Cardiovascular Safety and Superiority of Anti-Obesity Medications

Figures & data

Table 1 Key Points for Cardiovascular Outcome Trials According to the European Medicine Agency Guidelines for Assessing Cardiovascular Risk

Requirements for Cardiovascular Outcome Trials
Population	The recruited population needs to be at a higher risk of having CV events, ie, MACE
Safety outcomes	Primary composite MACE: CV-related death, non-fatal myocardial infarction, and non-fatal stroke are the preferred safety outcomes. Can also include 3P-MACE-plus: hospitalisation for unstable angina, heart failure, and possibly other endpoints. Sufficient number of MACEs and sufficient power illuminate non-excessive risks
Quantification of cardiovascular risk	The analysis of cardiovascular events may include meta-analysis or large, separate, CV-safety trial of the new agent demonstrating an HR upper limit (95% CI, two-sided) <1.8. If the HR falls between 1.3 −1.8, post-marketing trial may be required to reaffirm and show that the HR is <1.3. Superiority, which means that the HR was <1.3 in the pre-marketing trial, indicates that no further post-marketing trial is required.
Evaluation of results	Illustrating the mechanism of action and effects on known CV risk factors. Additional CVOTs may be requested if there are any indications of high risk of CV events or a lack of precision.

Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular events.

Table 2 A Summary of Anti-Obesity Drug Trials

Drug	Trials	FDA Approval	EMA Approval	Cardiovascular Safety	Weight Loss	Reason for Withdrawal	Comments
Anti-obesity medications
Phentermine/topiramate	CONQUER SEQUEL AQCLAIM	Yes (2012)	No	Statistically power was not enough to measure cardiovascular safety	Significant weight loss	EMA: Lacked support for long-term CV safety; concerns over cognitive and harmful psychiatric events; potential for abuse	- Showed the most robust decrease in weight loss compared with other anti-obesity medications. - Showed troubling adverse events, such as psychiatric and cognition problems.
Naltrexone/bupropion	LIGHT CONVENE	Yes (2014)	Yes (2015)	Statistical power was not enough to measure cardiovascular safety	Significant weight loss	NA	- It can cause elevation of BP and heart rate, making it challenging to prescribe to patients with significant CVD. - The failure of not only one but two CVOTs to illuminate the cardiovascular safety of the naltrexone/bupropion combination represents a significant setback.
T2DM medications
Liraglutide	LEADER	Yes (2014)	Yes (2015)	1.8 mg (dose) Superiority 3.0 mg (dose) NA	1.8 mg caused modest weight loss 3.0 mg caused significant weight loss	NA	- The applicability of liraglutide 3.0 mg in terms of cardiovascular superiority remains unknown.
Semaglutide	SUSTAIN-6 PIONEER6	Yes (2019)	Yes (2019)	Non-inferiority	Significant weight loss	NA
SGLT2 inhibitor	EMPA-REG CANVAS DAPA-HF	Yes (2014) Yes (2013) Yes (2020)	Yes (2014) Yes (2013) Yes (2020)	Superiority Superiority Non-inferiority	Modest weight loss (2 kg)	NA NA NA	- SGLT-2 inhibitors successfully showed superiority in 3-point MACE and heart failure hospitalisation. - Weight loss effect was minimal

Abbreviations: BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcome trial; EMA, European Medicines Agency; FDA, Food and Drug Administration; HR, hazard ratio; MACE, major adverse cardiovascular events; NA, not available; SGLT2, sodium-glucose co-transporter-2; T2DM, type 2 diabetes mellitus.