Research Proposal Topics in Type 2 Diabetes Treatment
High-Priority Research Gaps Based on Current Guidelines
1. Comparative Effectiveness of GLP-1 RA vs SGLT2i in Patients with Cardiovascular Risk Factors Only
The most critical research need is determining which cardioprotective agent—GLP-1 receptor agonists or SGLT2 inhibitors—provides superior outcomes in patients with type 2 diabetes who have cardiovascular risk factors but no established cardiovascular disease, heart failure, or chronic kidney disease. 1
- Current guidelines show considerable uncertainty about the absolute benefits of these agents in patients with risk factors only, leading to variability in recommendations on how to define "high-risk" patients 1
- Network meta-analysis demonstrates that both SGLT2 inhibitors and GLP-1 agonists reduce all-cause mortality and major adverse cardiovascular events compared with usual care, but direct head-to-head comparisons are infrequent 1
- This gap is particularly important because all patients with diabetes are at high risk of cardiovascular disease, heart failure, and chronic kidney disease over time, yet we lack data on when to initiate these disease-modifying agents 1
Proposed study design:
- Randomized controlled trial comparing GLP-1 RA vs SGLT2i vs combination therapy in patients with T2DM and ≥2 cardiovascular risk factors (hypertension, dyslipidemia, smoking, family history) but no established ASCVD, HF, or CKD
- Primary outcomes: composite cardiovascular events, all-cause mortality, progression to heart failure or CKD
- Duration: minimum 3-5 years to capture meaningful cardiovascular outcomes
- Sample size: ≥5,000 participants to ensure adequate power 1
2. Optimal Timing and Sequencing of Dual GLP-1/SGLT2i Combination Therapy
Research is urgently needed to validate when to initiate combination GLP-1 RA plus SGLT2i therapy—whether at diagnosis in high-risk patients or after failure of monotherapy—and to determine the cost-effectiveness of this approach. 1
- Guidelines suggest combination therapy for high-risk patients not meeting glycemic targets, but evidence supporting this recommendation is limited 1
- Cost-effectiveness analyses show GLP-1 agonists and SGLT2 inhibitors may be of intermediate value when added to metformin or background therapy compared with adding nothing, but are low value as first-line monotherapy 1
- Real-world evidence and cost-effectiveness studies in broad populations would help target interventions to have the greatest impact on outcomes 1
Proposed study design:
- Pragmatic randomized trial comparing three strategies: (1) early combination GLP-1 RA + SGLT2i at diagnosis, (2) sequential addition after metformin failure, (3) standard care with intensification based on HbA1c
- Include cost-effectiveness analysis with quality-adjusted life-years as outcome 1
- Stratify by baseline cardiovascular risk, BMI, and kidney function
- Duration: 3 years minimum
3. Mechanisms and Clinical Significance of Tirzepatide's Superior Efficacy
Investigation into why dual GIP/GLP-1 receptor agonist tirzepatide demonstrates substantially greater glucose control and weight loss compared with selective GLP-1 receptor agonists, and whether this translates to superior cardiovascular and renal outcomes. 2, 3, 4, 5
- Tirzepatide improves markers of insulin sensitivity and beta-cell function to a greater extent than dulaglutide, with insulin sensitivity effects only partly attributable to weight loss (13-21% explained by weight loss), suggesting dual receptor agonism confers distinct mechanisms 4
- Network meta-analysis did not find sufficient data on tirzepatide for most outcomes, indicating a critical evidence gap 1
- Preliminary results show similar if not improved glycemic control and weight loss with triple agonism (GLP-1/GIP/glucagon), but gastrointestinal adverse events are not mitigated compared to traditional GLP-1 RAs 2
Proposed study design:
- Cardiovascular outcomes trial comparing tirzepatide vs semaglutide vs empagliflozin in patients with T2DM and established cardiovascular disease
- Mechanistic substudy examining beta-cell function (HOMA2-B, proinsulin/insulin ratios), insulin resistance (HOMA2-IR, adiponectin, IGFBP-1/2), and body composition changes 4
- Primary outcome: 3-point MACE (cardiovascular death, non-fatal MI, non-fatal stroke)
- Secondary outcomes: heart failure hospitalization, CKD progression, weight loss
- Duration: minimum 2 years for cardiovascular outcomes 6
4. Optimal Management Strategies for Type 2 Diabetes in Advanced CKD (eGFR <30 mL/min/1.73 m²)
There are virtually no data to inform best practice in the care of patients with diabetes and advanced chronic kidney disease, particularly in dialysis-dependent kidney disease, representing a population with enormous health disparities and mortality. 1, 7
- Current guidelines recommend GLP-1 RAs for patients with advanced CKD (eGFR <30 mL/min/1.73 m²) due to lower hypoglycemia risk, but evidence is limited 7
