What interventions reduce all-cause mortality in adults with type 2 diabetes?

Interventions That Reduce All-Cause Mortality in Type 2 Diabetes

Add an SGLT-2 inhibitor or GLP-1 receptor agonist to metformin and lifestyle modifications—both drug classes reduce all-cause mortality with high-certainty evidence, while DPP-4 inhibitors, insulin, and tirzepatide do not. 1

First-Line Therapy: Metformin

• Start metformin as first-line pharmacologic therapy for all patients with type 2 diabetes unless contraindicated, as it reduces all-cause mortality by 36% compared to conventional therapy (P = 0.011) 2
• Metformin maintained a 27% reduction in all-cause mortality on 17-year extended follow-up (7.2 deaths per 1000 patient-years, P = 0.002) 2
• Combine metformin with lifestyle modifications including dietary improvement, weight management, and physical activity 3

Second-Line Therapy: SGLT-2 Inhibitors

When glycemic control remains inadequate on metformin, add an SGLT-2 inhibitor as the preferred second-line agent because it reduces all-cause mortality, major adverse cardiovascular events, chronic kidney disease progression, and heart failure hospitalizations—all with high-certainty evidence. 1, 2

Mortality Benefits

• SGLT-2 inhibitors reduce all-cause mortality compared to usual care (RR 0.86,95% CI 0.80-0.93; high certainty of evidence) 1
• SGLT-2 inhibitors reduce all-cause mortality compared to insulin (RR 0.70,95% CI 0.51-0.98; low to moderate certainty of evidence) 1

Additional Cardiovascular and Renal Benefits

• Reduce major adverse cardiovascular events compared to usual care (RR 0.90,95% CI 0.83-0.98; moderate certainty of evidence) 1
• Reduce heart failure hospitalizations (high certainty of evidence) 1, 2
• Reduce progression of chronic kidney disease (high certainty of evidence) 1, 2
• Reduce severe hypoglycemia compared to sulfonylureas and insulin (low to high certainty of evidence) 1, 2

Specific Agent Considerations

• Empagliflozin is FDA-approved to reduce cardiovascular death in adults with type 2 diabetes and established cardiovascular disease 4
• Prioritize SGLT-2 inhibitors specifically in patients with congestive heart failure, chronic kidney disease, or when cardiovascular mortality reduction is the primary goal 2, 3

Alternative Second-Line Therapy: GLP-1 Receptor Agonists

GLP-1 receptor agonists are an equally effective alternative to SGLT-2 inhibitors for reducing all-cause mortality, with additional benefits for stroke reduction and substantial weight loss. 1, 2

Mortality Benefits

• GLP-1 agonists reduce all-cause mortality compared to usual care (RR 0.88,95% CI 0.83-0.94; high certainty of evidence) 1
• GLP-1 agonists reduce all-cause mortality compared to insulin (RR 0.62,95% CI 0.41-0.93; moderate certainty of evidence) 1
• GLP-1 agonists reduce all-cause mortality compared to DPP-4 inhibitors (RR 0.61,95% CI 0.39-0.95; moderate certainty of evidence) 1

Additional Cardiovascular Benefits

• Reduce major adverse cardiovascular events compared to usual care (RR 0.91,95% CI 0.87-0.96; high certainty of evidence) 1
• Reduce stroke compared to usual care (RR 0.86,95% CI 0.77-0.95; high certainty of evidence) 1
• Reduce severe hypoglycemia compared to sulfonylureas and insulin (low to high certainty of evidence) 1, 2

Specific Agent Considerations

• Semaglutide (Ozempic) is FDA-approved to reduce major cardiovascular events including heart attack, stroke, and death in adults with type 2 diabetes and known heart disease 5
• Prioritize GLP-1 agonists specifically in patients with increased stroke risk or when weight loss is an important treatment goal 2, 3
• High-potency GLP-1 agonists result in weight loss exceeding 5% in most individuals, with some achieving greater than 10% weight loss 6

