Treatment of Diabetes Mellitus

• Lippincott Illustrated Reviews: Pharmacology
• Goldman-Cecil Medicine, 22e
• Harrison's Principles of Internal Medicine, 22e

Glycemic Targets

• HbA1c target: ≤7% for most non-pregnant adults
• Fasting plasma glucose: <126 mg/dL (diagnostic threshold)
• Hospital - critically ill: 140-180 mg/dL
• Hospital - non-critically ill: 100-180 mg/dL

Type 1 Diabetes Treatment

Insulin Regimens

• Total daily dose: 0.3-1.0 unit/kg/day
• ~50% given as basal insulin; remainder divided as premeal boluses
• Prandial dosing: ~1 unit per 10-15 g carbohydrate + correction factor

Standard vs. Intensive Therapy

• Standard: 2 injections/day
• Intensive: ≥3 injections/day with frequent glucose monitoring (preferred)
• Intensive therapy significantly reduces microvascular complications (retinopathy, nephropathy, neuropathy) but carries higher hypoglycemia risk
• Intensive therapy is not recommended in: long-standing diabetes, significant microvascular disease, advanced age, hypoglycemic unawareness

Adjunct for Type 1: Pramlintide (Amylin Analog)

• Synthetic amylin analog, administered subcutaneously before meals
• Delays gastric emptying, decreases postprandial glucagon, improves satiety
• Reduce mealtime insulin dose by 50% when initiating to avoid severe hypoglycemia
• Contraindicated in gastroparesis or hypoglycemic unawareness

Type 2 Diabetes Treatment

Step 1: Lifestyle Modification (All Patients)

• Medical nutrition therapy
• Physical activity (aerobic + resistance exercise)
• Weight loss (5-7% of body weight reduces progression from prediabetes)
• Smoking cessation

Step 2: First-Line Pharmacotherapy

Metformin (Biguanide) - Preferred First-Line Drug

• Initiated at diagnosis
• Mechanism: Reduces hepatic gluconeogenesis, slows intestinal sugar absorption, improves peripheral insulin sensitivity. Does NOT promote insulin secretion.
• No hypoglycemia risk as monotherapy
• Also useful for prediabetes and PCOS
• Contraindicated: eGFR <30 mL/min/1.73m² (lactic acidosis risk)
• Temporarily hold before IV contrast procedures
• Monitor vitamin B12 with long-term use
• Adverse effects: GI (diarrhea, nausea, vomiting) - titrate slowly with meals

Step 3: Add-On Agents (when metformin is inadequate)

GLP-1 Receptor Agonists (Preferred with CVD/obesity)

• Agents: Semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide
• Semaglutide is available in both injectable and oral form
• Mechanism: Mimic the incretin effect - stimulate glucose-dependent insulin release, suppress glucagon, delay gastric emptying, reduce appetite
• Dulaglutide, liraglutide, and semaglutide have demonstrated cardiovascular benefit (reduced MACE)
• Adverse effects: Nausea, vomiting, risk of pancreatitis, possible thyroid C-cell tumors (contraindicated in personal/family history of medullary thyroid cancer or MEN2)
• 2026 update: GLP-1 RAs are now supported for use in type 1 diabetes for the first time; semaglutide and tirzepatide (GIP/GLP-1 dual agonist) are also leading agents for obesity management

SGLT2 Inhibitors (Preferred with heart failure/CKD)

• Agents: Canagliflozin, dapagliflozin, empagliflozin
• Mechanism: Block SGLT2 in proximal tubule → increase urinary glucose excretion
• Provide cardiovascular and renal protective benefits independent of glucose lowering
• Adverse effects: Urinary tract and genital infections, risk of DKA (not approved in type 1 due to euglycemic DKA risk)
• Avoid in severe renal impairment

DPP-4 Inhibitors

• Agents: Sitagliptin, saxagliptin, alogliptin, linagliptin
• Mechanism: Inhibit DPP-4 (enzyme that breaks down GLP-1) → prolong incretin action → glucose-dependent insulin release
• Well tolerated; once-daily dosing
• Do NOT combine with GLP-1 receptor agonists (overlapping mechanism, increased toxicity)
• Risk of pancreatitis; most require renal dose adjustment (except linagliptin)

Sulfonylureas

• Agents: Glipizide, glimepiride, glyburide (second generation preferred)
• Mechanism: Block ATP-sensitive K+ channels on β cells → depolarization → Ca²+ influx → insulin secretion
• Risk of hypoglycemia and weight gain
• Avoid glyburide in renal impairment

Thiazolidinediones (TZDs)

• Agents: Pioglitazone, rosiglitazone
• Mechanism: PPAR-γ agonists → decrease insulin resistance in muscle, fat, liver
• Effective in highly insulin-resistant patients; no hypoglycemia risk
• Adverse effects: Fluid retention, heart failure, weight gain, fracture risk
• Avoid in liver disease or heart failure; check LFTs before initiation

Meglitinides

• Agents: Repaglinide, nateglinide
• Short-acting insulin secretagogues; taken with meals for postprandial control
• Lower hypoglycemia risk than sulfonylureas

α-Glucosidase Inhibitors

• Agents: Acarbose, miglitol
• Inhibit intestinal breakdown of complex carbohydrates → blunt postprandial glucose spikes
• Mainly GI adverse effects (flatulence, diarrhea)

Other Agents

• Bromocriptine (dopamine agonist) and Colesevelam (bile acid sequestrant): modest A1C reduction, limited by adverse effects and pill burden

Step 4: Insulin in Type 2 Diabetes

• Basal insulin alone (most common starting point)
• Basal-plus (basal + 1 prandial injection)
• Full basal-bolus regimen

Gestational Diabetes

• First-line: lifestyle modification
• If pharmacotherapy needed: insulin is preferred; metformin is an option (stop after 1st trimester if used for PCOS)
• If on metformin: exercise, weight loss, and metformin post-delivery reduce long-term diabetes risk

Comorbidity Management (ADA 2026)

Recent Evidence (2024-2026)

• A 2024 systematic review in Age and Ageing provides updated recommendations specifically for older and frail adults with T2DM (PMID 39572394)
• A 2025 meta-analysis in JAMA Pediatrics confirms efficacy and safety of GLP-1 RAs in children and adolescents with obesity or T2DM (PMID 40952752)
• The ADA Standards 2026 now support GLP-1 RAs in T1DM and mandate AID systems as preferred insulin delivery in T1DM