https://orcid.org/0000-0001-8324-3275
Abstract
The prevalence of overweight and obesity has reached pandemic proportions. Obesity is known to increase the risk for Type 2 diabetes and hypertension, as well as the risk for overt cardiovascular (CV) disease, including myocardial infarction, heart failure, and stroke. The rising prevalence of obesity may counteract the recent advances in primary and secondary prevention of CV disease. Overweight and obesity are common in patients with CV disease; however, cardiologists face several challenges in managing body weight in this population. Many may not consider obesity as a therapeutic target probably because there were no previous highly effective and safe pharmacologic interventions to consider. In addition, they may not have the expertise or resources to implement lifestyle interventions and may have limited familiarity with obesity pharmacotherapy. Moreover, the long-term CV effects of obesity pharmacotherapy remain uncertain due to limited CV outcome data with weight loss as the primary intervention. Although current CV guidelines recognize the importance of weight loss, they primarily focus on lifestyle modifications, with fewer details on strategies to utilize obesity pharmacotherapy and surgery. However, the recent 2022 American Diabetes Association/European Association for the Study of Diabetes consensus on the management of Type 2 diabetes has moved up weight management to the front of the treatment algorithm, by prioritizing the use of pharmacologic interventions such as glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, which have potent weight-lowering effects, in addition to glucose-lowering effects. This review appraises the current evidence regarding the CV effects of weight-loss interventions. Considering this evidence, practical guidance is provided to assist cardiologists in developing and implementing treatment plans, which may allow optimal weight management while maximizing CV benefits and minimizing side effects to improve the overall well-being of people with CV disease.
Current evidence on the effect of each obesity intervention on weight, cardiovascular risk factors, and cardiovascular outcomes, along with indications for the use of these interventions. Tirzepatide not yet approved for weight management in EU but has completed Phase 3 weight loss trials and has ongoing cardiovascular outcome trials in patients with obesity. Weight losses displayed are estimates. AE, adverse event; BMI, body mass index; CV, cardiovascular; DBP, diastolic blood pressure; GI, gastrointestinal; OD, once-daily; OTC, over-the counter; OW, once-weekly; SBP, systolic blood pressure; SQ, subcutaneous; T2D, Type 2 diabetes; TID, three times daily.
Introduction
The prevalence of obesity has reached pandemic proportions. A 2019 survey showed that more than half of the adults living in the European Union (EU) were overweight [body mass index (BMI) of >25 to <30 kg/m2], and 17% were clinically obese (BMI ≥ 30 kg/m2).1 The burden is higher in the USA, where nearly 75% of adults are overweight, and over 40% meet the criteria for clinical obesity.2 Individuals with obesity are at high risk for the development of Type 2 diabetes (T2D) and cardiovascular (CV) risk factors such as hyperlipidaemia and hypertension.3 Moreover, obesity has a strong association with the incidence of overt CV disease, including coronary artery disease (CAD), heart failure (HF), and stroke, and recent evidence indicates that this association is causal in nature.3,4 The rising prevalence of obesity may therefore counteract the recent advances in primary and secondary prevention of CV disease.
Given this, it is important that weight management should play an integral role within the CV discipline. However, cardiologists face several challenges in managing patients with overweight or obesity. First, efforts to introduce lifestyle interventions for weight loss may seem futile, as studies have demonstrated that such weight-lowering interventions can be difficult to effectively implement, and sustained weight loss is very challenging. Furthermore, there is no evidence to date that lifestyle interventions lead to improved CV outcomes.5 Second, cardiologists often have limited expertise with obesity pharmacotherapy.6 In fact, some prejudice against obesity pharmacotherapy may exist since older medications, such as sibutramine and fenfluramine, were withdrawn from the market due to evidence of increased CV risk.7 Third, commonly used CV and glucose-lowering medications may impact weight in various ways, complicating weight management.8–10 Fourth, although current CV guidelines recognize the importance of weight loss, they primarily focus on lifestyle modifications, with fewer details on strategies to utilize for obesity pharmacotherapy and surgery.11–14 This may be, in part, due to the limited evidence on new and efficient interventions for obesity at the time these guidelines were formulated. In contrast, the recent 2022 American Diabetes Association/European Association for the Study of Diabetes consensus on the management of T2D has moved up weight management to the front of the treatment algorithm, prioritizing the use of pharmacologic interventions such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA such as tirzepatide, which have potent weight-lowering effects, in addition to glucose-lowering effects.
The emerging evidence on obesity pharmacotherapy and metabolic bariatric surgery merits a discussion regarding their place within cardiology. This review article highlights interventions with known weight-reducing effects and is licenced for weight management in Europe as well as including agents already with Phase 3 clinical trial data and appraises the current evidence regarding their CV effects. Practical guidance is provided to assist cardiologists in developing treatment plans, which may allow optimal weight management while maximizing CV benefits and minimizing intolerability and maximizing safe use.
Recognizing obesity as a disease
The concepts that obesity may simply be a ‘lifestyle choice’ or a ‘risk factor’ have remained pervasive amongst the general population as well as within the academic community. Recent evidence, however, has challenged the validity of these concepts, and it has been increasingly acknowledged that obesity is indeed ‘a chronic relapsing disease, which in turn acts as a gateway to a range of other chronic non-communicable diseases that affect survival and quality of life’.15 Many organizations now recognize obesity as a disease, including the European Commission, the Royal College of Physicians, and the American Medical Association.15–17 This is an important step towards ensuring that both the general public and the medical community take a systematic approach to the prevention, diagnosis, and management of obesity.
Obesity and cardiovascular disease
Atherosclerosis and coronary artery disease
The risk of CAD is 72% higher in men with obesity and ∼300% higher in women with obesity, compared with non-obese counterparts.3 Obesity-associated hypertension, hyperglycaemia, and dyslipidaemia are important drivers of CAD. However, even in the absence of these cardio-metabolic risk factors, increased visceral adiposity is associated with overt atherosclerotic lesions. This is likely driven by obesity-induced inflammation and oxidative stress; patients with obesity are known to have elevated levels of several pro-inflammatory adipokines such as interleukin-6, tumour necrosis factor-alpha, and C-reactive protein. Cellular level studies, including mRNA expression studies, show that adipocytes are a prominent source of these cytokines. Visceral adipose tissues (including ectopic fat depots) are particularly prone to infiltration with macrophages and subsequent up-regulation of inflammatory adipokines. Obesity-related inflammation has a number of downstream consequences, including endothelial damage, oxidation of LDL, and diminished nitric oxide levels, all of which contribute to the progression of atherosclerosis.18
Heart failure and arrhythmias
In both men and women, obesity is associated with a ∼80% increase in the risk of HF, especially with preserved ejection fraction (HFpEF).3 Increased adiposity directly impacts the heart, in part by ectopic myocardial fat deposition and fibrosis, which can lead to the development of HFpEF.18 In addition to direct effects on the heart, increased adiposity is associated with increased circulating blood volume. This increased stroke volume required to maintain circulation increases cardiac demand and results in wall stress, myocardial injury, left ventricular (LV) hypertrophy and remodelling, and systolic and diastolic abnormalities.18 Patients with obesity also have an increased burden of ventricular tachycardia and fibrillation, likely due to conduction abnormalities secondary to LV hypertrophy and fibrosis. Estimates suggest that obesity may be largely responsible for the recently documented increase in the burden of atrial fibrillation.18
Overview of current evidence on weight loss interventions
This review focuses on the CV effects of three types of weight-reducing interventions: (i) lifestyle interventions, (ii) obesity pharmacotherapy, and (iii) bariatric surgery. Focus is given to pharmacotherapy currently approved in the EU for weight management or those agents already with Phase 3 clinical trial results, while interventions that were not approved or withdrawn from the EU are discussed in the Supplementary data online, supplementary appendix. Table 1 provides an overview of the key clinical trials conducted for each available weight loss intervention, along with their findings. Figure 1 summarizes the effect of each weight-loss intervention on CV risk factors (blood pressure, heart rate, and lipid profile).
