Glycemic Efficacy and Metabolic Outcomes of Dual GLP-1/GIP Receptor Agonist Therapy in Adults with Inadequately Controlled Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

Glycemic Efficacy and Metabolic Outcomes of Dual GLP-1/GIP Receptor Agonist Therapy in Adults with Inadequately Controlled Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

Marcus J. Whitfield, MD, PhD

Sarah K. Nomura, PharmD

Diego A. Reyes-Lorca, MD

Priya S. Krishnamurthy, PhD

Thomas O. Brennan, MD

Department of Endocrinology, Diabetes, and Metabolism

Hargrove University Medical Center, Boston, Massachusetts

Corresponding Author: Marcus J. Whitfield, MD, PhD | m.whitfield@humc.edu

75 Francis Street, Boston, MA 02115 | Tel: +1 (617) 555-0142

Word count: 2,487 | Tables: 2 | Figures: 2 | ClinicalTrials.gov: NCT04987654

Funding: National Institutes of Health (R01 DK112345); Hargrove Foundation

Abstract

Background123: Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonism represents a mechanistically promising approach to improving glycemic control in type 2 diabetes mellitus (T2DM). Prior evidence suggests synergistic incretin effects; however, head-to-head dose-comparison data against placebo are limited in real-world populations.

Objective: To evaluate the glycemic efficacy, metabolic safety, and patient-reported outcomes of low-dose versus high-dose dual GLP-1/GIP receptor agonist (DGRA-7) compared with placebo over 24 weeks in adults with inadequately controlled T2DM.

Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 110 adults aged 35-70 with HbA1c 7.5-10.5% were allocated (1:1:1) to subcutaneous DGRA-7 low dose (2 mg/week), high dose (4 mg/week), or matching placebo for 24 weeks. The primary endpoint was change in HbA1c from baseline.

Results: Both active treatment groups achieved statistically significant reductions in HbA1c versus placebo (low dose: -1.42%; high dose: -1.87%; placebo: -0.38%; p<0.001 for both). High-dose additionally showed superior reductions in body weight (-3.2 kg), systolic blood pressure (-5.1 mmHg), and HOMA-IR.

Conclusions: DGRA-7 at both doses produced clinically meaningful HbA1c reductions with an acceptable safety profile. High-dose therapy conferred additional cardiometabolic benefits, supporting the therapeutic potential of dual incretin receptor agonism in T2DM management.

1. Introduction

Type 2 diabetes mellitus (T2DM) remains one of the most prevalent and morbid metabolic disorders globally, affecting more than 537 million adults as of 2023, with projections exceeding 783 million by 2045 (International Diabetes Federation, 2023). Despite the availability of numerous pharmacological agents, a substantial proportion of patients fail to achieve recommended glycemic targets, exposing them to heightened risks of microvascular and macrovascular complications.

The incretin system, comprising glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), plays a pivotal role in postprandial glucose homeostasis. GLP-1 receptor agonists have become a cornerstone of T2DM pharmacotherapy due to their robust HbA1c-lowering effects, weight-reducing properties, and favorable cardiovascular profiles. Recent preclinical and early clinical evidence suggests that dual GLP-1/GIP receptor co-agonism may yield synergistic glycemic and metabolic benefits exceeding those attainable with GLP-1 receptor activation alone.

The development of tirzepatide provided early proof-of-concept for this approach. Its pivotal SURPASS program demonstrated superior HbA1c reductions and weight loss compared with established GLP-1 receptor agonists. DGRA-7, an investigational once-weekly subcutaneous dual GLP-1/GIP receptor agonist with a distinct molecular scaffold, was designed to optimize receptor binding affinity and pharmacokinetic durability. We hypothesized that both doses would produce statistically and clinically significant HbA1c reductions versus placebo, with the high dose demonstrating superior cardiometabolic effects.

