Reported cardiovascular events and cardiometabolic risk markers with orforglipron and danuglipron in adults with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized trials

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Abstract

[BACKGROUND AND OBJECTIVE] To evaluate the effects of orforglipron and danuglipron on cardiovascular events and cardiometabolic risk markers in patients with type 2 diabetes mellitus (T2DM) and/or obesity. [METHODS] We searched PubMed, Embase, Scopus, Web of Science, the Cochrane Library, and ClinicalTrials.gov through May 5, 2026. Two authors independently performed study selection, data extraction, and quality assessment. Meta-analyses estimated pooled risk ratios (RRs), least-squares mean differences (LSMDs), and 95% confidence intervals (CIs). [RESULTS] Thirteen randomized controlled trials (RCTs) involving 9,076 participants were included. Compared with controls, orforglipron/danuglipron showed no statistically significant difference in extended major adverse cardiovascular events (MACE) (RR = 1.10, 95% CI [0.59 to 2.05], I² = 0.0%, P = 0.760, 6 studies; intervention: 32/4741, control: 13/1928) or myocardial infarction (MI) (RR = 0.54, 95% CI [0.06 to 4.60], I² = 0.0%, P = 0.576, 2 studies; intervention: 2/881, control: 0/156). Extended MACE and MI were mainly derived from adverse event reports. Given sparse, indirect event data and low GRADE certainty, these findings warrant caution. In contrast, orforglipron and danuglipron reduced several cardiometabolic risk markers, including HbA1c (LSMD = - 1.07%, 95% CI [- 1.49 to - 0.64], I² = 99.1%, P < 0.001), fasting plasma glucose (LSMD = - 27.75 mg/dL, 95% CI [- 37.99 to - 17.50], I² = 98.2%, P < 0.001), and body weight (LSMD = - 4.68 kg, 95% CI [- 6.26 to - 3.10], I² = 95.4%, P < 0.001). These estimates showed substantial between-study heterogeneity, warranting cautious interpretation. Current randomized evidence supports changes in cardiometabolic risk markers, but uncertainty remains regarding the effects on hard cardiovascular events. [CONCLUSIONS] Current randomized evidence suggests that orforglipron and danuglipron reduce short- to medium-term cardiometabolic risk markers in patients with T2DM or obesity. However, no significant differences in extended MACE or MI were observed; the point estimates were imprecise, and cardiovascular effects remain unconfirmed. These findings are limited by sparse events, low-certainty evidence, and the lack of dedicated cardiovascular outcome trial (CVOT) designs; therefore, definitive conclusions regarding cardiovascular effects cannot be drawn. [TRIAL REGISTRATION] The study protocol was pre-registered and published on PROSPERO (CRD420251067874; https://www.crd.york.ac.uk/prospero/ ).

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