Choosing Between SGLT-2 Inhibitors and GLP-1 Agonists

Both drug classes reduce all-cause mortality with high-certainty evidence, so select based on comorbidities:

• Choose SGLT-2 inhibitors when the patient has congestive heart failure, chronic kidney disease, or needs heart failure hospitalization reduction 2, 3
• Choose GLP-1 agonists when the patient has increased stroke risk, needs substantial weight loss (>10% body weight), or stroke prevention is the priority 2, 3

Therapies That Do NOT Reduce All-Cause Mortality

DPP-4 Inhibitors

• Do not add DPP-4 inhibitors to metformin—they fail to reduce all-cause mortality or morbidity despite providing glycemic control (RR 1.01,95% CI 0.94-1.08; high certainty of evidence) 1
• The American College of Physicians provides a strong recommendation against using DPP-4 inhibitors for mortality reduction 1

Insulin

• Insulin does not reduce all-cause mortality compared to usual care (RR 1.23,95% CI 0.89-1.70; low certainty of evidence) 1
• Approximately one-third of patients with type 2 diabetes require insulin during their lifetime, but it should be reserved for glycemic control when other agents are insufficient 6

Tirzepatide

• Tirzepatide does not reduce all-cause mortality compared to usual care (RR 0.98,95% CI 0.56-1.73; low certainty of evidence) 1
• Despite being a dual GIP/GLP-1 agonist with superior weight loss effects, mortality data remain insufficient 3

Sulfonylureas

• Sulfonylureas showed only a 6% relative reduction in all-cause mortality that was not statistically significant (P = 0.44) 2
• Sulfonylureas increase severe hypoglycemia risk compared to SGLT-2 inhibitors and GLP-1 agonists 1, 2

Critical Safety Consideration: Preventing Severe Hypoglycemia

When SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins to minimize severe hypoglycemia risk. 2, 3

• Hypoglycemic events occur approximately 30% annually with intensive sulfonylurea or insulin therapy versus 1% with newer agents 2
• SGLT-2 inhibitors and GLP-1 agonists combined with metformin carry minimal hypoglycemia risk, making self-monitoring of blood glucose likely unnecessary 7, 3

Glycemic Targets

• Target HbA1c between 7% and 8% for most adults with type 2 diabetes 2, 7, 3
• Deintensify pharmacologic treatment when HbA1c falls below 6.5% to prevent hypoglycemia and overtreatment 2, 3
• Intensive glycemic control targeting HbA1c below 6.0% increased all-cause mortality in the ACCORD trial among patients with long-standing diabetes and cardiovascular disease 2

Practical Implementation Algorithm

1. Start metformin (unless contraindicated) plus lifestyle modifications 1, 3
2. If glycemic control inadequate after 3-6 months, add:
   • SGLT-2 inhibitor if patient has heart failure, chronic kidney disease, or cardiovascular disease 2, 3
   • GLP-1 agonist if patient has stroke risk, needs weight loss, or lacks heart failure/kidney disease 2, 3
3. When adding SGLT-2 inhibitor or GLP-1 agonist, reduce or stop sulfonylureas and consider reducing insulin 2, 3
4. Reassess every 3-6 months and adjust based on HbA1c, tolerability, and treatment goals 3
5. Never add DPP-4 inhibitors for mortality or morbidity reduction 1

Common Pitfalls to Avoid

• Do not continue sulfonylureas once SGLT-2 inhibitors or GLP-1 agonists achieve glycemic control—they are inferior for mortality outcomes and increase hypoglycemia risk 2, 3
• Do not target HbA1c below 6.5%—this increases mortality risk without additional benefit 2, 3
• Do not assume class effects for all agents—specific SGLT-2 inhibitors (empagliflozin, dapagliflozin) and GLP-1 agonists (liraglutide, semaglutide, dulaglutide) demonstrated mortality benefits in cardiovascular outcomes trials 8
• Do not delay adding SGLT-2 inhibitors or GLP-1 agonists in high-risk patients—early treatment provides cardiovascular and mortality benefits beyond glycemic control 6, 9