Expected effects of weight loss interventions on cardiovascular risk factors
Key clinical trials conducted with each weight loss intervention, along with their findings
| Trial | Population | Sample size | Baseline weight (kg) | Follow-up (weeks) | Weight loss (%) | Change in pulse (b.p.m.) | Change in SBP (mmHg) | Change in DBP (mmHg) | Change in LDL | Change in HDL | Change in TGs |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Intensive lifestyle intervention | |||||||||||
| Look AHEAD, 201319 | BMI ≥25 kg/m2 Diabetes | ILI: 2570 DSE: 2575 | ILI: 101 DSE: 101 | 499 | ILI: −6.0a DSE: −3.5 | N/A | ILI: −2b DSE: −2 | ILI: −3.7 DSE: −4.5 | ILI: −22.5 mg/dLb DSE: −23.7 mg/dL | ILI: +5.2 mg/dLb DSE: +4.3 mg/dL | ILI: −31 mg/dL DSE: −30 mg/dL |
| Diabetes Prevention Programme, 200220 | BMI ≥24 kg/m2 Pre-diabetes | ILI: 1079 Met: 1073 Pla: 1082 | ILI: 94 Met: 94 Pla: 94 | 146 | ILI: −6.0a Met: −2.1a Pla: −0.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| Liraglutide | |||||||||||
| SCALE Obesity and Prediabetes, 201521 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Lira 3.0 mg SQ OD: 2487 Pla: 1244 | Lira 3.0: 106 Pla: 106 | 56 | Lira 3.0: −8.0a Pla: −2.6 | Lira 3.0: +2.5a Pla: 0.1 | Lira 3.0: −4.2a Pla: −1.5 | Lira 3.0: −2.6a Pla: −1.9 | Lira 3.0: −3.0%a Pla: −1.0% | Lira 3.0: +2.3%a Pla: +0.7% | Lira 3.0: −13.3%a Pla: −5.5% |
| SCALE Diabetes, 201522 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Lira 3.0 mg SQ OD: 423 Lira 1.8 mg SQ OD: 211 Pla: 212 | Lira 3.0: 106 Lira 1.8: 106 Pla: 107 | 56 | Lira 3.0: −6.0a Lira 1.8: −4.7a Pla: −2.0 | N/A | Lira 3.0: −2.8a Lira 1.8: −3.5a Pla: −0.4 | Lira 3.0: −0.9 Lira 1.8: −1.1 Pla: −0.5 | Lira 3.0: −0.6% Lira 1.8: −3.1% Pla: +5.0% | Lira 3.0: +4.7%a Lira 1.8: +4.5% Pla: + 1.9% | Lira 3.0: −14.7%a Lira 1.8: −9.5% Pla: +0.4% |
| Semaglutide | |||||||||||
| STEP 1 trial, 202123 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 1306 Pla: 655 | Sema 2.4: 105 Pla: 105 | 68 | Sema 2.4: −14.9a Pla: −2.4 | Sema 2.4: −3.5a Pla: −0.7 | Sema 2.4: −6.2a Pla: −1.1 | Sema 2.4: −2.8a Pla: −0.4 | Sema 2.4: −3.0%a Pla: +1% | Sema 2.4: +5.0%a Pla: +1% | Sema 2.4: −22.0%a Pla: −7% |
| STEP 2 trial, 202124 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Sema 2.4 mg SQ OW: 404 Sema 1.0 mg SQ OW: 403 Pla: 403 | Sema 2.4: 100 Sema 1.0: 99 Pla: 101 | 68 | Sema 2.4: −9.64a Sema 1.0: −7.0a Pla: −3.42 | N/A | Sema 2.4: −3.9a Sema 1.0: −2.9a Pla: −0.5 | Sema 2.4: −1.6 Sema 1.0: −0.6 Pla: −0.9 | Sema 2.4: 0% Sema 1.0: −1.0% Pla: 0% | Sema 2.4: +7% Sema 1.0: +5% Pla: +4% | Sema 2.4: −22%a Sema 1.0: −17%a Pla: −9% |
| STEP 3 trial, 202125 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 407 Pla: 204 | Sema 2.4: 107 Pla: 104 | 68 | Sema 2.4: −16.0a Pla: −5.7 | N/A | Sema 2.4: −5.6a Pla: −1.6 | Sema 2.4: −3.0a Pla: −0.8 | Sema 2.4: −4.7%a Pla: +2.6% | Sema 2.4: +6.5% Pla: +5.0% | Sema 2.4: −22.5%a Pla: −6.5% |
| Tirzepatide | |||||||||||
| SURMOUNT-1, 202226 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Tirze 5 mg SQ OW: 630 Tirze 10 mg SQ OW: 636 Tirze 15 mg SQ OW: 630 Pla: 643 | Tirze 5: 103 Tirze 10: 106 Tirze 15: 106 Pla: 105 | 72 | Tirze 5: −15.0a Tirze 10: −19.5a Tirze 15: −20.9a Pla: −3.1 | Tirze: +1.8a Pla: +0.1 | Tirze: −7.2a Pla: −1.0 | Tirze: −4.8a Pla: −0.8 | Tirze: −5.8%a Pla: −1.7% | Tirze: +8.0%a Pla: −0.7% | Tirze: −24.8%a Pla: −5.6% |
| Naltrexone/bupropion | |||||||||||
| COR-I, 201027 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 583 NB 16/360 mg per day (in 2 doses): 578 Placebo: 581 | NB 32: 100 NB 16: 100 Pla: 100 | 56 | NB 32: −6.1a NB 16: −Pla: −1.3 | NB 32: +0.4a NB 16: +1.1a Pla: −1.0 | NB 32: −0.1a NB 16: +0.3a Pla: −1.9 | NB 32: 0.0a NB 16: +0.1a Pla: −0.9 | NB 32: −2.0%a NB 16: −1.5%a Pla: −0.5% | NB 32: +8.0%a NB 16: +7.6%a Pla: +0.8% | NB 32: −12.7%a NB 16: −8.0%a Pla: −3.1% |
| COR-II, 201328 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 1001 Placebo: 495 | NB 32: 100 Pla: 99 | 56 | NB 32: −6.4a Pla: −1.2 | NB 32: +0.8a Pla: −0.3 | NB 32: +0.6a Pla: −0.5 | NB 32: +0.4 Pla: +0.3 | NB 32: −6.2 mg/dLa Pla: −2.1 mg/dL | NB 32: +3.6 mg/dLa Pla: −0.9 mg/dL | NB 32: −9.8%a Pla: −0.5% |
| COR-BMOD, 201129 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 591 Placebo: 202 | NB 32: 102 Pla: 100 | 56 | NB 32: −9.3a Pla: −5.1 | NB 32: +1.1 Pla: +0.2 | NB 32: −1.3 Pla: −3.9 | NB 32: −1.4 Pla: −2.8 | NB 32: +7.1% Pla: +10.0% | NB 32: +9.4%a Pla: +2.8% | NB 32: −16.6%a Pla: −8.5% |
| COR-Diabetes, 201330 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | NB 32/360 mg per day (in 2 doses): 265 Placebo: 159 | NB 32: 106 Pla: 105 | 56 | NB 32: −5.0a Pla: −1.8 | N/A | NB 32: 0 Pla: −1.1 | NB 32: −1.1 Pla: −1.5 | NB 32: −1.4 mg/dL Pla: 0 mg/dL | NB 32: +3.0a mg/dL Pla: −0.3 mg/dL | NB 32: −11.2%a Pla: −0.8% |
