mechanism: Block ATP-sensitive K⁺ (KATP) channels on beta-cell membrane → depolarization → Ca²⁺ influx → exocytosis of insulin. - Lippincott Illustrated Reviews: Pharmacology, p. 813

Pharmacokinetics:

Oral, 90-99% protein bound, hepatically metabolized, renally excreted
Duration 12-24 hours (can dose once daily)
Half-life is short (3-5 h) but hypoglycemic effect lasts 12-24 h

Uses: Type 2 DM; 50-80% of patients respond. May fail over time (secondary failure due to progressive beta-cell loss).

Adverse effects: Hypoglycemia (most important), weight gain (1-3 kg)

Contraindications: Type 1 DM, pregnancy, hepatic/renal insufficiency. Glyburide is generally avoided due to higher hypoglycemia risk. Glipizide and glimepiride are safer in renal impairment and elderly. - Lippincott, p. 813

Drug interactions (see diagram below):

Sulfonylurea drug interactions - Lippincott Illustrated Reviews Pharmacology

B. Meglitinides (Non-sulfonylurea secretagogues)

Drugs: Repaglinide, Nateglinide

Mechanism: Also close KATP channels on beta cells, but with rapid onset and shorter duration - classified as postprandial glucose regulators.

PK: Taken just before meals. Metabolized by CYP2C8/3A4 (repaglinide) and CYP2C9/3A4 (nateglinide).

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

Note: Do NOT combine with sulfonylureas (overlapping mechanism, increased hypoglycemia risk). - Lippincott, p. 815

3. BIGUANIDES

Drug: Metformin (first-line for Type 2 DM)

Mechanism: Primarily reduces hepatic gluconeogenesis (decreases hepatic glucose output). Also improves peripheral insulin sensitivity. Does NOT stimulate insulin secretion. - Ganong's Review of Medical Physiology, p. ~2065

Advantages:

No hypoglycemia (does not raise insulin)
Weight neutral or modest weight loss
Cardiovascular benefit (UKPDS data)
Low cost

Adverse effects:

GI side effects (nausea, diarrhea) - take with food
Lactic acidosis (rare but serious)
Vitamin B12 deficiency with long-term use

Contraindications: eGFR <30 mL/min (hold if eGFR 30-45), hepatic disease, severe heart failure, IV contrast procedures (hold temporarily), alcohol abuse. - Goodman & Gilman, p. 1054

4. THIAZOLIDINEDIONES (TZDs / Glitazones)

Drugs: Pioglitazone, Rosiglitazone

Mechanism: Agonist at PPAR-γ (peroxisome proliferator-activated receptor gamma) → enhances insulin sensitivity in liver, adipose tissue, and skeletal muscle. Require endogenous insulin to work. - Goodman & Gilman, p. 1056

Uses: Type 2 DM; reduce A1c by 0.5-1.4%. Effective as monotherapy or in combination with metformin, sulfonylureas, or insulin.

Lipid effects:

Pioglitazone: Reduces triglycerides by 10-15%, raises HDL. PPAR-α partial agonism.
Rosiglitazone: Minimal effect on TG; may raise LDL.

Adverse effects:

Weight gain (2-4 kg in first year) and edema
Fluid retention → risk of heart failure (up to 2-fold increase)
Increased risk of osteoporotic fractures
Macular edema

Contraindications: Symptomatic/moderate-to-severe heart failure, active hepatic disease. - Lippincott, p. 820

5. GLP-1 RECEPTOR AGONISTS (Incretin Mimetics)

Drugs: Semaglutide, Liraglutide, Dulaglutide, Exenatide, Lixisenatide, Albiglutide

Mechanism: Mimic endogenous GLP-1 hormone:

Stimulate glucose-dependent insulin secretion from beta cells
Suppress glucagon secretion (postprandial)
Slow gastric emptying
Reduce food intake (enhance satiety)
Promote beta-cell proliferation

Route: All are injectable (subcutaneous); semaglutide is also available orally (Rybelsus).

