Pharmacological therapy in the obese patient: is it only a matter of fat loss?

Abstract

Obesity is a chronic, multifactorial condition strongly associated with increased cardiovascular and metabolic risk, as well as the development of systemic complications. Recent evidence from randomized controlled trials—including SELECT, STEP-HFpEF, STEP-HFpEF DM, SUMMIT, and SURMOUNT-5—has demonstrated the effectiveness of glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonists in the treatment of obesity, with clinical benefits that appear to extend beyond weight reduction alone. In addition to substantial reductions in fat mass, these agents improve cardiovascular parameters (including reductions in major adverse cardiovascular events), functional capacity, and quality of life. Additional benefits have been observed at the metabolic level, with reductions in glycated haemoglobin, blood pressure, triglycerides, and systemic inflammatory markers such as high-sensitivity C-reactive protein. These results confirm that pharmacological modulation of the incretin axis should not be viewed merely as an adjunctive strategy for weight loss, but rather as an integrated therapeutic intervention capable of modifying overall cardiovascular risk and improving the inflammatory and metabolic profile of the obese patient. In light of these findings, a re-evaluation of the role of pharmacological therapy in the clinical management paradigm of obesity is warranted.

Introduction

Obesity is closely associated with increased cardiovascular morbidity and mortality, as well as with the development of ischaemic heart disease, arterial hypertension, heart failure, and type 2 diabetes mellitus. Historically, obesity management relied primarily on lifestyle modification and, in selected cases, bariatric surgery; pharmacological options were limited, of modest efficacy, and often burdened by significant adverse effects.

In recent years, the development of innovative agents—GLP-1 (glucagon-like peptide-1) receptor agonists and dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 receptor agonists—has triggered a paradigm shift. These molecules, initially designed for the treatment of type 2 diabetes, have demonstrated potent anorectic effects and metabolic benefits even in non-diabetic individuals. Their clinical impact extends far beyond simple weight reduction, prompting the crucial question: is pharmacological treatment in the obese patient merely a matter of adipose tissue loss, or can it also favourably influence cardiovascular risk and overall metabolic health?

This article examines the most recent evidence regarding novel anti-obesity medications, particularly GLP-1 receptor agonists and dual GIP/GLP-1 agonists, with a focus on their additional cardiovascular and metabolic benefits.

GLP-1 receptor agonists and dual GIP/GLP-1 agonists

GLP-1 receptor agonists

GLP-1 receptor agonists (GLP-1 RAs) are analogues of the incretin hormone GLP-1 and exert a prolonged action that mimics the effects of the endogenous peptide on glucose metabolism and appetite regulation. Agents such as liraglutide and semaglutide enhance satiety at the level of the central nervous system and slow gastric emptying, thereby promoting a marked reduction in caloric intake.¹

In the STEP clinical trials dedicated to obesity treatment (Semaglutide Treatment Effect in People with obesity), once-weekly subcutaneous semaglutide 2.4 mg induced average weight reductions approaching 15% of baseline body weight over 1–2 years—results that historically were achievable only with bariatric surgery.²

In the SELECT trial (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity), conducted in more than 17 000 individuals with obesity and established cardiovascular disease, treatment with subcutaneous semaglutide 2.4 mg for a median follow-up of ∼3.3 years produced a mean weight reduction of 9.4% at 2 years, compared with 0.9% in the placebo group.³

The most common adverse effects of GLP-1 RAs are gastrointestinal (nausea, vomiting, and diarrhoea), generally mild and more prominent during early dose escalation. Less frequent events such as acute pancreatitis and cholelithiasis have been reported, although the overall safety profile of GLP-1 RAs is considered favourable.

Dual GIP/GLP-1 agonists

Tirzepatide is the first representative of a new class of ‘multi-incretin agonist’ drugs that activate both the GIP receptor and the GLP-1 receptor. This synergistic dual mechanism results in metabolic and anorectic effects that exceed those of single GLP-1 receptor agonists.