| LIGHT, 201631 | BMI ≥27 kg/m2 Diabetes (with hypertension, dyslipidaemia, low HDL, or smoker) | NB 32/360 mg per day (in 2 doses): 4455 Placebo: 4450 | NB 32 mg: 105 Pla: 106 | 208 | NB 32 mg: −3.71a Pla:−1.13 | NB 32: +0.7 Pla: +0.6 | NB 32: +1.4 Pla: +0.5 | N/A | N/A | N/A | N/A |
| Orlistat | |||||||||||
| Chanoine et al, 200532 | Adolescents BMI ≥2 units of 95th percentile (12 years: >28.5 boys, >29.5 girls; 16 years: 31.8 boys, 31.9 girls) Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 352 Placebo: 181 | Orl 120: 98 Pla: 95 | 54 | Orl 120: +0.54a Pla: +3.3 | N/A | Orl 120: +1.09 Pla: +1.31 | Orl 120: −0.51a Pla: +1.30 | Orl 120: −0.99 Pla: +0.88 | Orl 120: +0.07 Pla: −0.31 | Orl 120: +17.9 Pla: +11.68 |
| Sjöström et al., 199833 | BMI ≥28 kg/m2 Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 343 Placebo: 340 | Orl 120: 99 Pla: 100 | 52 | Orl 120: −10.2a Pla: −6.1 | N/A | Orl 120: −6a Pla: −3 | Orl 120: −4.5a Pla: −2.7 | Orl 120: −0.36 mmol/La Pla: −0.04 mmol/L | Orl 120: + 0.07 mmol/L Pla: −0.32 mmol/L | Orl 120: −0.13 mmol/L Pla: −0.13 mmol/L |
| Bariatric surgery | |||||||||||
| STAMPEDE, 201734 | BMI ≥27 kg/m2 HbA1c > 7.0% | GB: 49 SG: 47 MT: 38 | GB: 107 SG: 100 MT: 105 | 260 | GB: −21.7a SG: −18.5a MT: −5.0 | NA | GB: −3.3c SG: −8.4c MT: −4.1 | GB: −5.8c SG: −8.1c MT: −4.4 | GB: +12.4%c SG: +16.6%c MT: +3.7% | GB: +31.9%a SG: +29.6%a MT: +7.0% | GB: −39.8%a SG: −29.4%a MT: −8.3% |
| GATEWAY, 201835 | BMI ≥30 kg/m2 Hypertension No diabetes | GB: 50 MT: 50 | GB: 102 MT: 100 | 52 | GB: −28.9a MT: −0.69 | N/A | GB: +0.8c MT: +5.2 | GB: −0.4c MT: +2.4 | GB: −35.0a MT: −7.4 | GB: +9.8a MT: +1.7 | GB: −81.5a MT: −22.9 |
| Trial | Population | Sample size | Baseline weight (kg) | Follow-up (weeks) | Weight loss (%) | Change in pulse (b.p.m.) | Change in SBP (mmHg) | Change in DBP (mmHg) | Change in LDL | Change in HDL | Change in TGs |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Intensive lifestyle intervention | |||||||||||
| Look AHEAD, 201319 | BMI ≥25 kg/m2 Diabetes | ILI: 2570 DSE: 2575 | ILI: 101 DSE: 101 | 499 | ILI: −6.0a DSE: −3.5 | N/A | ILI: −2b DSE: −2 | ILI: −3.7 DSE: −4.5 | ILI: −22.5 mg/dLb DSE: −23.7 mg/dL | ILI: +5.2 mg/dLb DSE: +4.3 mg/dL | ILI: −31 mg/dL DSE: −30 mg/dL |
| Diabetes Prevention Programme, 200220 | BMI ≥24 kg/m2 Pre-diabetes | ILI: 1079 Met: 1073 Pla: 1082 | ILI: 94 Met: 94 Pla: 94 | 146 | ILI: −6.0a Met: −2.1a Pla: −0.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| Liraglutide | |||||||||||
| SCALE Obesity and Prediabetes, 201521 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Lira 3.0 mg SQ OD: 2487 Pla: 1244 | Lira 3.0: 106 Pla: 106 | 56 | Lira 3.0: −8.0a Pla: −2.6 | Lira 3.0: +2.5a Pla: 0.1 | Lira 3.0: −4.2a Pla: −1.5 | Lira 3.0: −2.6a Pla: −1.9 | Lira 3.0: −3.0%a Pla: −1.0% | Lira 3.0: +2.3%a Pla: +0.7% | Lira 3.0: −13.3%a Pla: −5.5% |
| SCALE Diabetes, 201522 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Lira 3.0 mg SQ OD: 423 Lira 1.8 mg SQ OD: 211 Pla: 212 | Lira 3.0: 106 Lira 1.8: 106 Pla: 107 | 56 | Lira 3.0: −6.0a Lira 1.8: −4.7a Pla: −2.0 | N/A | Lira 3.0: −2.8a Lira 1.8: −3.5a Pla: −0.4 | Lira 3.0: −0.9 Lira 1.8: −1.1 Pla: −0.5 | Lira 3.0: −0.6% Lira 1.8: −3.1% Pla: +5.0% | Lira 3.0: +4.7%a Lira 1.8: +4.5% Pla: + 1.9% | Lira 3.0: −14.7%a Lira 1.8: −9.5% Pla: +0.4% |
| Semaglutide | |||||||||||
| STEP 1 trial, 202123 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 1306 Pla: 655 | Sema 2.4: 105 Pla: 105 | 68 | Sema 2.4: −14.9a Pla: −2.4 | Sema 2.4: −3.5a Pla: −0.7 | Sema 2.4: −6.2a Pla: −1.1 | Sema 2.4: −2.8a Pla: −0.4 | Sema 2.4: −3.0%a Pla: +1% | Sema 2.4: +5.0%a Pla: +1% | Sema 2.4: −22.0%a Pla: −7% |
| STEP 2 trial, 202124 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Sema 2.4 mg SQ OW: 404 Sema 1.0 mg SQ OW: 403 Pla: 403 | Sema 2.4: 100 Sema 1.0: 99 Pla: 101 | 68 | Sema 2.4: −9.64a Sema 1.0: −7.0a Pla: −3.42 | N/A | Sema 2.4: −3.9a Sema 1.0: −2.9a Pla: −0.5 | Sema 2.4: −1.6 Sema 1.0: −0.6 Pla: −0.9 | Sema 2.4: 0% Sema 1.0: −1.0% Pla: 0% | Sema 2.4: +7% Sema 1.0: +5% Pla: +4% | Sema 2.4: −22%a Sema 1.0: −17%a Pla: −9% |
| STEP 3 trial, 202125 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 407 Pla: 204 | Sema 2.4: 107 Pla: 104 | 68 | Sema 2.4: −16.0a Pla: −5.7 | N/A | Sema 2.4: −5.6a Pla: −1.6 | Sema 2.4: −3.0a Pla: −0.8 | Sema 2.4: −4.7%a Pla: +2.6% | Sema 2.4: +6.5% Pla: +5.0% | Sema 2.4: −22.5%a Pla: −6.5% |
| Tirzepatide | |||||||||||
| SURMOUNT-1, 202226 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Tirze 5 mg SQ OW: 630 Tirze 10 mg SQ OW: 636 Tirze 15 mg SQ OW: 630 Pla: 643 | Tirze 5: 103 Tirze 10: 106 Tirze 15: 106 Pla: 105 | 72 | Tirze 5: −15.0a Tirze 10: −19.5a Tirze 15: −20.9a Pla: −3.1 | Tirze: +1.8a Pla: +0.1 | Tirze: −7.2a Pla: −1.0 | Tirze: −4.8a Pla: −0.8 | Tirze: −5.8%a Pla: −1.7% | Tirze: +8.0%a Pla: −0.7% | Tirze: −24.8%a Pla: −5.6% |