Dosing frequency:

Daily: Exenatide (twice daily), Liraglutide, Lixisenatide
Weekly: Semaglutide, Dulaglutide, Exenatide extended release

Advantages:

Weight loss (significant with semaglutide and liraglutide)
No hypoglycemia as monotherapy
Cardiovascular and renal benefits (liraglutide: LEADER trial; semaglutide: SUSTAIN-6) - especially in patients with established ASCVD or high CV risk

Adverse effects: Nausea, vomiting, constipation (most common); risk of pancreatitis; contraindicated in personal/family history of medullary thyroid carcinoma or MEN-2. - Lippincott, p. 820-821

6. DPP-4 INHIBITORS (Gliptins)

Drugs: Sitagliptin, Saxagliptin, Alogliptin, Linagliptin

Mechanism: Inhibit dipeptidyl peptidase-4, the enzyme that degrades endogenous incretins (GLP-1 and GIP) → prolongs their action → glucose-dependent insulin release and reduced glucagon secretion. - Goodman & Gilman, p. 1058

Key features:

Oral, once daily
Weight neutral
Low hypoglycemia risk
Well tolerated

Adverse effects: Nasopharyngitis, possible increased risk of heart failure (saxagliptin - SAVOR-TIMI trial caution), possible pancreatitis (rare).

Renal dosing: Most require dose adjustment in CKD, except linagliptin (excreted mainly via bile/feces).

7. SGLT2 INHIBITORS (Gliflozins)

Drugs: Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin

Mechanism: Inhibit sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule of the kidney → prevents renal glucose reabsorption → increases urinary glucose excretion (glucosuria). Insulin-independent mechanism. - Lippincott, p. 822

Advantages (beyond glucose lowering):

Weight loss (caloric loss via glycosuria)
Blood pressure reduction (osmotic diuresis)
Cardiovascular benefit: Empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS) - reduce CV mortality and HF hospitalization
Renal protection: Delay progression of diabetic kidney disease
Heart failure with reduced EF (HFrEF): Dapagliflozin (DAPA-HF), empagliflozin (EMPEROR-Reduced) - benefit even without diabetes

Adverse effects:

Genital mycotic infections (candidiasis - most common)
Urinary tract infections
Urinary frequency/polyuria
Euglycemic DKA (rare but serious, especially in type 1 off-label use)
Canagliflozin: increased risk of lower limb amputations and bone fractures

Contraindications: eGFR <20-30 mL/min (glucose-lowering effect requires adequate GFR); Type 1 DM (risk of DKA). - Lippincott, p. 822

8. ALPHA-GLUCOSIDASE INHIBITORS

Drugs: Acarbose, Miglitol

Mechanism: Inhibit intestinal alpha-glucosidase enzymes → delay digestion and absorption of complex carbohydrates and sucrose → blunt postprandial glucose rise.

Adverse effects: GI - flatulence, bloating, diarrhea (common, limits use). Do not cause hypoglycemia as monotherapy.

9. OTHER AGENTS

Colesevelam (bile acid sequestrant): Reduces A1c by ~0.5% as adjunct to metformin; also lowers LDL.
Bromocriptine (dopamine agonist): Approved for Type 2 DM; modest A1c reduction.
Pramlintide (amylin analogue): Injectable; used with insulin (both Type 1 and 2); suppresses glucagon, slows gastric emptying, reduces postprandial glucose. - Goodman & Gilman, p. 1060

10. TREATMENT APPROACH SUMMARY

Clinical Situation	Preferred Drug(s)
Type 1 DM	Insulin (mandatory)
Type 2 DM - First line	Metformin
T2DM + Established CVD/high CV risk	Add GLP-1 agonist or SGLT2 inhibitor
T2DM + Heart failure	Add SGLT2 inhibitor (especially dapagliflozin, empagliflozin)
T2DM + CKD	Add SGLT2 inhibitor (renal protection)
T2DM + Obesity	GLP-1 agonist (semaglutide, liraglutide)
Postprandial hyperglycemia	Meglitinides, acarbose, rapid-acting insulin
Hospitalized patients	Insulin (IV or subcutaneous basal-bolus)

Sources:

Goodman & Gilman's The Pharmacological Basis of Therapeutics, 16th Ed., Chapter 51 (Insulin, Sulfonylureas, GLP-1 agonists, TZDs, SGLT2i)
Lippincott Illustrated Reviews: Pharmacology, Chapter 24 (Antidiabetic drugs, pp. 813-824)
Ganong's Review of Medical Physiology, 26th Ed., Chapter 24 (Oral hypoglycemic agents)
Costanzo Physiology, 7th Ed., Chapter 4 (Pathophysiology of insulin)

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