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Diabetes Treatment: Drugs, Dosages, Dose Adjustment, and Insulin

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1. Glycemic Targets (ADA / AACE Guidelines)

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2. Non-Insulin Oral / Injectable Agents - Dosages & Mechanisms

A. Biguanides (First-line)

• Mechanism: Reduces hepatic gluconeogenesis, enhances insulin sensitivity, reduces intestinal glucose absorption
• Dosing: Start 500 mg twice daily (or 500 mg once daily if GI-sensitive)
• Range: 500-2500 mg/day in divided doses
• XR formulation: 500 mg once daily, titrate up
• Adverse effects: Nausea, diarrhea, GI upset (take with food), lactic acidosis (rare, 0.03 cases/1000 patients)
• Contraindications: eGFR < 30, hepatic failure, severe heart failure, IV contrast (hold 48 hrs)
• When to adjust: Reduce/hold if eGFR falls below 45; stop if below 30

B. Sulfonylureas (Second-line, insulin secretagogues)

• Adverse effects: Hypoglycemia (especially glyburide), weight gain
• When to adjust: Reduce dose in elderly; caution in renal impairment

C. SGLT-2 Inhibitors (Cardio- and renoprotective)

• Mechanism: Increase urinary glucose excretion
• Benefits: Proven CV and kidney protection (use preferentially in patients with CVD, HF, or CKD)
• Adverse effects: Genital/urinary infections, polyuria, DKA (rare), hypotension
• Dose adjustment: Hold if eGFR < 45 (canagliflozin/dapagliflozin); empagliflozin < 20

D. GLP-1 Receptor Agonists (Injectable, weight-lowering)

• Mechanism: Stimulate glucose-dependent insulin secretion, suppress glucagon, promote satiety, slow gastric emptying
• Benefits: Weight loss, CV benefit (semaglutide, liraglutide), low hypoglycemia risk
• Adverse effects: Nausea, vomiting, headache, rare pancreatitis

E. DPP-4 Inhibitors ("Gliptins" - weight neutral)

• Mechanism: Inhibit DPP-4 enzyme, prolonging action of endogenous GLP-1
• Low hypoglycemia risk; weight neutral
• Saxagliptin: Avoid in HF (increases hospitalizations)

F. Alpha-Glucosidase Inhibitors

• Acarbose / Voglibose: 25-100 mg 3x/day with first bite of each meal
• Reduce postprandial glucose by delaying carbohydrate absorption
• Adverse effects: Flatulence, bloating (tolerated better if started low, titrated slowly)
• Contraindicated in IBD, bowel obstruction, severe renal/hepatic disease
• Note: Acarbose 300 mg/day has similar efficacy to metformin 1500 mg/day in newly diagnosed DM

G. Thiazolidinediones (TZDs)

• Pioglitazone: 15-30 mg once daily (max 45 mg)
• Improve insulin sensitivity (PPAR-gamma agonist)
• Adverse effects: Weight gain, fluid retention, edema, fractures; avoid in HF

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3. When to Adjust Doses

• Deteriorating glycemic control (HbA1c rising above target despite adherence and lifestyle measures): Step up therapy
• Renal impairment: Metformin hold/reduce at eGFR < 45-30; SGLT-2 inhibitors lose efficacy below eGFR 45; DPP-4 inhibitors need renal dose adjustments (except linagliptin)
• Hypoglycemia: Reduce sulfonylurea or insulin dose
• Weight gain: Reconsider sulfonylureas/TZDs; switch to SGLT-2 or GLP-1 agonist
• Cardiovascular disease or HF: Preferentially add SGLT-2 inhibitor or GLP-1 agonist to metformin
• HbA1c measured quarterly if not at target; twice yearly if stable

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4. When to Switch to / Initiate Insulin

1. HbA1c > 9.0% - initiate insulin directly, especially with symptomatic hyperglycemia (polyuria, polydipsia, weight loss)
2. HbA1c > 8.5% with symptoms - do not delay insulin
3. Oral agents have failed to reach HbA1c target after adequate trial (typically 3 months at max tolerated dose)
4. Newly diagnosed Type 2 DM with HbA1c ≥ 9% and symptomatic: short-term intensive insulin (2 weeks - 3 months) can reset beta cell function
5. Hospitalization / acute illness - all oral agents should be stopped; insulin is preferred inpatient
6. Corticosteroid use - steroids significantly raise glucose; insulin required
7. Surgery / NPO status
8. Pregnancy - metformin/glyburide may be used in select cases but insulin is standard
9. Progressive beta cell failure - most T2DM patients will eventually need insulin over time

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5. Insulin Types, Onset, Peak, Duration

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6. Insulin Dosing - How to Start and Titrate

Starting Basal Insulin (Most Common First Step)

• If fasting glucose < 80 mg/dL: Reduce dose by 3 units
• If fasting glucose 80-110: No change
• If fasting glucose > 110: Increase by 3 units

Intensifying to Basal-Plus or Basal-Bolus

• Start with 4 units or 10% of basal dose before the largest meal
• Titrate up by 1-2 units based on 2-hr postprandial glucose (target < 180 mg/dL)

• Total daily dose (TDD): 0.3-0.5 units/kg/day for T2DM (can be higher due to insulin resistance)
• Split: 50% as basal, 50% divided equally before 3 meals
• Titrate each prandial dose based on corresponding postprandial glucose

Type 1 Diabetes Starting Dose

• Total daily dose: 0.4-1.0 units/kg/day
• Basal: 50% of TDD as long-acting (glargine or detemir)
• Bolus: 50% divided as rapid-acting before meals
• Adjust per carbohydrate counting and correction factor

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7. Stepwise Treatment Algorithm (T2DM)

Step 1: Lifestyle modification (diet, exercise, weight loss)
   ↓ Not at target in 3 months
Step 2: Metformin (+ SGLT-2 or GLP-1 if CVD/CKD present)
   ↓ Not at target in 3 months
Step 3: Add second agent based on patient profile:
   - CVD/HF/CKD → SGLT-2 inhibitor (empagliflozin/dapagliflozin)
   - Obesity → GLP-1 agonist (semaglutide/liraglutide)
   - Hypoglycemia concern → DPP-4 inhibitor or GLP-1 agonist
   - Cost limitation → Sulfonylurea
   ↓ Not at target
Step 4: Add third agent or basal insulin
   ↓ HbA1c > 8.5-9.0% or symptoms
Step 5: Initiate INSULIN (basal first → basal-plus → basal-bolus)

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Key Clinical Notes

• Metformin should be continued alongside insulin unless contraindicated - it reduces insulin requirements and prevents weight gain
• Sulfonylureas may be continued with basal insulin but carry increased hypoglycemia risk
• GLP-1 agonists are very effective in combination with basal insulin (less weight gain, less hypoglycemia)
• SGLT-2 inhibitors can be added to insulin in T2DM for CV/renal protection but require caution for DKA risk
• In hospital settings: All non-insulin oral agents should be held; sliding scale or insulin infusion protocols are used
• HbA1c should be rechecked every 3 months until stable, then every 6 months