| Naltrexone/bupropion | |||||||||||
| COR-I, 201027 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 583 NB 16/360 mg per day (in 2 doses): 578 Placebo: 581 | NB 32: 100 NB 16: 100 Pla: 100 | 56 | NB 32: −6.1a NB 16: −Pla: −1.3 | NB 32: +0.4a NB 16: +1.1a Pla: −1.0 | NB 32: −0.1a NB 16: +0.3a Pla: −1.9 | NB 32: 0.0a NB 16: +0.1a Pla: −0.9 | NB 32: −2.0%a NB 16: −1.5%a Pla: −0.5% | NB 32: +8.0%a NB 16: +7.6%a Pla: +0.8% | NB 32: −12.7%a NB 16: −8.0%a Pla: −3.1% |
| COR-II, 201328 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 1001 Placebo: 495 | NB 32: 100 Pla: 99 | 56 | NB 32: −6.4a Pla: −1.2 | NB 32: +0.8a Pla: −0.3 | NB 32: +0.6a Pla: −0.5 | NB 32: +0.4 Pla: +0.3 | NB 32: −6.2 mg/dLa Pla: −2.1 mg/dL | NB 32: +3.6 mg/dLa Pla: −0.9 mg/dL | NB 32: −9.8%a Pla: −0.5% |
| COR-BMOD, 201129 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 591 Placebo: 202 | NB 32: 102 Pla: 100 | 56 | NB 32: −9.3a Pla: −5.1 | NB 32: +1.1 Pla: +0.2 | NB 32: −1.3 Pla: −3.9 | NB 32: −1.4 Pla: −2.8 | NB 32: +7.1% Pla: +10.0% | NB 32: +9.4%a Pla: +2.8% | NB 32: −16.6%a Pla: −8.5% |
| COR-Diabetes, 201330 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | NB 32/360 mg per day (in 2 doses): 265 Placebo: 159 | NB 32: 106 Pla: 105 | 56 | NB 32: −5.0a Pla: −1.8 | N/A | NB 32: 0 Pla: −1.1 | NB 32: −1.1 Pla: −1.5 | NB 32: −1.4 mg/dL Pla: 0 mg/dL | NB 32: +3.0a mg/dL Pla: −0.3 mg/dL | NB 32: −11.2%a Pla: −0.8% |
| LIGHT, 201631 | BMI ≥27 kg/m2 Diabetes (with hypertension, dyslipidaemia, low HDL, or smoker) | NB 32/360 mg per day (in 2 doses): 4455 Placebo: 4450 | NB 32 mg: 105 Pla: 106 | 208 | NB 32 mg: −3.71a Pla:−1.13 | NB 32: +0.7 Pla: +0.6 | NB 32: +1.4 Pla: +0.5 | N/A | N/A | N/A | N/A |
| Orlistat | |||||||||||
| Chanoine et al, 200532 | Adolescents BMI ≥2 units of 95th percentile (12 years: >28.5 boys, >29.5 girls; 16 years: 31.8 boys, 31.9 girls) Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 352 Placebo: 181 | Orl 120: 98 Pla: 95 | 54 | Orl 120: +0.54a Pla: +3.3 | N/A | Orl 120: +1.09 Pla: +1.31 | Orl 120: −0.51a Pla: +1.30 | Orl 120: −0.99 Pla: +0.88 | Orl 120: +0.07 Pla: −0.31 | Orl 120: +17.9 Pla: +11.68 |
| Sjöström et al., 199833 | BMI ≥28 kg/m2 Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 343 Placebo: 340 | Orl 120: 99 Pla: 100 | 52 | Orl 120: −10.2a Pla: −6.1 | N/A | Orl 120: −6a Pla: −3 | Orl 120: −4.5a Pla: −2.7 | Orl 120: −0.36 mmol/La Pla: −0.04 mmol/L | Orl 120: + 0.07 mmol/L Pla: −0.32 mmol/L | Orl 120: −0.13 mmol/L Pla: −0.13 mmol/L |
| Bariatric surgery | |||||||||||
| STAMPEDE, 201734 | BMI ≥27 kg/m2 HbA1c > 7.0% | GB: 49 SG: 47 MT: 38 | GB: 107 SG: 100 MT: 105 | 260 | GB: −21.7a SG: −18.5a MT: −5.0 | NA | GB: −3.3c SG: −8.4c MT: −4.1 | GB: −5.8c SG: −8.1c MT: −4.4 | GB: +12.4%c SG: +16.6%c MT: +3.7% | GB: +31.9%a SG: +29.6%a MT: +7.0% | GB: −39.8%a SG: −29.4%a MT: −8.3% |
| GATEWAY, 201835 | BMI ≥30 kg/m2 Hypertension No diabetes | GB: 50 MT: 50 | GB: 102 MT: 100 | 52 | GB: −28.9a MT: −0.69 | N/A | GB: +0.8c MT: +5.2 | GB: −0.4c MT: +2.4 | GB: −35.0a MT: −7.4 | GB: +9.8a MT: +1.7 | GB: −81.5a MT: −22.9 |
SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; BMI, body mass index; Look AHEAD, Action for Health in Diabetes; ILI, intensive lifestyle intervention; DSE, diabetes support and education; Met, metformin; Pla, placebo; N/A, not available; SCALE, Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities; Lira, liraglutide; STEP, Semaglutide Treatment Effect in People with Obesity; Sema, semaglutide; SURMOUNT, A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight; Tirze, Tirzepatide; DP, diethylpropion; NB, naltrexone/bupropion; COR, A Study of the Safety and Efficacy of Two Doses of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects; NB, Naltrexone/bupropion; LIGHT, Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors; Orl, orlistat; STAMPEDE, Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently; GB, Gastric bypass; SG, sleeve gastrectomy; MT, medical therapy; GATEWAY, Gastric Bypass to Treat Obese Patients With Steady Hypertension.
aP < .05 for intervention vs. control.
bAlthough values for these parameters were similar between the ILI and DSE groups at the end of the trial, a significant improvement was noted with ILI on average over the entire trial period.
cA significant benefit of the intervention on this parameter was not observed likely due to lower anti-hypertensive/anti-lipidaemic drug use in the intervention arm/anti-lipidaemic drug use in the intervention arm.