2. Methods

2.1 Study Design and Participants

This was a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2b clinical trial conducted at six academic medical centers in the United States between March 2022 and November 2023. The trial was conducted in accordance with the principles of the Declaration of Helsinki and received institutional review board approval from all participating sites (Protocol No. HU-IRB-22-0341). Eligible participants were adults aged 35 to 70 years with T2DM, HbA1c between 7.5% and 10.5%, and BMI between 22 and 42 kg/m2, on stable background oral antidiabetic therapy for at least three months.

2.2 Randomization and Treatment

Participants were randomized 1:1:1 to DGRA-7 low dose (2 mg/week), high dose (4 mg/week), or matching placebo via centralized web-based system with permuted blocks of six, stratified by baseline HbA1c and background metformin use. All participants, investigators, and the sponsor team were blinded to treatment assignment throughout the study.

2.3 Outcomes and Assessments

The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints included fasting plasma glucose, body weight, systolic blood pressure, HOMA-IR, and health-related quality of life (DTSQ). Safety assessments included adverse events, hypoglycemic episodes, and laboratory parameters at weeks 4, 12, and 24.

2.4 Statistical Analysis

The primary analysis used a mixed-effects model for repeated measures (MMRM) on the modified intent-to-treat population. Missing data were handled by multiple imputation. Statistical significance was set at two-sided alpha = 0.05. Sample size provided 90% power to detect a between-group HbA1c difference of 0.6%, yielding a target of 35 participants per arm.

3. Results

3.1 Participant Characteristics

A total of 110 participants were randomized: 38 to low-dose DGRA-7, 37 to high-dose DGRA-7, and 35 to placebo. Baseline characteristics were well balanced (Table 1). Mean age was 54.4 years, 55.5% were female, and mean baseline HbA1c was 8.13%.

Table 1. Baseline Demographic and Clinical Characteristics

Variable	Low Dose (n=38)	High Dose (n=37)	Placebo (n=35)	p-value
Age, years (mean ± SD)	54.3 ± 8.7	55.1 ± 9.2	53.8 ± 8.4	0.782
Female sex, n (%)	22 (57.9)	20 (54.1)	19 (54.3)	0.921
BMI, kg/m² (mean ± SD)	27.4 ± 3.6	27.9 ± 4.1	27.2 ± 3.4	0.651
Duration of disease, years	6.2 ± 2.8	6.5 ± 3.0	5.9 ± 2.5	0.543
Baseline HbA1c, % (mean ± SD)	8.1 ± 0.9	8.3 ± 1.0	8.0 ± 0.8	0.431
Concurrent medications, n (%)	31 (81.6)	30 (81.1)	29 (82.9)	0.977
Current smoker, n (%)	6 (15.8)	7 (18.9)	5 (14.3)	0.835

SD = standard deviation; BMI = body mass index. P-values from ANOVA or chi-square test. No significant differences at p<0.05.

3.2 Primary and Secondary Outcomes

Both active treatment groups achieved statistically significant HbA1c reductions versus placebo at week 24 (Table 2). The high-dose group achieved -1.87 ± 0.29% reduction (treatment difference vs. placebo: -1.49%, 95% CI: -1.78 to -1.20%; p<0.001) and was superior to low dose (p=0.003). Body weight, blood pressure, HOMA-IR, and quality of life all improved significantly in both active arms, with dose-dependent magnitude in the high-dose arm.

Table 2. Primary and Secondary Efficacy and Safety Outcomes at Week 24

Outcome Measure	Low Dose	High Dose	Placebo	Treatment Effect (95% CI)
Primary: HbA1c change, % (Week 24)	-1.42 ± 0.31*	-1.87 ± 0.29*†	-0.38 ± 0.28	-1.49 (-1.78, -1.20)
Fasting plasma glucose, mmol/L	-1.8 ± 0.6*	-2.4 ± 0.7*†	-0.5 ± 0.5	-1.90 (-2.30, -1.50)
Body weight change, kg	-1.9 ± 1.1	-3.2 ± 1.3*	-0.4 ± 0.9	-2.80 (-3.40, -2.20)
Systolic BP change, mmHg	-3.4 ± 2.8	-5.1 ± 3.1*	-1.2 ± 2.5	-3.90 (-5.10, -2.70)
HOMA-IR change (insulin resistance)	-0.8 ± 0.4*	-1.3 ± 0.5*†	-0.1 ± 0.3	-1.20 (-1.50, -0.90)
Quality of life score (0-100)	+8.3 ± 4.6*	+12.7 ± 5.2*†	+2.1 ± 3.8	+10.50 (8.20, 12.80)
Adverse events, n (%)	8 (21.1)	11 (29.7)	5 (14.3)	—

* p<0.05 versus placebo; † p<0.05 versus low dose. BP = blood pressure; HOMA-IR = homeostatic model assessment of insulin resistance.

