What are the findings of the Cardiovascular Outcomes Trial (CVOT) for tirzepatide (a dual GIP and GLP-1 receptor agonist)?

Tirzepatide Cardiovascular Outcomes Trial (CVOT) Results

The cardiovascular outcomes trial (CVOT) for tirzepatide is currently ongoing with the SURPASS-CVOT study, which is expected to be completed in 2024, and definitive cardiovascular safety and efficacy data are not yet available. 1, 2

Current Status of Tirzepatide CVOT

• SURPASS-CVOT is a randomized, double-blind, active-controlled cardiovascular outcomes trial comparing tirzepatide to dulaglutide 1.5mg in people with type 2 diabetes and established atherosclerotic cardiovascular disease 2
• The trial has enrolled 13,299 participants across 640 sites in 30 countries with a mean age of 64.1 years, diabetes duration of 14.7 years, and baseline HbA1c of 8.4% 2
• The primary outcome is time to first occurrence of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or stroke 2
• The trial is event-driven and will continue until at least 1,615 participants experience an adjudication-confirmed MACE 2

Preliminary Cardiovascular Safety Data

• In the SURPASS-4 trial, which included patients with type 2 diabetes and elevated cardiovascular risk, tirzepatide did not show an increased risk of major adverse cardiovascular events compared to insulin glargine 3
• Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina) occurred in 109 participants with a hazard ratio of 0.74 (95% CI 0.51-1.08) for tirzepatide compared to insulin glargine 3
• This preliminary data suggests that tirzepatide treatment was not associated with excess cardiovascular risk, but the definitive assessment awaits completion of the dedicated SURPASS-CVOT trial 3, 4

Tirzepatide Efficacy in Type 2 Diabetes

• Tirzepatide has demonstrated superior glycemic control compared to other antidiabetic medications, with HbA1c reductions ranging from 1.24% to 2.11% versus placebo and 0.6% to 1.14% versus active comparators 5
• In SURPASS-4, tirzepatide showed mean HbA1c changes of -2.43% (10mg dose) and -2.58% (15mg dose) versus -1.44% with insulin glargine at 52 weeks 3
• Tirzepatide produces significant weight loss of up to 15.5kg compared to placebo or active comparators, with higher doses (10mg and 15mg) showing greater weight reduction than the 5mg dose 6, 5

Cardiovascular Effects of GLP-1 Receptor Agonists

• Other GLP-1 receptor agonists like liraglutide and semaglutide have demonstrated reduction in MACE in patients with type 2 diabetes and cardiovascular disease, including those with peripheral artery disease 1
• In the LEADER trial, liraglutide reduced the primary composite MACE outcome compared to placebo (13.0% vs 14.9%, HR: 0.87, P<0.001) 1
• In SUSTAIN-6, semaglutide reduced the primary composite MACE outcome compared to placebo (6.6% vs 8.9%, HR: 0.74, P<0.001) 1
• These benefits do not appear to be a class effect as they were not replicated with other GLP-1 receptor agonists like lixisenatide, exenatide, and dulaglutide 1

Safety Profile of Tirzepatide

• The most common adverse events with tirzepatide are gastrointestinal, including nausea (12-23%), diarrhea (13-22%), decreased appetite (9-11%), and vomiting (5-9%) 3
• Most gastrointestinal side effects are mild to moderate and occur during the dose-escalation phase 3
• Tirzepatide has shown a lower risk of hypoglycemia (6-9%) compared to insulin glargine (19%), particularly in patients not on sulfonylureas 3

Clinical Implications and Future Directions

• Current guidelines recognize tirzepatide as having very high efficacy for glucose lowering in type 2 diabetes 1
• Tirzepatide is also being studied for potential benefits in obesity, heart failure, and nonalcoholic steatohepatitis 7
• The SUMMIT trial is expected to provide additional data on tirzepatide's long-term benefits in cardiovascular health management 4
• For patients with chronic kidney disease and type 2 diabetes, emerging evidence suggests benefits of tirzepatide on kidney outcomes based on reductions in albuminuria and rate of eGFR decline 1

Key Considerations for Clinical Practice

• While awaiting definitive CVOT results, clinicians should consider tirzepatide primarily for its proven benefits in glycemic control and weight reduction 1, 6
• For patients specifically requiring cardiovascular risk reduction, GLP-1 receptor agonists with established cardiovascular benefits (liraglutide, semaglutide) may be preferred until tirzepatide's CVOT is completed 1
• Dose escalation should be gradual to minimize gastrointestinal side effects, with higher doses providing greater weight loss and glycemic benefits 6, 3
• Monitor patients for potential consequences of delayed absorption of oral medications, particularly those with narrow therapeutic index 6