Key clinical trials conducted with each weight loss intervention, along with their findings
| Trial | Population | Sample size | Baseline weight (kg) | Follow-up (weeks) | Weight loss (%) | Change in pulse (b.p.m.) | Change in SBP (mmHg) | Change in DBP (mmHg) | Change in LDL | Change in HDL | Change in TGs |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Intensive lifestyle intervention | |||||||||||
| Look AHEAD, 201319 | BMI ≥25 kg/m2 Diabetes | ILI: 2570 DSE: 2575 | ILI: 101 DSE: 101 | 499 | ILI: −6.0a DSE: −3.5 | N/A | ILI: −2b DSE: −2 | ILI: −3.7 DSE: −4.5 | ILI: −22.5 mg/dLb DSE: −23.7 mg/dL | ILI: +5.2 mg/dLb DSE: +4.3 mg/dL | ILI: −31 mg/dL DSE: −30 mg/dL |
| Diabetes Prevention Programme, 200220 | BMI ≥24 kg/m2 Pre-diabetes | ILI: 1079 Met: 1073 Pla: 1082 | ILI: 94 Met: 94 Pla: 94 | 146 | ILI: −6.0a Met: −2.1a Pla: −0.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| Liraglutide | |||||||||||
| SCALE Obesity and Prediabetes, 201521 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Lira 3.0 mg SQ OD: 2487 Pla: 1244 | Lira 3.0: 106 Pla: 106 | 56 | Lira 3.0: −8.0a Pla: −2.6 | Lira 3.0: +2.5a Pla: 0.1 | Lira 3.0: −4.2a Pla: −1.5 | Lira 3.0: −2.6a Pla: −1.9 | Lira 3.0: −3.0%a Pla: −1.0% | Lira 3.0: +2.3%a Pla: +0.7% | Lira 3.0: −13.3%a Pla: −5.5% |
| SCALE Diabetes, 201522 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Lira 3.0 mg SQ OD: 423 Lira 1.8 mg SQ OD: 211 Pla: 212 | Lira 3.0: 106 Lira 1.8: 106 Pla: 107 | 56 | Lira 3.0: −6.0a Lira 1.8: −4.7a Pla: −2.0 | N/A | Lira 3.0: −2.8a Lira 1.8: −3.5a Pla: −0.4 | Lira 3.0: −0.9 Lira 1.8: −1.1 Pla: −0.5 | Lira 3.0: −0.6% Lira 1.8: −3.1% Pla: +5.0% | Lira 3.0: +4.7%a Lira 1.8: +4.5% Pla: + 1.9% | Lira 3.0: −14.7%a Lira 1.8: −9.5% Pla: +0.4% |
| Semaglutide | |||||||||||
| STEP 1 trial, 202123 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 1306 Pla: 655 | Sema 2.4: 105 Pla: 105 | 68 | Sema 2.4: −14.9a Pla: −2.4 | Sema 2.4: −3.5a Pla: −0.7 | Sema 2.4: −6.2a Pla: −1.1 | Sema 2.4: −2.8a Pla: −0.4 | Sema 2.4: −3.0%a Pla: +1% | Sema 2.4: +5.0%a Pla: +1% | Sema 2.4: −22.0%a Pla: −7% |
| STEP 2 trial, 202124 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Sema 2.4 mg SQ OW: 404 Sema 1.0 mg SQ OW: 403 Pla: 403 | Sema 2.4: 100 Sema 1.0: 99 Pla: 101 | 68 | Sema 2.4: −9.64a Sema 1.0: −7.0a Pla: −3.42 | N/A | Sema 2.4: −3.9a Sema 1.0: −2.9a Pla: −0.5 | Sema 2.4: −1.6 Sema 1.0: −0.6 Pla: −0.9 | Sema 2.4: 0% Sema 1.0: −1.0% Pla: 0% | Sema 2.4: +7% Sema 1.0: +5% Pla: +4% | Sema 2.4: −22%a Sema 1.0: −17%a Pla: −9% |
| STEP 3 trial, 202125 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 407 Pla: 204 | Sema 2.4: 107 Pla: 104 | 68 | Sema 2.4: −16.0a Pla: −5.7 | N/A | Sema 2.4: −5.6a Pla: −1.6 | Sema 2.4: −3.0a Pla: −0.8 | Sema 2.4: −4.7%a Pla: +2.6% | Sema 2.4: +6.5% Pla: +5.0% | Sema 2.4: −22.5%a Pla: −6.5% |
| Tirzepatide | |||||||||||
| SURMOUNT-1, 202226 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Tirze 5 mg SQ OW: 630 Tirze 10 mg SQ OW: 636 Tirze 15 mg SQ OW: 630 Pla: 643 | Tirze 5: 103 Tirze 10: 106 Tirze 15: 106 Pla: 105 | 72 | Tirze 5: −15.0a Tirze 10: −19.5a Tirze 15: −20.9a Pla: −3.1 | Tirze: +1.8a Pla: +0.1 | Tirze: −7.2a Pla: −1.0 | Tirze: −4.8a Pla: −0.8 | Tirze: −5.8%a Pla: −1.7% | Tirze: +8.0%a Pla: −0.7% | Tirze: −24.8%a Pla: −5.6% |
| Naltrexone/bupropion | |||||||||||
| COR-I, 201027 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 583 NB 16/360 mg per day (in 2 doses): 578 Placebo: 581 | NB 32: 100 NB 16: 100 Pla: 100 | 56 | NB 32: −6.1a NB 16: −Pla: −1.3 | NB 32: +0.4a NB 16: +1.1a Pla: −1.0 | NB 32: −0.1a NB 16: +0.3a Pla: −1.9 | NB 32: 0.0a NB 16: +0.1a Pla: −0.9 | NB 32: −2.0%a NB 16: −1.5%a Pla: −0.5% | NB 32: +8.0%a NB 16: +7.6%a Pla: +0.8% | NB 32: −12.7%a NB 16: −8.0%a Pla: −3.1% |
| COR-II, 201328 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 1001 Placebo: 495 | NB 32: 100 Pla: 99 | 56 | NB 32: −6.4a Pla: −1.2 | NB 32: +0.8a Pla: −0.3 | NB 32: +0.6a Pla: −0.5 | NB 32: +0.4 Pla: +0.3 | NB 32: −6.2 mg/dLa Pla: −2.1 mg/dL | NB 32: +3.6 mg/dLa Pla: −0.9 mg/dL | NB 32: −9.8%a Pla: −0.5% |
| COR-BMOD, 201129 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 591 Placebo: 202 | NB 32: 102 Pla: 100 | 56 | NB 32: −9.3a Pla: −5.1 | NB 32: +1.1 Pla: +0.2 | NB 32: −1.3 Pla: −3.9 | NB 32: −1.4 Pla: −2.8 | NB 32: +7.1% Pla: +10.0% | NB 32: +9.4%a Pla: +2.8% | NB 32: −16.6%a Pla: −8.5% |
| COR-Diabetes, 201330 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | NB 32/360 mg per day (in 2 doses): 265 Placebo: 159 | NB 32: 106 Pla: 105 | 56 | NB 32: −5.0a Pla: −1.8 | N/A | NB 32: 0 Pla: −1.1 | NB 32: −1.1 Pla: −1.5 | NB 32: −1.4 mg/dL Pla: 0 mg/dL | NB 32: +3.0a mg/dL Pla: −0.3 mg/dL | NB 32: −11.2%a Pla: −0.8% |
| LIGHT, 201631 | BMI ≥27 kg/m2 Diabetes (with hypertension, dyslipidaemia, low HDL, or smoker) | NB 32/360 mg per day (in 2 doses): 4455 Placebo: 4450 | NB 32 mg: 105 Pla: 106 | 208 | NB 32 mg: −3.71a Pla:−1.13 | NB 32: +0.7 Pla: +0.6 | NB 32: +1.4 Pla: +0.5 | N/A | N/A | N/A | N/A |
| Orlistat | |||||||||||
| Chanoine et al, 200532 | Adolescents BMI ≥2 units of 95th percentile (12 years: >28.5 boys, >29.5 girls; 16 years: 31.8 boys, 31.9 girls) Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 352 Placebo: 181 | Orl 120: 98 Pla: 95 | 54 | Orl 120: +0.54a Pla: +3.3 | N/A | Orl 120: +1.09 Pla: +1.31 | Orl 120: −0.51a Pla: +1.30 | Orl 120: −0.99 Pla: +0.88 | Orl 120: +0.07 Pla: −0.31 | Orl 120: +17.9 Pla: +11.68 |
| Sjöström et al., 199833 | BMI ≥28 kg/m2 Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 343 Placebo: 340 | Orl 120: 99 Pla: 100 | 52 | Orl 120: −10.2a Pla: −6.1 | N/A | Orl 120: −6a Pla: −3 | Orl 120: −4.5a Pla: −2.7 | Orl 120: −0.36 mmol/La Pla: −0.04 mmol/L | Orl 120: + 0.07 mmol/L Pla: −0.32 mmol/L | Orl 120: −0.13 mmol/L Pla: −0.13 mmol/L |
