What medication reduces mortality in a patient with type 2 diabetes mellitus (T2DM)?

Medications That Reduce Mortality in Type 2 Diabetes

Metformin is the first-line medication that reduces all-cause mortality in type 2 diabetes, followed by SGLT-2 inhibitors or GLP-1 receptor agonists as second-line agents, both of which have high-certainty evidence for mortality reduction. 1

First-Line Therapy: Metformin

• Metformin should be initiated at diagnosis of type 2 diabetes unless contraindicated, as it reduces all-cause mortality by 36% compared to conventional therapy (P = 0.011). 1, 2
• On extended 17-year follow-up, metformin maintained a 27% reduction in all-cause mortality (7.2 deaths per 1000 patient-years, P = 0.002). 1
• Metformin is recommended as first-line therapy by the American Diabetes Association, American College of Physicians, and European guidelines due to its proven survival benefit, effectiveness in lowering HbA1c by approximately 1-1.5 percentage points, weight-neutral or weight-loss promoting effect, low hypoglycemia risk, and low cost. 3, 4
• Observational data show patients on metformin had longer survival than matched non-diabetic controls, and lower mortality compared to sulfonylureas. 1, 4

Metformin Contraindications and Safety

• Metformin is contraindicated in patients with eGFR <30 mL/min/1.73 m², but can be safely used with eGFR ≥30 mL/min/1.73 m². 3
• Discontinue metformin in acute conditions associated with lactic acidosis risk, such as cardiogenic or distributive shock. 3
• Monitor for vitamin B12 deficiency with long-term use, as metformin is associated with deficiency and potential worsening of neuropathy symptoms. 3

Second-Line Therapy: SGLT-2 Inhibitors (Preferred)

• SGLT-2 inhibitors reduce all-cause mortality with high-certainty evidence and should be added to metformin as second-line therapy, particularly in patients with established cardiovascular disease, heart failure, or chronic kidney disease. 1, 5
• The American College of Physicians provides a strong recommendation with high-certainty evidence that SGLT-2 inhibitors reduce all-cause mortality compared to usual care. 1
• SGLT-2 inhibitors also reduce major adverse cardiovascular events (moderate to high certainty), progression of chronic kidney disease (high certainty), and heart failure hospitalizations (high certainty). 1
• Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease, established kidney disease, or heart failure, an SGLT-2 inhibitor with demonstrated cardiovascular benefit is recommended as part of the glucose-lowering regimen independent of A1C. 3

Specific SGLT-2 Inhibitor Considerations

• Empagliflozin can be initiated in patients with eGFR ≥20 mL/min/1.73 m². 5
• Canagliflozin carries an increased risk of lower-limb amputation (HR 1.97,95% CI 1.41-2.75), so monitor patients for infection or ulcers of the lower limb and discontinue if these occur. 1
• Monitor renal function (eGFR) at least annually, with increased frequency to every 3-6 months if eGFR falls below 60 mL/min/1.73 m². 5

Alternative Second-Line Therapy: GLP-1 Receptor Agonists

• GLP-1 receptor agonists reduce all-cause mortality with high-certainty evidence and are the preferred alternative to SGLT-2 inhibitors, particularly in patients with increased stroke risk or when weight loss is an important treatment goal. 1
• GLP-1 receptor agonists reduce all-cause mortality compared to usual care (high certainty) and compared to DPP-4 inhibitors (moderate certainty). 1
• For patients with established atherosclerotic cardiovascular disease where major adverse cardiovascular events are the gravest threat, the level of evidence for benefit is greatest for GLP-1 receptor agonists. 3
• GLP-1 receptor agonists also reduce major adverse cardiovascular events (moderate to high certainty) and stroke (high certainty). 1
• GLP-1 receptor agonists are preferred over insulin when greater glucose lowering is needed beyond oral agents. 3

Medications That Do NOT Reduce Mortality

DPP-4 Inhibitors

• The American College of Physicians strongly recommends against adding DPP-4 inhibitors to metformin, as they do not reduce morbidity or all-cause mortality despite providing glycemic control (low to high certainty of evidence). 1, 5

Insulin

• Insulin does not reduce all-cause mortality compared to usual care (low to high certainty of evidence). 1
• Intensive glycemic control with insulin showed no reduction in all-cause mortality in the VADT trial (HR 1.05,95% CI 0.89-1.25). 1

Sulfonylureas

• Sulfonylureas do not reduce all-cause mortality, with the UKPDS 33 trial showing only a 6% relative reduction that was not statistically significant (P = 0.44). 1
• Early addition of metformin to sulfonylureas resulted in an increased risk for diabetes-related death (P = 0.039) compared with continued treatment with sulfonylureas alone. 1

Critical Safety Considerations

• When SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, reduce or discontinue sulfonylureas or long-acting insulins to minimize severe hypoglycemia risk. 1
• Hypoglycemic events were much more common with intensive therapy using sulfonylureas or insulin (approximately 30% vs. 1% annually in UKPDS trials). 1
• The VADT trial showed a 3-fold higher rate of hypoglycemic episodes with impaired consciousness in the intensive therapy group (9 vs. 3 episodes per 100 patient-years). 1

Glycemic Targets

• Target HbA1c between 7% and 8% for most adults with type 2 diabetes, and deintensify pharmacologic treatments when HbA1c falls below 6.5% to avoid hypoglycemia and overtreatment. 1, 5
• The ACCORD trial was stopped early due to increased all-cause mortality when targeting HbA1c below 6.0% in patients with long-standing diabetes and cardiovascular disease. 1
• Intensification of treatment should not be delayed for patients not meeting treatment goals, with reevaluation every 3-6 months. 3

Treatment Algorithm

1. Start metformin at diagnosis unless contraindicated (eGFR <30 mL/min/1.73 m² or acute conditions risking lactic acidosis). 3

2. Add SGLT-2 inhibitor as second-line therapy if patient has established cardiovascular disease, heart failure, chronic kidney disease, or when mortality reduction is the primary goal. 3, 1

3. Consider GLP-1 receptor agonist instead of SGLT-2 inhibitor if patient has increased stroke risk or weight loss is a priority treatment goal. 3, 1

4. Evaluate response after 3 months and adjust therapy accordingly, avoiding DPP-4 inhibitors and minimizing use of sulfonylureas or insulin unless necessary for glycemic control. 1, 5

5. Reduce or discontinue sulfonylureas/insulin when SGLT-2 inhibitors or GLP-1 agonists achieve adequate control to prevent severe hypoglycemia. 1