In the SURMOUNT trials in individuals with obesity, tirzepatide produced unprecedented reductions in body weight. In SURMOUNT-1, conducted in adults with obesity without diabetes, maximal-dose (15 mg weekly) subcutaneous tirzepatide reduced body weight by a mean of 20.9% at 72 weeks, compared with 3.1% in the placebo group (P < 0.001).⁴ Intermediate doses (10 mg) also achieved weight loss approaching 19–20%.⁴

In SURMOUNT-2, which enrolled individuals with obesity and type 2 diabetes, tirzepatide 15 mg achieved a 14.7% reduction in body weight at 72 weeks vs. 3.2% in the placebo group, demonstrating efficacy even in diabetic patients.⁵

A direct comparison between tirzepatide and semaglutide (SURMOUNT-5) recently confirmed the superiority of the dual agonist: after 72 weeks of treatment, individuals with obesity without diabetes achieved a mean 20.2% weight loss with tirzepatide 10/15 mg (95% CI, −21.4 to −19.1) vs. 13.7% with semaglutide 2.4 mg (95% CI, −14.9 to −12.6; P < 0.001).⁶

Tirzepatide shares the same gastrointestinal adverse effects seen with GLP-1 RAs, yet overall maintains a favourable safety profile. The combined GIP/GLP-1 mechanism is particularly potent not only in suppressing appetite and caloric intake but also in improving insulin sensitivity and peripheral glucose utilization. Consequently, significant reductions in HbA1c are observed in diabetic patients.

Notably, these second-generation incretin-mimetic therapies are approaching the effectiveness of bariatric surgery in terms of weight loss and reduction of metabolic comorbidities, while maintaining an exclusively pharmacological approach.

Cardiovascular and metabolic benefits

The most recent evidence clearly indicates that the clinical benefits of GLP-1 and GIP/GLP-1 agonists in obese patients extend far beyond the reduction of fat mass, involving significant cardio- and vasculoprotective effects together with improvements in the global metabolic profile (Table 1).

Table 1.

Main clinical trials on pharmacological therapies for obesity.

Study	Population	Drug	Duration	Primary Endpoint(s)	Main Results
SELECT	Overweight/obese individuals without type 2 diabetes and established cardiovascular disease	Semaglutide 2.4 mg	Median follow-up ∼3.3 years	MACE (CV death, non-fatal MI, non-fatal stroke)	20% reduction in MACE vs. placebo; significant reduction in new-onset diabetes
STEP-HFpEF	Obese patients with HFpEF	Semaglutide 2.4 mg	52 weeks	Change in KCCQ-CSS; change in body weight	Significant improvement in symptoms, functional capacity, QoL; weight loss ∼13%
STEP-HFpEF DM	Obese patients with HFpEF and type 2 diabetes	Semaglutide 2.4 mg	52 weeks	Change in KCCQ-CSS; change in body weight	Benefits similar to STEP-HFpEF; efficacy preserved in diabetic patients
SURMOUNT-5	Obese individuals without type 2 diabetes	Tirzepatide (10/15 mg) vs. semaglutide 2.4 mg	72 weeks	Change in body weight from baseline	Greater weight loss with tirzepatide (∼20%) vs. semaglutide (∼14%)
SUMMIT	Obese patients with HFpEF (with or without type 2 diabetes)	Tirzepatide (10/15 mg)	Median follow-up ∼2 years	Composite of CV death or worsening HF	Reduced HF events; weight loss ∼13–15%; improved KCCQ-CSS and exercise capacity
SCALE Obesity	Obese individuals without type 2 diabetes	Liraglutide 3.0 mg	56 weeks	% achieving ≥5% weight loss; change in body weight	Mean weight loss ∼8 kg; >60% achieved ≥5% weight loss
SCALE Diabetes	Obese individuals with type 2 diabetes	Liraglutide 3.0 mg	56 weeks	Change in HbA1c; % achieving ≥5% weight loss	HbA1c reduction (∼ −0.9%) and significant weight loss vs. placebo

CV: cardiovascular; DM: diabetes mellitus; HbA1c: glycated haemoglobin; HFpEF: heart failure with preserved ejection fraction; KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; MACE: major adverse cardiovascular events; MI: myocardial infarction; QoL: quality of life.

