What is a potential research proposal topic for investigating combination therapies in type 2 diabetes management?

Research Proposal Topic: Comparative Effectiveness of Triple Therapy Combinations in Type 2 Diabetes

Primary Research Question

Investigate whether triple therapy with metformin + SGLT2 inhibitor + GLP-1 agonist reduces all-cause mortality and major adverse cardiovascular events (MACE) compared to metformin + sulfonylurea + insulin in patients with type 2 diabetes who have failed dual therapy, with specific focus on patients with established cardiovascular disease or chronic kidney disease.

Rationale and Evidence Gaps

Current State of Evidence

• Dual therapy is well-established: All dual-regimen combination therapies reduce HbA1c by approximately 1 additional percentage point compared with monotherapy 1
• Newer agents show mortality benefits: SGLT2 inhibitors (RR 0.86,95% CI 0.80-0.93) and GLP-1 agonists (RR 0.88,95% CI 0.83-0.94) reduce all-cause mortality compared with usual care, while DPP-4 inhibitors, tirzepatide, and insulin do not differ from usual care 1
• Cardiovascular benefits are agent-specific: SGLT2 inhibitors reduce heart failure hospitalization and CKD progression, while GLP-1 agonists reduce stroke compared with usual care 1

Critical Knowledge Gap

• Triple therapy combinations are understudied: Current guidelines recommend stepwise addition of medications 1, but there is insufficient direct comparative evidence on which triple therapy combinations optimize mortality, cardiovascular outcomes, and quality of life 1
• Older combinations may be harmful: Sulfonylureas as add-on therapy to metformin are associated with increased all-cause mortality (HR 1.44,95% CI 1.12-1.84) and major hypoglycemic episodes (HR 2.78,95% CI 1.66-4.66) compared with other oral agents 2
• Conflicting mortality data exists: One study showed combination sulfonylurea-metformin increased cardiovascular mortality (OR 1.73,95% CI 1.17-2.55) 3, while another showed decreased all-cause mortality (RR 0.77,95% CI 0.70-0.85) 4

Proposed Study Design

Population

• Adults with type 2 diabetes inadequately controlled (HbA1c ≥8.0%) on metformin plus one additional agent for ≥3 months 1
• Enriched for high-risk patients: established ASCVD, heart failure, or CKD (eGFR 30-60 mL/min/1.73m²) 1
• Minimum sample size: 2,000 participants per arm based on prior cardiovascular outcome trials 1

Intervention Arms

1. Modern triple therapy: Metformin + SGLT2 inhibitor + GLP-1 agonist
2. Traditional triple therapy: Metformin + sulfonylurea + basal insulin

Primary Outcomes (Prioritizing Mortality and Morbidity)

• Co-primary endpoints:
  • All-cause mortality 1
  • 3-point MACE (cardiovascular death, non-fatal MI, non-fatal stroke) 1
• Minimum follow-up: 52 weeks, ideally 2-3 years 1

Secondary Outcomes

• Heart failure hospitalization 1
• CKD progression (≥40% decline in eGFR or progression to ESRD) 1
• Severe hypoglycemia requiring assistance 2
• Quality of life measures 1
• Body weight change 1, 5
• HbA1c reduction 1

Clinical Significance

Why This Matters Now

• Guidelines prioritize cardiovascular outcomes: For patients with ASCVD, heart failure, or CKD, SGLT2 inhibitors or GLP-1 agonists with demonstrated cardiovascular benefit should be added regardless of HbA1c level 6, 7
• Cost-effectiveness is uncertain: While newer agents are more expensive, their mortality benefits may justify costs if triple therapy proves superior 1
• Real-world practice lags evidence: Many patients still receive sulfonylurea-insulin combinations despite safety concerns 2, 3

Expected Impact

This trial would directly inform whether clinicians should preferentially use modern triple therapy (metformin + SGLT2i + GLP-1 agonist) over traditional combinations in high-risk patients, potentially preventing cardiovascular deaths and hypoglycemic episodes while improving quality of life 1, 2.