| Bariatric surgery | |||||||||||
| STAMPEDE, 201734 | BMI ≥27 kg/m2 HbA1c > 7.0% | GB: 49 SG: 47 MT: 38 | GB: 107 SG: 100 MT: 105 | 260 | GB: −21.7a SG: −18.5a MT: −5.0 | NA | GB: −3.3c SG: −8.4c MT: −4.1 | GB: −5.8c SG: −8.1c MT: −4.4 | GB: +12.4%c SG: +16.6%c MT: +3.7% | GB: +31.9%a SG: +29.6%a MT: +7.0% | GB: −39.8%a SG: −29.4%a MT: −8.3% |
| GATEWAY, 201835 | BMI ≥30 kg/m2 Hypertension No diabetes | GB: 50 MT: 50 | GB: 102 MT: 100 | 52 | GB: −28.9a MT: −0.69 | N/A | GB: +0.8c MT: +5.2 | GB: −0.4c MT: +2.4 | GB: −35.0a MT: −7.4 | GB: +9.8a MT: +1.7 | GB: −81.5a MT: −22.9 |
| Trial | Population | Sample size | Baseline weight (kg) | Follow-up (weeks) | Weight loss (%) | Change in pulse (b.p.m.) | Change in SBP (mmHg) | Change in DBP (mmHg) | Change in LDL | Change in HDL | Change in TGs |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Intensive lifestyle intervention | |||||||||||
| Look AHEAD, 201319 | BMI ≥25 kg/m2 Diabetes | ILI: 2570 DSE: 2575 | ILI: 101 DSE: 101 | 499 | ILI: −6.0a DSE: −3.5 | N/A | ILI: −2b DSE: −2 | ILI: −3.7 DSE: −4.5 | ILI: −22.5 mg/dLb DSE: −23.7 mg/dL | ILI: +5.2 mg/dLb DSE: +4.3 mg/dL | ILI: −31 mg/dL DSE: −30 mg/dL |
| Diabetes Prevention Programme, 200220 | BMI ≥24 kg/m2 Pre-diabetes | ILI: 1079 Met: 1073 Pla: 1082 | ILI: 94 Met: 94 Pla: 94 | 146 | ILI: −6.0a Met: −2.1a Pla: −0.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| Liraglutide | |||||||||||
| SCALE Obesity and Prediabetes, 201521 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Lira 3.0 mg SQ OD: 2487 Pla: 1244 | Lira 3.0: 106 Pla: 106 | 56 | Lira 3.0: −8.0a Pla: −2.6 | Lira 3.0: +2.5a Pla: 0.1 | Lira 3.0: −4.2a Pla: −1.5 | Lira 3.0: −2.6a Pla: −1.9 | Lira 3.0: −3.0%a Pla: −1.0% | Lira 3.0: +2.3%a Pla: +0.7% | Lira 3.0: −13.3%a Pla: −5.5% |
| SCALE Diabetes, 201522 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Lira 3.0 mg SQ OD: 423 Lira 1.8 mg SQ OD: 211 Pla: 212 | Lira 3.0: 106 Lira 1.8: 106 Pla: 107 | 56 | Lira 3.0: −6.0a Lira 1.8: −4.7a Pla: −2.0 | N/A | Lira 3.0: −2.8a Lira 1.8: −3.5a Pla: −0.4 | Lira 3.0: −0.9 Lira 1.8: −1.1 Pla: −0.5 | Lira 3.0: −0.6% Lira 1.8: −3.1% Pla: +5.0% | Lira 3.0: +4.7%a Lira 1.8: +4.5% Pla: + 1.9% | Lira 3.0: −14.7%a Lira 1.8: −9.5% Pla: +0.4% |
| Semaglutide | |||||||||||
| STEP 1 trial, 202123 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if untreated weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 1306 Pla: 655 | Sema 2.4: 105 Pla: 105 | 68 | Sema 2.4: −14.9a Pla: −2.4 | Sema 2.4: −3.5a Pla: −0.7 | Sema 2.4: −6.2a Pla: −1.1 | Sema 2.4: −2.8a Pla: −0.4 | Sema 2.4: −3.0%a Pla: +1% | Sema 2.4: +5.0%a Pla: +1% | Sema 2.4: −22.0%a Pla: −7% |
| STEP 2 trial, 202124 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | Sema 2.4 mg SQ OW: 404 Sema 1.0 mg SQ OW: 403 Pla: 403 | Sema 2.4: 100 Sema 1.0: 99 Pla: 101 | 68 | Sema 2.4: −9.64a Sema 1.0: −7.0a Pla: −3.42 | N/A | Sema 2.4: −3.9a Sema 1.0: −2.9a Pla: −0.5 | Sema 2.4: −1.6 Sema 1.0: −0.6 Pla: −0.9 | Sema 2.4: 0% Sema 1.0: −1.0% Pla: 0% | Sema 2.4: +7% Sema 1.0: +5% Pla: +4% | Sema 2.4: −22%a Sema 1.0: −17%a Pla: −9% |
| STEP 3 trial, 202125 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Sema 2.4 mg SQ OW: 407 Pla: 204 | Sema 2.4: 107 Pla: 104 | 68 | Sema 2.4: −16.0a Pla: −5.7 | N/A | Sema 2.4: −5.6a Pla: −1.6 | Sema 2.4: −3.0a Pla: −0.8 | Sema 2.4: −4.7%a Pla: +2.6% | Sema 2.4: +6.5% Pla: +5.0% | Sema 2.4: −22.5%a Pla: −6.5% |
| Tirzepatide | |||||||||||
| SURMOUNT-1, 202226 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | Tirze 5 mg SQ OW: 630 Tirze 10 mg SQ OW: 636 Tirze 15 mg SQ OW: 630 Pla: 643 | Tirze 5: 103 Tirze 10: 106 Tirze 15: 106 Pla: 105 | 72 | Tirze 5: −15.0a Tirze 10: −19.5a Tirze 15: −20.9a Pla: −3.1 | Tirze: +1.8a Pla: +0.1 | Tirze: −7.2a Pla: −1.0 | Tirze: −4.8a Pla: −0.8 | Tirze: −5.8%a Pla: −1.7% | Tirze: +8.0%a Pla: −0.7% | Tirze: −24.8%a Pla: −5.6% |
| Naltrexone/bupropion | |||||||||||
| COR-I, 201027 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 583 NB 16/360 mg per day (in 2 doses): 578 Placebo: 581 | NB 32: 100 NB 16: 100 Pla: 100 | 56 | NB 32: −6.1a NB 16: −Pla: −1.3 | NB 32: +0.4a NB 16: +1.1a Pla: −1.0 | NB 32: −0.1a NB 16: +0.3a Pla: −1.9 | NB 32: 0.0a NB 16: +0.1a Pla: −0.9 | NB 32: −2.0%a NB 16: −1.5%a Pla: −0.5% | NB 32: +8.0%a NB 16: +7.6%a Pla: +0.8% | NB 32: −12.7%a NB 16: −8.0%a Pla: −3.1% |
| COR-II, 201328 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 1001 Placebo: 495 | NB 32: 100 Pla: 99 | 56 | NB 32: −6.4a Pla: −1.2 | NB 32: +0.8a Pla: −0.3 | NB 32: +0.6a Pla: −0.5 | NB 32: +0.4 Pla: +0.3 | NB 32: −6.2 mg/dLa Pla: −2.1 mg/dL | NB 32: +3.6 mg/dLa Pla: −0.9 mg/dL | NB 32: −9.8%a Pla: −0.5% |
| COR-BMOD, 201129 | BMI ≥30 kg/m2 (or ≥27 kg/m2 if weight-related comorbidities present) No Type 2 diabetes | NB 32/360 mg per day (in 2 doses): 591 Placebo: 202 | NB 32: 102 Pla: 100 | 56 | NB 32: −9.3a Pla: −5.1 | NB 32: +1.1 Pla: +0.2 | NB 32: −1.3 Pla: −3.9 | NB 32: −1.4 Pla: −2.8 | NB 32: +7.1% Pla: +10.0% | NB 32: +9.4%a Pla: +2.8% | NB 32: −16.6%a Pla: −8.5% |
| COR-Diabetes, 201330 | BMI ≥27 kg/m2 HbA1c 7.0%–10.0% | NB 32/360 mg per day (in 2 doses): 265 Placebo: 159 | NB 32: 106 Pla: 105 | 56 | NB 32: −5.0a Pla: −1.8 | N/A | NB 32: 0 Pla: −1.1 | NB 32: −1.1 Pla: −1.5 | NB 32: −1.4 mg/dL Pla: 0 mg/dL | NB 32: +3.0a mg/dL Pla: −0.3 mg/dL | NB 32: −11.2%a Pla: −0.8% |
| LIGHT, 201631 | BMI ≥27 kg/m2 Diabetes (with hypertension, dyslipidaemia, low HDL, or smoker) | NB 32/360 mg per day (in 2 doses): 4455 Placebo: 4450 | NB 32 mg: 105 Pla: 106 | 208 | NB 32 mg: −3.71a Pla:−1.13 | NB 32: +0.7 Pla: +0.6 | NB 32: +1.4 Pla: +0.5 | N/A | N/A | N/A | N/A |