Evidence in cardiovascular prevention and reduction of major adverse events

Earlier studies in patients with diabetes had already suggested a cardioprotective effect of GLP-1 receptor agonists. For example, the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) demonstrated that liraglutide reduced the risk of major adverse cardiovascular events (MACE) by 13% in high-risk patients with type 2 diabetes.⁷

These findings are consistent with current evidence in obese individuals without diabetes. The SELECT trial, published in 2023, provided definitive proof of the cardiovascular benefit of semaglutide in secondary prevention among obese patients. A total of 17 604 individuals with BMI ≥27 kg/m² and established cardiovascular disease but no diabetes were randomized to weekly subcutaneous semaglutide 2.4 mg vs. placebo and followed for a median of ∼3.3 years.³

Semaglutide produced a 20% reduction in MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Events occurred in 6.5% of patients on semaglutide vs. 8.0% of placebo recipients (HR 0.80; 95% CI, 0.72–0.90; P < 0.001).³

This reduction in major cardiovascular events in a non-diabetic population expands the cardiovascular indication of GLP-1 RAs to a broader group and represents a landmark achievement in cardiometabolic risk management in obesity. Based on SELECT, semaglutide 2.4 mg became the first anti-obesity medication approved (FDA 2023) for cardiovascular risk reduction in individuals with obesity and prior cardiovascular events.

Importantly, the cardiovascular benefits of semaglutide were observed despite a high prevalence of statin and optimal medical therapy use, suggesting a drug-specific additional effect. The mechanisms are likely multifactorial. Beyond weight loss, semaglutide in SELECT led to:

• A greater reduction in systolic blood pressure (−3.8 mmHg vs. –0.5 mmHg).

• A dramatic decrease in the incidence of new-onset diabetes (3.5% vs. 12.0%; HR 0.27).³

The latter finding highlights semaglutide’s ability to prevent progression from prediabetes to overt diabetes—an important cardiovascular risk factor.

Overall, data from SELECT and recent meta-analyses indicate that incretin-based therapies produce:

• ∼28% reduction in myocardial infarction and

• up to ∼20% reduction in all-cause mortality,^8,9

without significant increases in major adverse events. These are clinically meaningful benefits, positioning incretin therapy as a core component of cardiovascular prevention strategies in obese patients.

Evidence in heart failure with preserved ejection fraction

Until recently, no treatments specifically addressed the metabolic component of heart failure with preserved ejection fraction (HFpEF). In this setting, new GLP-1 agonists have shown remarkable results.

The STEP-HFpEF trial, published in 2023, evaluated weekly semaglutide 2.4 mg vs. placebo in 529 patients with HFpEF and obesity (BMI ≥30) over 1 year.² The two primary endpoints—changes in cardiovascular symptoms and quality of life measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight—improved markedly in the semaglutide group.

Key results:

• KCCQ-CSS improved by +16.6 vs. +8.7 with placebo (difference +7.8 points; 95% CI, 4.8–10.9; P < 0.001).

• Weight decreased by –13.3% vs. −2.6% (difference −10.7% points; P < 0.001).

• 6-min walk distance increased by +21.5 m vs. +1.2 m (P < 0.001).

• hsCRP decreased by −43% vs. −7% (P < 0.001).

• A hierarchical composite analysis demonstrated a global clinical benefit (win ratio 1.72; P < 0.001).²

A parallel trial in patients with HFpEF, obesity, and diabetes (STEP-HFpEF DM, N = 616) confirmed similar improvements:¹⁰

• KCCQ-CSS: +13.7 vs. +6.4 (difference +7.3; P < 0.001).

• Weight loss: −9.8% vs. −3.4% (difference −6.4%; P < 0.001).

• 6-min walk distance: +14 m vs. +1 m (P = 0.008).

Patients treated with semaglutide also reported fewer serious adverse events and improved overall clinical status, suggesting an effect on the underlying HFpEF pathophysiology.

Evidence with GIP/GLP-1 dual agonism in HFpEF

Further confirmation comes from the SUMMIT trial, which evaluated tirzepatide for the first time in HFpEF. In this study, 731 patients with HFpEF and obesity were randomized to tirzepatide vs. placebo and followed for a median of 2 years.¹¹

Results showed that tirzepatide met the primary composite endpoint of reducing cardiovascular death or worsening heart failure:

• 9.9% vs. 15.3%; HR 0.62 (95% CI, 0.41–0.95; P = 0.026).