- SGLT2 inhibitors have demonstrated reduction in CKD progression and heart failure hospitalization, but data in advanced CKD are sparse 1
- Additional studies of GLP-1 RA, dual GIP/GLP-1 RA, and SGLT2i will hopefully provide new avenues to reduce mortality in this population 1
Proposed study design:
- Randomized controlled trial in patients with T2DM and eGFR 15-29 mL/min/1.73 m² or on dialysis
- Compare GLP-1 RA vs SGLT2i (if eGFR permits) vs standard care
- Primary outcomes: all-cause mortality, cardiovascular events, progression to dialysis (in non-dialysis patients)
- Safety outcomes: hypoglycemia rates, adverse events, quality of life measures
- Duration: 2-3 years
5. Glucose-Centric vs Weight-Centric Treatment Approaches and Impact on Diabetes Remission
Studies explicitly examining glucose-centric versus weight-centric approaches to diabetes management are needed, including the impact of prioritizing early aggressive therapy to induce remission. 1
- Current guidelines emphasize weight management with more effective behavioral and medical therapies, but direct comparisons to guide treatment selection based on impact and cost-effectiveness are lacking 1
- The absolute benefits of prioritizing remission through intensive weight loss interventions versus traditional glycemic control strategies remain unclear 1
- Questions remain about whether targets should be driven by the safety of measures used to achieve them, and whether treatment should be maintained once patients achieve or exceed glycemic targets 1
Proposed study design:
- Randomized trial comparing three strategies: (1) weight-centric approach (intensive lifestyle + high-dose GLP-1 RA targeting ≥15% weight loss), (2) glucose-centric approach (traditional HbA1c-driven escalation), (3) combined approach
- Primary outcomes: diabetes remission rates (HbA1c <6.5% off medications for ≥3 months), cardiovascular events, quality of life
- Secondary outcomes: medication burden, cost-effectiveness, durability of remission
- Duration: 3 years with extended follow-up to 5 years
6. Optimal Implementation of Continuous Glucose Monitoring in Type 2 Diabetes
Further studies to understand the role and optimal implementation of continuous glucose monitoring (CGM) and episodic CGM in type 2 diabetes are needed, particularly in patients not on insulin therapy. 1
- Current evidence for CGM use in type 2 diabetes is limited compared to type 1 diabetes 1
- Questions remain about which patient populations benefit most, optimal frequency of use, and integration with treatment intensification decisions
- Cost-effectiveness of CGM in various type 2 diabetes populations requires investigation
Proposed study design:
- Pragmatic randomized trial in patients with T2DM not on insulin with HbA1c 7.5-10%
- Compare continuous CGM vs intermittent CGM vs standard self-monitoring blood glucose
- Stratify by medication regimen (metformin only, oral combinations, GLP-1 RA, etc.)
- Primary outcomes: HbA1c reduction, time in range, hypoglycemia rates, treatment satisfaction
- Include cost-effectiveness analysis
- Duration: 12 months
7. Sex, Race, and Ethnicity Differences in Response to Newer Diabetes Medications
Inadequate studies exist regarding appropriate targets and interventions across sex, race, and ethnicity, with current studies failing to be representative and suffering from health inequities. 1
- Better recruitment, retention, and analysis to ensure safety and effectiveness in populations historically under-represented in studies is a minimal first step to enhance health justice 1
- Sex balance is a dimension where present studies fail to be representative 1
- Differential responses to GLP-1 RAs, SGLT2i, and dual agonists by demographic subgroups remain poorly characterized 1
Proposed study design:
- Post-hoc analysis of existing cardiovascular outcomes trials with adequate representation, or prospective cohort study
- Examine differential effects of GLP-1 RA, SGLT2i, and tirzepatide on glycemic control, weight loss, cardiovascular outcomes, and adverse events by sex, race, and ethnicity
- Ensure adequate sample sizes in each subgroup (minimum 500 participants per subgroup) 1
- Explore potential mechanisms for differential responses (pharmacokinetics, body composition, genetic factors)
Common Pitfalls to Avoid in Study Design
- Insufficient duration: Cardiovascular and renal outcomes require minimum 2-3 years of follow-up; studies with 52 weeks may miss important long-term effects 1
- Inadequate sample size: Enrollment of at least 500 participants is necessary for meaningful safety and efficacy assessment 1
- Lack of direct comparisons: Network meta-analyses are limited by infrequent direct comparisons between drugs of interest and possible incoherence due to differences in baseline patient characteristics 1
- Insufficient subgroup data: Predefined analyses by demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons are essential 1
- Industry sponsorship bias: Non-industry-sponsored studies are critical for unbiased assessment, particularly for cost-effectiveness analyses 1