| Orlistat | |||||||||||
| Chanoine et al, 200532 | Adolescents BMI ≥2 units of 95th percentile (12 years: >28.5 boys, >29.5 girls; 16 years: 31.8 boys, 31.9 girls) Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 352 Placebo: 181 | Orl 120: 98 Pla: 95 | 54 | Orl 120: +0.54a Pla: +3.3 | N/A | Orl 120: +1.09 Pla: +1.31 | Orl 120: −0.51a Pla: +1.30 | Orl 120: −0.99 Pla: +0.88 | Orl 120: +0.07 Pla: −0.31 | Orl 120: +17.9 Pla: +11.68 |
| Sjöström et al., 199833 | BMI ≥28 kg/m2 Exclude Type 2 diabetes requiring medication | Orl 120 mg (3× day): 343 Placebo: 340 | Orl 120: 99 Pla: 100 | 52 | Orl 120: −10.2a Pla: −6.1 | N/A | Orl 120: −6a Pla: −3 | Orl 120: −4.5a Pla: −2.7 | Orl 120: −0.36 mmol/La Pla: −0.04 mmol/L | Orl 120: + 0.07 mmol/L Pla: −0.32 mmol/L | Orl 120: −0.13 mmol/L Pla: −0.13 mmol/L |
| Bariatric surgery | |||||||||||
| STAMPEDE, 201734 | BMI ≥27 kg/m2 HbA1c > 7.0% | GB: 49 SG: 47 MT: 38 | GB: 107 SG: 100 MT: 105 | 260 | GB: −21.7a SG: −18.5a MT: −5.0 | NA | GB: −3.3c SG: −8.4c MT: −4.1 | GB: −5.8c SG: −8.1c MT: −4.4 | GB: +12.4%c SG: +16.6%c MT: +3.7% | GB: +31.9%a SG: +29.6%a MT: +7.0% | GB: −39.8%a SG: −29.4%a MT: −8.3% |
| GATEWAY, 201835 | BMI ≥30 kg/m2 Hypertension No diabetes | GB: 50 MT: 50 | GB: 102 MT: 100 | 52 | GB: −28.9a MT: −0.69 | N/A | GB: +0.8c MT: +5.2 | GB: −0.4c MT: +2.4 | GB: −35.0a MT: −7.4 | GB: +9.8a MT: +1.7 | GB: −81.5a MT: −22.9 |
SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; BMI, body mass index; Look AHEAD, Action for Health in Diabetes; ILI, intensive lifestyle intervention; DSE, diabetes support and education; Met, metformin; Pla, placebo; N/A, not available; SCALE, Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities; Lira, liraglutide; STEP, Semaglutide Treatment Effect in People with Obesity; Sema, semaglutide; SURMOUNT, A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight; Tirze, Tirzepatide; DP, diethylpropion; NB, naltrexone/bupropion; COR, A Study of the Safety and Efficacy of Two Doses of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects; NB, Naltrexone/bupropion; LIGHT, Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors; Orl, orlistat; STAMPEDE, Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently; GB, Gastric bypass; SG, sleeve gastrectomy; MT, medical therapy; GATEWAY, Gastric Bypass to Treat Obese Patients With Steady Hypertension.
aP < .05 for intervention vs. control.
bAlthough values for these parameters were similar between the ILI and DSE groups at the end of the trial, a significant improvement was noted with ILI on average over the entire trial period.
cA significant benefit of the intervention on this parameter was not observed likely due to lower anti-hypertensive/anti-lipidaemic drug use in the intervention arm/anti-lipidaemic drug use in the intervention arm.
Lifestyle interventions
Lifestyle intervention refers to regular individual or group treatment sessions designed to modify health, nutritional, and exercise behaviours with the goal of reducing weight. In these sessions, patients are seen by experts across multiple disciplines, including dietitians, exercise physiologists, and/or psychologists who are not readily available in the ‘real world’.36 Several trials have evaluated the efficacy of lifestyle interventions vs. usual care for weight loss in individuals with overweight or obesity. Across these trials, the characteristics of participants enrolled and the precise intervention delivered varied; however, the lifestyle intervention group consistently experienced significantly greater weight loss than the usual care group.19,20,37–41 However, in trials with longer follow-ups, weight loss with lifestyle intervention was greatest up till 1 year, after which participants tended to regain weight. This tendency to regain weight has been attributed to lack of long-term adherence to the lifestyle intervention as well as the metabolic adaptations that take place following weight loss, primarily decrements in anorexigenic hormones and an elevation of the orexigenic hormone ghrelin. The consequence is an ‘energy gap’ in which more energy is desired than is required, which manifests as increased hunger despite decreased energy requirements.42
The key trials studying lifestyle intervention for weight loss are summarized in Table 1. The Look Action for Health in Diabetes (AHEAD) trial was conducted to assess whether an intensive lifestyle intervention can improve long-term CV outcomes in T2D patients who were also overweight or obese.19 This trial enrolled over 5100 participants and randomized them to either an intensive lifestyle intervention or diabetes support and education. The intensive lifestyle intervention was aimed at attaining and maintaining a weight loss of ≥7%. Target calorie intake was set as 1200–1800 calories per day, and target physical activity was set as ≥175 min per week of moderate intensity exercise. In the first 6 months, participants received weekly group and individual counselling sessions; the frequency of these reduced over time. The median follow-up of participants in the Look AHEAD trial was 9.6 years. Intensive lifestyle intervention did not improve CV outcomes in the overall population of the Look AHEAD trial, and the study was terminated early for futility. The primary outcome (composite of CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization from angina) occurred at a rate of 1.83 and 1.92 events per 100 patient-years in the intervention and control groups, respectively [hazard ratio (HR): 0.95 (0.83, 1.09); P = .51]. Similar findings were seen with each individual component of the primary composite outcome.
