What is the appropriate approach to prescribing drugs for a patient with diabetes, considering factors such as age, weight, kidney (renal) function, and other health conditions like hypertension or hyperlipidemia?

Prescribing Drugs for Diabetes: A Structured Approach

Initial Therapy: Start with Metformin

Metformin is the mandatory first-line agent for all newly diagnosed Type 2 diabetes patients unless contraindications exist, and should be initiated at or soon after diagnosis alongside lifestyle modifications. 1, 2

• Start metformin 500-1000 mg twice daily or extended-release formulation once daily 2
• Metformin is inexpensive, has long-established efficacy and safety, and may reduce cardiovascular events and death 1
• Titrate dose gradually based on tolerance and glycemic response 1

Critical Metformin Contraindications and Monitoring

Metformin is contraindicated when eGFR <30 mL/min/1.73m² and should not be initiated when eGFR is 30-45 mL/min/1.73m². 3

• Obtain eGFR before initiating metformin 3
• Check eGFR at least annually in all patients; more frequently in elderly or those at risk for renal impairment 3
• In patients with eGFR falling below 45 mL/min/1.73m², assess benefit-risk of continuing therapy 3
• Temporarily discontinue metformin before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73m², history of hepatic impairment, alcoholism, or heart failure 3
• Avoid metformin in patients with clinical or laboratory evidence of hepatic disease 3

Adding Second-Line Agents: Prioritize Cardio-Renal Protection

When metformin monotherapy fails to achieve HbA1c targets after 3 months, add a second agent based on the presence of cardiovascular disease, heart failure, or chronic kidney disease—not simply on glucose control alone. 1, 2

For Patients with Established CVD, Heart Failure, or CKD

SGLT2 inhibitors are required additions for patients with established CVD, heart failure, or CKD regardless of HbA1c level, as they reduce cardiovascular events, heart failure hospitalization, and mortality. 2, 4

• Initiate SGLT2 inhibitors when eGFR ≥20 mL/min/1.73m² and continue until dialysis 4
• These agents provide cardiovascular and renal protection independent of glucose-lowering effects 2, 4

GLP-1 receptor agonists are recommended for patients with CVD or very high cardiovascular risk to reduce cardiovascular events and mortality. 2, 4

• Add GLP-1 RA if eGFR >30 mL/min/1.73m² 4
• Titrate slowly due to gastrointestinal side effects (nausea, vomiting, diarrhea) 1
• Not preferred in older adults with unexplained weight loss, undernutrition, or recurrent gastrointestinal problems 1

For Patients Without CVD/CKD: Choose Based on Patient Factors

When adding to metformin in patients without established CVD or CKD, select from: sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists, or basal insulin 1

Key selection factors:

• Hypoglycemia risk: Avoid sulfonylureas in elderly, those with erratic meals, or high hypoglycemia risk 1
• Weight: GLP-1 agonists and SGLT2 inhibitors promote weight loss; sulfonylureas and insulin cause weight gain 1, 5
• Cost: Sulfonylureas and metformin are least expensive 1
• Renal function: DPP-4 inhibitors preferred when eGFR <30 mL/min/1.73m² 1, 4

Special Considerations for Older Adults

Glycemic targets and medication choices must be individualized based on health status, not age alone. 1

Healthy Older Adults (Few Comorbidities, Intact Function)

• Target HbA1c <7.0-7.5% 1
• Blood pressure <130/80 mmHg 1
• Statin therapy unless contraindicated 1

Complex/Intermediate Health (Multiple Comorbidities, Mild-Moderate Cognitive Impairment)

• Target HbA1c <8.0% 1
• Fasting glucose 90-150 mg/dL 1
• Blood pressure <130/80 mmHg 1
• Statin therapy unless contraindicated 1

Very Complex/Poor Health (End-Stage Illness, Moderate-Severe Cognitive Impairment, ADL Dependence)

• Avoid reliance on HbA1c; base decisions on avoiding hypoglycemia and symptomatic hyperglycemia 1
• Fasting glucose 100-180 mg/dL 1
• Blood pressure <140/90 mmHg 1
• Consider likelihood of benefit with statin 1

Medication Simplification in Older Adults

For older adults on complex insulin regimens, simplify by converting to basal insulin only and adding non-insulin agents. 1

• Use 70% of total daily insulin dose as basal insulin in the morning 1
• If prandial insulin >10 units/dose, decrease by 50% and add non-insulin agent 1
• Titrate basal insulin based on fasting glucose over 1 week, adjusting by 2 units 1

Managing Hypertension in Diabetes

ACE inhibitors or ARBs are mandatory first-line therapy for diabetic patients with hypertension, coronary artery disease, or albuminuria. 2, 6

• Target blood pressure <130/80 mmHg for most patients 1, 6
• Less stringent target <140/90 mmHg acceptable in elderly or those with severe coronary disease 6
• Multiple-drug therapy generally required to achieve targets 6
• Monitor serum creatinine/eGFR and potassium at least annually 6

For diabetic nephropathy with proteinuria, titrate ACE inhibitor/ARB to maximum approved doses for dose-dependent renoprotection. 4

Managing Hyperlipidemia in Diabetes

All diabetic patients over age 40 with any cardiovascular risk factors require high-intensity statins as mandatory first-line therapy. 2, 6

• Primary goal: LDL-C <100 mg/dL (2.6 mmol/L) for high-risk patients 2, 6
• Very high-risk or established CVD: LDL-C <70 mg/dL (1.8 mmol/L) 2, 6
• Obtain fasting lipid profile at least annually 6

Critical Pitfalls to Avoid

• Never use chlorpropamide in older adults due to prolonged half-life and increased hypoglycemia risk 1
• Never combine ACE inhibitors with ARBs or direct renin inhibitors 6
• Never ignore renal function monitoring when using metformin, ACE inhibitors, or ARBs—can lead to lactic acidosis or dangerous hyperkalemia 6, 3
• Avoid tight glycemic control (HbA1c <7%) in frail elderly or those with limited life expectancy—overtreatment increases hypoglycemia risk without benefit 1
• Do not delay treatment intensification when targets are not met after 3 months 1