Glucagon-like peptide-1 agonists, weight and blood pressure change after smoking cessation

This editorial refers to ‘Blood pressure changes during smoking cessation in a randomized, double-blind, placebo-controlled trial of dulaglutide treatment’, by J. Beck et al., https://doi.org/10.1093/eurjpc/zwaf055.

Cigarette smoking is the leading cause of preventable mortality and reduced life expectancy and is a major risk factor for cardiovascular morbidity and mortality. Smoking cessation reduces cardiovascular risk but is often associated with weight gain. Weight gain after smoking cessation is a concern because it may attenuate the main benefit of smoking cessation. Post-cessation weight gain may be associated with an increased risk of type 2 diabetes mellitus, but even weight gains of up to 10 kg (2 to 6 years after quitting) are associated with reduced cardiovascular mortality.¹ The benefits of quitting smoking are so important that the benefits in terms of cardiovascular risk and all-cause mortality are not compromised by post-cessation weight gain.

In this issue of the Journal, Beck et al.² report on a secondary analysis of their trial evaluating 3 months of subcutaneous injection of placebo or dulaglutide, 1.5 mg weekly for up to 12 weeks, for smoking cessation.³ Dulaglutide, a glucagon-like peptide-1 (GLP-1) agonist, antagonized weight gain after smoking cessation but had no effect on smoking abstinence rates.³ This secondary analysis aimed to report on changes in blood pressure and weight and found that overall systolic blood pressure was stable over 52 weeks of follow-up, but was reduced in those whose weight gain was less than 3 kg. Path analysis confirmed that the reduction in systolic blood pressure was associated with reduced weight gain. Importantly, the authors report a rebound weight gain after stopping dulaglutide at 3 months, which was associated with a relatively large increase in systolic blood pressure.

Including smokers in a smoking cessation programme may result in reducing systolic and diastolic blood pressure, and more among those with hypertension,⁴ but this is not associated with smoking cessation rates.⁴ Similar findings are reported by Beck et al.² Systolic and diastolic blood pressure were not modified by smoking abstinence at any time points.² However, in the subgroup of participants who abstained from smoking, weight changes at Week 12 were +2.3 kg (1; 3) (median, interquartile range) in the placebo group and −0.8 kg (−3; 1) in the dulaglutide group, suggesting that dulaglutide antagonized the weight gain associated with abstinence. Treatments were stopped at Week 12, and at Week 52, weight gain was similar in the dulaglutide and placebo groups (+4.2 kg in both groups).

Post-cessation weight gain does not affect all individuals who quit smoking. At 12 months after cessation, 16% of untreated quitters may lose weight, 37% gain less than 5 kg, 34% gain 5–10 kg, and 13% more than 10 kg.⁵

In Beck et al.² reduced blood pressure after smoking cessation was associated with reduced weight gain; thus, preventing weight gain after smoking cessation may reduce blood pressure. Very low-calorie diets, personalized weight management, or exercise interventions provide controversial results in post-cessation weight control.⁶ Among approved smoking cessation medications, nicotine replacement therapy and varenicline have been found to modestly antagonize post-cessation weight gain.^5,6 Bupropion reduces weight gain after quitting smoking.^5,6 However, because it is an amphetamine derivative, this effect is unlikely to be associated with a reduction in blood pressure.

Dulaglutide or other GLP-1 analogues may be useful not only in counteracting weight gain after smoking cessation but also in reducing the incidence of type 2 diabetes after smoking cessation. Unfortunately, Beck et al.² do not report changes in blood glucose or HbA1c. Further studies with GLP-1 agonists should assess the triad of post-smoking cessation: weight, blood pressure, and glycaemic changes.

Beck et al.² observed that the benefits on weight and blood pressure were lost after stopping dulaglutide. Abrupt discontinuation of a medication may result in withdrawal symptoms, discontinuation syndrome, or rebound. Withdrawal symptoms are associated with the withdrawal of substances with addictive properties. Discontinuation syndrome means that when an effective treatment is stopped, the original signs and symptoms of the disorder reappear. In some cases, stopping medication triggers an increase in signs and symptoms over the baseline level, a rebound. For example, rebound hypertension occurs after abrupt discontinuation of beta-blockers and antihypertensive drugs.⁷ The weight control benefit of 20 weeks of treatment with semaglutide, another GLP-1 agonist, was lost when participants were switched to placebo,⁸ a discontinuation syndrome. However, in another report, weight gain was greater after stopping semaglutide than after stopping placebo, a rebound effect.⁹ Similarly, stopping nicotine replacement therapies leads to increased relapse rate to smoking compared with stopping their corresponding placebos.¹⁰

Tobacco smoking is a chronic health disorder that may require chronic treatments to maintain abstinence. Further studies with GLP-1 agonists should assess their long-term administration to prevent weight gain after smoking cessation and to avoid a discontinuation syndrome or a rebound.

Funding

None.

References

Author notes