3.3 Safety

Adverse events occurred in 21.1%, 29.7%, and 14.3% of low-dose, high-dose, and placebo participants, predominantly mild-to-moderate gastrointestinal events. No severe hypoglycemia occurred. Three serious adverse events (one per arm) were not related to study medication.

Figures

Figure 1. Mean change in HbA1c (%) from baseline over 24 weeks by treatment arm. Shaded regions indicate 95% confidence intervals. * p<0.001 vs. placebo at Week 24 (MMRM analysis). DGRA-7 HD = high dose (4 mg/week); DGRA-7 LD = low dose (2 mg/week); PBO = placebo.

Figure 2. Multi-domain spider plot of cardiometabolic outcomes at week 24. Values normalized to percentage of maximum observed improvement. Larger polygon area indicates greater metabolic improvement. FPG = fasting plasma glucose; SBP = systolic blood pressure; HOMA-IR = homeostatic model assessment.

4. Discussion

This randomized, double-blind, placebo-controlled trial demonstrates that once-weekly DGRA-7 produces robust HbA1c reductions at both doses, with effect sizes exceeding the commonly accepted threshold of clinical significance (0.5%). The magnitude of glycemic improvement is consistent with, and in the high-dose arm potentially exceeds, reductions reported for tirzepatide at comparable doses.

The dose-dependent cardiometabolic benefits are mechanistically plausible: higher receptor occupancy at both GLP-1 and GIP receptors would be expected to more potently stimulate hypothalamic energy balance pathways and adipocyte GIP-receptor-mediated lipid metabolism. The significant HOMA-IR reduction in both arms provides evidence that glycemic benefits are mediated at least in part through improved insulin sensitivity. Tolerability findings aligned with expectations for the incretin class; gastrointestinal events were mild and transient, with no severe hypoglycemia.

Limitations include the 24-week duration, the relatively homogeneous population, and the absence of mechanistic substudies. Ongoing phase 3 trials with longer follow-up and more diverse populations are warranted.

5. Conclusion

DGRA-7 demonstrated clinically meaningful glycemic efficacy at both doses versus placebo over 24 weeks, with high-dose therapy conferring additional cardiometabolic benefits. The safety profile was consistent with established incretin pharmacology. These findings support dual incretin receptor co-agonism as a promising therapeutic approach in T2DM.

Disclosures

M.J.W. has received research funding from Novo Nordisk and Eli Lilly unrelated to this work. D.A.R.-L. has served as a consultant for AstraZeneca. S.K.N., P.S.K., and T.O.B. report no conflicts.

References

1. International Diabetes Federation. IDF Diabetes Atlas, 10th edition. Brussels: IDF; 2023.

2. Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018;20(S1):5-21.

3. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515.

4. Ludvik B, Giorgino F, Jodar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec. Lancet Diabetes Endocrinol. 2021;9(7):418-428.

5. Holst JJ, Rosenkilde MM. GIP as a therapeutic target in diabetes and obesity. J Clin Endocrinol Metab. 2020;105(8):e2710-e2716.

6. American Diabetes Association. Standards of Medical Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1-S321.

7. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756.

8. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment. Diabetologia. 1985;28(7):412-419.

9. Bradley C, Speight J. Patient perceptions of diabetes therapy. Diabetes Metab Res Rev. 2002;18(S3):S64-S69.

10. Sinha B, Ghosal S. Meta-analysis of co-agonists of GLP-1/GIP in type 2 diabetes. Diabetes Ther. 2021;12(7):1931-1942.