What interventions improve all-cause mortality reduction in patients with diabetes or cardiovascular disease?

All-Cause Mortality Reducing Interventions in Diabetes and Cardiovascular Disease

Start metformin as first-line therapy, then add an SGLT-2 inhibitor as second-line therapy to maximize all-cause mortality reduction in patients with diabetes or cardiovascular disease. 1, 2

First-Line Therapy: Metformin

Metformin is mandatory 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. 2, 3

• The UKPDS 34 trial demonstrated metformin's 36% relative risk reduction in all-cause mortality (9% to 55%, P = 0.011) compared to conventional dietary therapy alone 2, 3
• 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) 2
• Metformin reduces all-cause mortality even in patients with chronic kidney disease stage 3, with a hazard ratio of 0.49 (95% CI 0.36-0.69) 4
• A 2015 Chinese cohort study showed metformin monotherapy reduced all-cause mortality by 29.5% and cardiovascular events by 30-35% compared to lifestyle modifications alone 5

Critical safety point: Metformin carries minimal hypoglycemia risk when used as monotherapy and does not cause weight gain. 3, 6

• Lactic acidosis risk is extremely low at less than one case per 100,000 treated patients 3
• Monitor vitamin B12 levels with long-term use, as deficiency can cause macrocytic anemia or peripheral neuropathy 6
• Assess renal function before initiation and periodically thereafter, especially in situations where kidney failure risk increases 6

Second-Line Therapy: SGLT-2 Inhibitors

Add an SGLT-2 inhibitor to metformin when glycemic control remains inadequate, as SGLT-2 inhibitors reduce all-cause mortality with high-certainty evidence. 1, 2

• 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 2
• 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, 2
• Prioritize SGLT-2 inhibitors specifically in patients with congestive heart failure, chronic kidney disease, or when cardiovascular mortality reduction is the primary goal 1, 2, 7

Specific SGLT-2 Inhibitor Agents

Empagliflozin (Jardiance):

• FDA-approved to reduce cardiovascular death in adults with type 2 diabetes and established cardiovascular disease 8
• Recommended starting dose is 10 mg once daily, which can be increased to 25 mg if additional glycemic control is needed 8
• Do not initiate if eGFR is less than 45 mL/min/1.73 m² and discontinue if eGFR persistently falls below this threshold 8

Canagliflozin (Invokana):

• FDA-approved to reduce major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 9
• FDA-approved to reduce end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with diabetic nephropathy with albuminuria 9
• Recommended starting dose is 100 mg once daily before the first meal, which can be increased to 300 mg in patients with eGFR ≥60 mL/min/1.73 m² who need additional glycemic control 9
• Important safety warning: 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, 9

Alternative Second-Line Therapy: GLP-1 Receptor Agonists

GLP-1 agonists are an alternative second-line option that also reduce all-cause mortality with high-certainty evidence. 1, 2

• GLP-1 agonists reduce all-cause mortality compared to usual care (high certainty) and compared to DPP-4 inhibitors (moderate certainty) 2
• Prioritize GLP-1 agonists specifically in patients with increased stroke risk or when weight loss is an important treatment goal 1, 2, 7
• GLP-1 agonists reduce major adverse cardiovascular events (moderate to high certainty) and stroke (high certainty) 1, 2

Choosing Between SGLT-2 Inhibitors and GLP-1 Agonists

Use this algorithm to decide:

1. If the patient has congestive heart failure or chronic kidney disease → Choose SGLT-2 inhibitor 1, 7
2. If the patient has increased stroke risk or needs weight loss → Choose GLP-1 agonist 1, 7
3. If both conditions exist → SGLT-2 inhibitor takes priority for mortality reduction 1, 2

Therapies That Do NOT Reduce All-Cause Mortality

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. 1, 2, 7

• DPP-4 inhibitors showed no reduction in all-cause mortality compared to usual care with low to high certainty of evidence 2
• This is a strong recommendation based on high-certainty evidence 1

Insulin does not reduce all-cause mortality compared to usual care (low to high certainty of evidence). 2

Sulfonylureas do not reduce all-cause mortality:

• The UKPDS 33 trial of intensive therapy with sulfonylureas or insulin showed only a 6% relative reduction in all-cause mortality that was not statistically significant (P = 0.44) 2
• The VADT trial showed no reduction in all-cause mortality with intensive glycemic control using sulfonylureas or insulin (HR 1.05,95% CI 0.89-1.25) 1, 2

Critical Safety Consideration: Preventing Severe Hypoglycemia

When SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, reduce or discontinue sulfonylureas or long-acting insulins immediately to minimize severe hypoglycemia risk. 1, 2, 7

• Hypoglycemic events were approximately 30% annually with intensive sulfonylurea/insulin therapy versus 1% with conventional therapy in UKPDS trials 2
• 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) 2
• Critical warning: Early addition of metformin to sulfonylureas resulted in an increased risk for diabetes-related death (P = 0.039) compared with continued sulfonylurea monotherapy 2

Glycemic Targets

Target HbA1c between 7% and 8% for most adults with type 2 diabetes. 1, 7, 10

• Deintensify pharmacologic treatments when HbA1c falls below 6.5% to avoid hypoglycemia and overtreatment 1, 7
• The ACCORD trial was stopped early due to increased all-cause mortality (1.41% vs. 1.14% per year; HR 1.22,95% CI 1.01-1.46) when targeting HbA1c below 6.0% in patients with long-standing diabetes and cardiovascular disease 1
• Intensive glycemic control targeting near-normal glucose levels does not reduce short-term cardiovascular events or stroke in patients with established type 2 diabetes 1

Monitoring Simplification

Self-monitoring of blood glucose is unnecessary in patients receiving metformin combined with either an SGLT-2 inhibitor or GLP-1 agonist, as these combinations carry minimal hypoglycemia risk. 1, 7

Common Pitfalls to Avoid

Do not continue sulfonylureas or insulin at full doses after adding SGLT-2 inhibitors or GLP-1 agonists - this creates severe hypoglycemia risk without mortality benefit 1, 2

Do not target HbA1c below 6.5% in patients with long-standing diabetes or established cardiovascular disease - this increases mortality risk without cardiovascular benefit 1

Do not use DPP-4 inhibitors as second-line therapy - they provide no mortality or morbidity benefit despite adequate glycemic control 1, 2

Do not withhold metformin in patients with stage 3 chronic kidney disease - evidence shows mortality benefit persists with acceptable safety in this population 4