Obesity can adversely affect several health conditions but about two-thirds of deaths attributable to excess body mass index (BMI) are cardiovascular. This makes cardiovascular risk management a priority goal in people with obesity.
Several biological mechanisms are implicated in the pathway between adiposity and the risk of cardiovascular diseases. Of these, elevated blood pressure (BP) stands out as the most important mediator of obesity-related risk. In a pooled analysis of cohort studies, about two-thirds of the excess risk for stroke and one-third of the risk for ischaemic heart disease that was related to high BMI were mediated through elevated blood pressure.
This is because adiposity is by far the most important precursor of elevated BP. In an analysis of the Framingham Offspring Study, excess body fat was attributed to approximately 70% of cases of early-onset hypertension in men and 64% in women.
In this context, it seems unsurprising that a large fraction of patients with hypertension are also obese. With the rising rates of obesity and elevated BP, effective and safe interventions targeting adiposity will continue to grow in importance.
A substudy of SURMOUNT-1 trial, recently published Heart, investigates the effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (or incretin-based therapy), on BP in individuals with obesity or overweight.
In this study, 72 weeks of tirzepatide treatment led to substantial reductions in both systolic blood pressure (SBP) and diastolic blood pressure (DBP). Specifically, the treatment resulted in a net reduction of 6.8 mm Hg in SBP and 4.2 mm Hg in DBP compared with placebo. These BP-lowering effects of tirzepatide were largely mediated through weight loss, with 68% of the reduction in SBP and 71% of the reduction in DBP attributed to changes in body weight.
The fact that GLP-1 receptor agonists are effective in reducing weight as well as BP has been reported previously. However, this substudy of SURMOUNT-1 adds several insights which could position this class of drug as an emerging first-line agent for BP control in obese patients.
Magnitude of BP reduction: The BP reductions achieved with tirzepatide are substantial and comparable to those of major antihypertensive drug classes in long-term cardiovascular outcomes trials. As the current report additionally suggests, BP reductions were larger in individuals without concurrent antihypertensive drugs at baseline (net SBP reduction 8.1 mm Hg vs 3.9 mm Hg in those with or without the use of antihypertensive therapies, respectively). This means that the true effect of tirzepatide on BP, at least in the short-term, might be even larger than the overall average effect after taking account of the higher rate of discontinuation of antihypertensive therapy in the tirzepatide arm.
2. Consistency across patient characteristics: With the exception of non-study antihypertensive use, BP reductions with tirzepatide were largely consistent across different baseline BP categories and hypertension stages. Thus, tirzepatide could be effective for a wide range of patients, including those whose BP or cardiovascular risk might not yet be high enough to warrant pharmacological treatment with antihypertensives. Despite the growing evidence for ‘the lower, the better’ BP paradigm, many individuals with obesity have a relatively low predicted cardiovascular risk due to their young age. Therefore, they would not typically be recommended for pharmacological BP treatment as per the current clinical practice guidelines. Indeed, in this study, the mean SBP of patients at baseline was 123 mm Hg (SD 12.7 mm Hg) which was reduced to 115 mm Hg with tirzepatide treatment.
3. Safety profile: Tirzepatide demonstrated a remarkable safety and tolerability profile with a low incidence of BP-related adverse events. Treatment-related serious adverse events occurred only in 0.2% of individuals in the treatment arm (vs 0% in the control arm). Excess risk of harm at low BP targets remains a key perceived concern among decision-makers despite the lack of strong evidence for it. The current study shows that although there were some adverse events, such as dizziness, they were manageable and did not significantly detract from the overall benefits of the treatment. Such a safety profile is crucial for patient adherence and long-term management of both weight and elevated BP.
In addition to these insights, there is growing evidence for the beneficial effect of incretin-based therapies on cardiovascular events. These findings collectively suggest that tirzepatide could be a game-changer in the management of elevated BP, particularly for patients with overweight or obesity. The drug’s ability to substantially and safely lower BP even before antihypertensives become an option could lead to de facto treatment of a large fraction of patient groups with elevated BP. The dual action of weight reduction and BP lowering would not only simplify treatment protocols on obese individuals but also enhances patient outcomes by tackling the root causes of cardiovascular disease. It is possible that in the future, many obese patients will begin their treatment journey with weight reduction therapy rather than traditional antihypertensive drugs.
Despite these highly encouraging findings, several questions remain to be addressed in future studies. Managing the increased risk of cardiovascular disease is typically a lifelong strategy and a 72-week treatment period seems too short for such a long-term approach. Indeed, the study shows some levelling off of blood pressure reduction after 24 weeks of treatment which needs further investigation. Given that most of the BP-lowering effect is mediated by weight reduction, it is also crucial to determine whether these weight reductions will be maintained over the long term with or without adjunctive lifestyle changes. A recent study indicated that treatment discontinuation of tirzepatide could lead to rapid weight regain.
More information on potential heterogeneous treatment effects by age will also be useful. For instance, studies have shown that the onset of adiposity in younger age shows a stronger association with incident hypertension than in old age. Whether this translates into an attenuation of the effect of tirzepatide in older individuals will need more research. Similar questions will be raised in other populations, not included in SURMOUNT-1, such as those with diabetes where heterogeneous effects of major classes of antihypertensives have been reported.
Another important question is whether these findings will extend to other incretin-based treatments, especially those without GIP. While some quantitative differences in effects are expected, it is unclear if these differences will be significant enough to affect treatment decisions. Finally, the costs of incretin-based therapies are currently prohibitive for population-based interventions. This cost barrier is particularly relevant when considering the availability of alternative, proven-effective cardiovascular disease prevention therapies, such as polypills, which can nearly halve the cardiovascular risk at very low costs.
Bearing these open questions in mind, the present study paves the way for the emergence of incretin-based drugs as a powerful intervention for blood pressure management and marks a significant advancement in obesity-mediated hypertension. The fight against elevated blood pressure, the leading cause of global morbidity and mortality, has long focused on weight management as a key strategy for blood pressure control. Incretin-based therapies offer an additional promising solution to this challenge.
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