How do GLP‑1 drugs affect cardiovascular risk markers while on treatment versus after discontinuation?
Executive summary
GLP‑1 receptor agonists improve multiple cardiovascular risk markers—weight, glycaemic control, blood pressure, lipids and inflammatory biomarkers—and reduce major adverse cardiovascular events (MACE) while patients are taking them, as shown in randomized trials and meta-analyses [1] [2]. Observational and emerging trial‑follow‑up data indicate that many of those favourable markers—and with them some of the cardiovascular protection—partially reverse after discontinuation, with weight regain, rising HbA1c and signals of increased cardiovascular events in real‑world cohorts, but the precise magnitude and duration of post‑cessation risk remain incompletely characterized [3] [4] [5] [6].
1. How GLP‑1 drugs shift cardiovascular risk markers during active therapy
Large cardiovascular outcome trials and pooled analyses report that GLP‑1 receptor agonists produce clinically meaningful reductions in MACE and improve intermediate risk markers: trials and meta‑analyses show reductions in cardiovascular death, non‑fatal myocardial infarction and stroke, alongside consistent decreases in body weight, modest blood pressure lowering, improvements in glycaemic indices and favourable shifts in lipids and inflammatory markers [1] [2] [7] [8]. These effects are mechanistically plausible: GLP‑1 signalling acts on metabolic pathways, vascular and myocardial cells and systemic inflammation, resulting in pleiotropic cardiometabolic benefits observed across randomized controlled trials in people with type 2 diabetes and in obesity trials [7] [8] [9]. The benefit on “hard” outcomes is robust in meta‑analysis of randomized trials—MACE reduced by about 13% and composite kidney outcomes also improved—providing high‑quality evidence that active drug exposure confers cardiovascular and renal protection in studied populations [1].
2. What happens to those markers after GLP‑1 therapy is stopped
Systematic reviews and cohort studies document a metabolic rebound after stopping GLP‑1 therapy: randomized‑trial follow‑up meta‑analysis found mean weight regain of roughly 5.6 kg and a modest rise in HbA1c after discontinuation in obesity trials, and real‑world cohort analyses link discontinuation to higher rates of major cardiovascular events compared with continued use [3] [4] [10]. A large retrospective real‑world study presented at a major cardiology meeting reported increased risks of coronary artery disease and heart failure after early discontinuation, and early stoppers showed persistently higher CAD and HF risks post‑discontinuation in that dataset [10] [5]. Systematic reviewers caution that while the pattern of metabolic and some event‑risk deterioration is consistent, the long‑term trajectory, timing and reversibility of cardiovascular risk after stopping are not yet fully defined [6] [3].
3. Biological links: why marker reversal can translate to more events
The same mechanisms that drive on‑treatment benefits—sustained lower weight, improved glycaemia, lower blood pressure, improved lipids and reduced inflammation—are traditional drivers of atherosclerotic and heart‑failure risk, so losing those gains plausibly raises event risk after cessation [7] [8]. Observational signals linking discontinuation to higher MACE are biologically coherent with documented rebound in weight and glycaemia seen in randomized and non‑randomized studies [3] [4]. However, causality is harder to prove outside randomized cessation trials because people who stop therapy differ for clinical and socioeconomic reasons—adverse effects, cost, or comorbid mental health conditions—which themselves influence cardiovascular outcomes [9] [11] [5].
4. Strengths, limits and competing interpretations in the evidence
Randomized controlled trials provide high‑quality evidence of cardiovascular benefit during treatment, but most trials were not designed to study outcomes after stopping therapy and often continued background care that differs from real life, creating a gap filled by observational studies that show concerning post‑cessation signals but are vulnerable to confounding [1] [4] [5]. Recent systematic reviews call for longitudinal discontinuation protocols and randomized withdrawal studies to quantify rebound risks precisely and to distinguish physiological rebound from selection biases in observational cohorts [6] [3]. Industry, payer and prescribing pressures—driven by expanding indications for obesity and high costs—may shape who stays on therapy and thus influence real‑world outcome patterns, an implicit agenda that complicates interpretation of discontinuation data [11] [12].
5. Practical takeaway and unresolved questions
The clearest message from current evidence is that cardiovascular risk markers and hard outcomes improve while people are on GLP‑1 therapy and that stopping therapy commonly leads to metabolic rebound and is associated in observational data with increased cardiovascular events, especially after early discontinuation, but the magnitude, timing and reversibility of post‑cessation cardiovascular risk remain open questions requiring randomized withdrawal and longer longitudinal studies [1] [3] [5] [6]. Clinicians and policy makers must weigh on‑treatment cardiovascular and metabolic benefits against tolerability, cost and patient preferences, and researchers must prioritize trials that investigate structured discontinuation, maintenance strategies and whether re‑introduction restores prior benefit [9] [6] [3].