The benefit was primarily driven by fewer worsening HF events:

• 8.0% vs. 14.2%; HR 0.54 (95% CI, 0.34–0.85).

Secondary clinical benefits included:

• KCCQ-CSS improvement: +19.5 vs. +12.7 (P < 0.001).

• 6-min walk distance: +26 m vs. +10 m (P < 0.001).

• Systolic BP reduction: −4.6 vs. +0.1 mmHg.

• hsCRP reduction: −39% vs. −6% (P < 0.001).

Weight loss at 1 year:

• −13.9% with tirzepatide vs. −2.2% with placebo (∼−11.7% difference; P < 0.001), similar to semaglutide in STEP-HFpEF.

These findings are clinically relevant, as obesity-related HFpEF has historically shown limited responsiveness to conventional therapies. Beyond weight loss, the improvements observed may be mediated by reductions in systemic inflammation—reflected in lower hsCRP levels—suggesting anti-inflammatory effects on myocardial and visceral tissues.

Evidence on global metabolic control

Beyond the benefits on body weight and cardiovascular outcomes, incretin-based therapies produce substantial improvements across a wide range of metabolic parameters. For instance, in the SCALE Diabetes trial (Satiety and Clinical Adiposity—Liraglutide Evidence), conducted in overweight and obese patients with type 2 diabetes, liraglutide 3.0 mg achieved an additional reduction in HbA1c of approximately 0.9% points over placebo at 56 weeks.¹²

Beneficial effects are also observed in non-diabetic individuals. As previously discussed, in the SELECT trial semaglutide markedly reduced the incidence of new-onset diabetes among patients with impaired fasting glucose—likely through improvements in peripheral insulin sensitivity and reductions in visceral adiposity.

Another central metabolic advantage concerns blood pressure control. Both GLP-1 receptor agonists and tirzepatide induce a modest but significant lowering of systemic arterial pressure (a mean reduction of 3–5 mmHg in systolic blood pressure), attributable to a combination of weight loss, natriuresis, and possible direct vasodilatory effects mediated by GLP-1.¹³

Lipid profiles also improve with these therapies. Reductions in plasma triglycerides and LDL cholesterol, accompanied by modest increases in HDL cholesterol, are consistently reported—changes that align with weight loss and with hepatic metabolic modulation: GLP-1 reduces hepatic VLDL synthesis.¹⁴

Finally, a particularly relevant effect is the reduction in systemic inflammation. The decline in hsCRP observed both in SELECT and in the HFpEF trials reflects attenuation of the chronic low-grade inflammatory state characteristic of obesity. Similarly, reductions in circulating interleukin-6 have been documented following GLP-1 RA therapy. In one trial involving patients with diabetes, 26 weeks of liraglutide treatment led to a significant decrease in IL-6 levels (−22.6% vs. placebo).¹⁵

This anti-inflammatory effect—mediated partly by adipose mass reduction and partly by direct immunomodulatory actions of GLP-1—may contribute to improved endothelial function and a reduction in cardiovascular risk. Notably, decreases in inflammatory markers often parallel improvements in other pathological parameters. In the aforementioned study, liraglutide also significantly reduced the urinary albumin-to-creatinine ratio, suggesting a link between anti-inflammatory effects and organ protection.

Together, these metabolic benefits—superimposed upon substantial fat mass reduction—contribute to the establishment of a markedly improved cardiometabolic risk profile.

Conclusions

The new pharmacological therapies for obesity mark the beginning of a new era in the management of patients with excess body weight. Their effects extend beyond simple adipose tissue reduction; these agents produce integrated improvements in metabolic, cardiovascular, and inflammatory status, offering clinical benefits previously unattainable in a high-risk population with numerous unmet needs.

The evolution of GLP-1 receptor agonists and multi-agonist incretin-based therapies redefines obesity as a complex chronic disease requiring a structured and personalized therapeutic approach. Current evidence demonstrates that pharmacological treatment of obesity is no longer an ancillary intervention, but rather an emerging pillar of cardiometabolic prevention, that is poised to transform clinical practice in the coming years.

Funding

No funding provided.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Terapia farmacologica del paziente obeso: è solo una questione di perdita di grasso?’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.