At 1-year follow-up, the mean percentage of body weight loss in the intervention group was 8.6%, compared with 0.7% in the control group. After the first year, patients in the lifestyle intervention group regained weight, and the difference in mean weight loss narrowed; however, it remained significant throughout the trial. Although no improvement in CV outcomes was detected, patients in the lifestyle intervention group showed more changes in glucose and lipid control, greater reductions in blood pressure, better physical mobility, and fewer microvascular complications.5,43 There were also fewer hospitalizations, lower healthcare costs, and improved quality of life. The benefits manifested early and were sustained over the trial period.
Current recommendations
Although the effect of lifestyle intervention on CV outcomes remains unresolved, there are several benefits, which merit lifestyle intervention as a foundational therapy upon which other weight loss options may be added. Lifestyle intervention is recommended by the US Preventive Services Taskforce, Centers for Medicare and Medicaid Services, and the Guidelines for Managing Overweight and Obesity in Adults.41,44,45 These guidelines recommend participation in the intervention for at least 6 months to achieve weight loss, with an extension of 1 year or more for maintenance. The first 6 months should ideally include at least 14 group or individual counselling sessions led by trained interventionists. The diet goal should be 1200–1500 kcal/day for women and 1500–1800 kcal/day for men with an individualized macronutrient composition. The recommended exercise target is ≥150 min/week or 30 min of walking 5 days per week, and recommended behavioural changes include goal setting, stimulus control, daily monitoring of food intake and physical activity, and weekly record of weight.
Obesity pharmacotherapy
Glucagon-like peptide-1 receptor agonists
GLP-1 RAs were developed as glucose-lowering agents for T2D by targeting the incretin pathway. GLP-1 RAs increase glucose-dependent insulin secretion and also reduce glucagon secretion, thus enhancing glucose uptake by peripheral tissues and reducing blood glucose levels. GLP-1 RAs also slows gastric emptying and also acts at the hypothalamic level to increase satiety. GLP-1 RAs demonstrated meaningful weight loss in trials of patients with T2D with marked heterogeneity across the GLP-1 agonist class, with the acylated human GLP-1 agonists, liraglutide and semaglutide, having the greatest efficacy. Some of these agents have since been evaluated in clinical trials for weight loss efficacy in patients with overweight or obesity. Although many of these trials reported change in CV risk factors, only one CV outcome trial (CVOT) has been completed with GLP-1 agonists in patients with overweight or obesity: the semaglutide effects on heart disease and stroke in patients with overweight or obesity (SELECT) trial.
Semaglutide
Five trials have evaluated the efficacy of weight loss with the weekly semaglutide in participants with overweight or obesity. Four trials were part of the pivotal STEP programme, each of which assessed subcutaneous semaglutide 2.4 mg once-weekly against placebo in a distinct subpopulation of people with overweight or obesity. The STEP 1 trial included 1961 adults without T2D; STEP 2 included 1595 individuals with T2D not on insulin; STEP 3 included 611 adults without T2D receiving intensive lifestyle intervention; and STEP 4 was a weight loss maintenance trial that randomized participants with no diabetes who achieved weight loss with 2.4 mg semaglutide in the run-in phase to either continuation of semaglutide or placebo.23–25,46 The follow-up time in all STEP trials was 68 weeks. A meta-analysis of all trials demonstrated an 11.4% placebo-adjusted weight loss with semaglutide. The odds of achieving a ≥ 5% or ≥10% weight loss was 9.8 and 13.3, respectively.47 Moreover, in the STEP-4 trial, patients who were previously on semaglutide and were randomized to discontinuation experienced weight regain, while patients who continued the drug maintained their weight loss. Across the STEP trials, semaglutide reduced systolic and diastolic blood pressure, LDL, and triglycerides and increased HDL. Semaglutide showed a tendency to increase heart rate.23–25,46,47 The STEP-HFpEF (Semaglutide Treatment Effect in People With Obesity and HFpEF) randomized 529 patients with HFpEF and obesity to either semaglutide 2.4 mg once-weekly or placebo. At 1-year, semaglutide not only reduced weight considerably, but also significantly improved health-related quality of life, functional status, and CRP levels.48 While the STEP trials assessed weight loss with once-weekly subcutaneous semaglutide, the Oral Semaglutide Treatment Effect in People with Obesity (OASIS) trials were designed to study a higher dose of once-daily oral semaglutide 50 mg/day. The recently published OASIS 1 trial echoed findings from the STEP 1 trial, showing a 15.1% weight loss with oral semaglutide 50 mg vs. 2.4% weight loss with placebo at 68 weeks of treatment in patients with overweight or obesity and no T2D.49
The recently concluded SELECT trial was the first CVOT with a GLP-1 RA in patients with overweight or obesity, and it randomized 17 604 patients with overweight or obesity and established CV disease (but no T2D) to either semaglutide 2.4 mg QW or placebo.50,51 According to the topline results from the trial, semaglutide demonstrated a 20% reduction in MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. These landmark findings have important implications for cardiologists—as they mean that semaglutide is not only a weight loss agent, but also a medication for secondary prevention of CV disease in patients with overweight or obesity.
Liraglutide
The effect of liraglutide on weight in patients with overweight or obesity has been studied in 18 randomized controlled trials. As weight loss with GLP-1 RA is dose-dependent, the dose in the trials used is a critical consideration. A dose of up to 1.8 mg OD has been licenced for glucose-lowering in T2D, and a higher dose of 3 mg was developed and tested in overweight and obese patients with and without T2D and has been licenced for weight management.
The Satiety and Clinical Adiposity—Liraglutide Evidence in people with T2D and no diabetes (SCALE) programme is one of the largest and most prominent programmes in the area testing the weight loss efficacy of 3 mg dose of liraglutide. This was a series of four randomized placebo-controlled trials, each of which included a distinct subpopulation of patients with obesity or overweight: (i) pre-diabetes, (ii) T2D, (iii) sleep apnoea, and (iv) weight loss maintenance.21,22,52,53 A network meta-analysis of published studies evaluating liraglutide in patients with overweight or obesity demonstrated a dose-dependent effect of subcutaneous liraglutide on weight reduction. A dose of ≤1.8 mg (the diabetes licenced dose) reduced weight by 2.7%, whereas a dose of >1.8 mg reduced weight by 4.5% compared with lifestyle modification alone.54 Another meta-analysis showed that the odds of achieving clinically significant weight losses of ≥5% and ≥10% with liraglutide were 4.9 and 4.8, respectively.47 These benefits were seen regardless of the presence of T2D; however, patients without diabetes experienced greater weight loss, a consistent finding across all trials of obesity pharmacotherapy. Additionally, liraglutide reduces systolic and diastolic blood pressure, LDL, and triglycerides and increases HDL in patients with overweight or obesity, which may be mediated by its weight loss effects.6,21,22,52,53
Whilst no CVOTs with liraglutide have been conducted in patients with overweight or obesity, a post hoc analysis of the SCALE trials demonstrated a trend towards fewer CV events in the group receiving liraglutide 3.0 mg; however, this analysis was limited by a small number of events.55 CV outcomes with liraglutide have, however, been assessed in patients with T2D. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial enrolled 9340 patients with T2D and demonstrated a significant reduction in major adverse cardiac events (MACE) with liraglutide (1.8 mg SQ daily) vs. placebo. Over 60% of the patients had a BMI > 30 kg/m2, and the treatment effect was consistent in patients with and without obesity.56 While findings from the LEADER trial are encouraging, they cannot be extrapolated to patients with obesity without T2D.
Orforglipron
Orforglipron is a novel GLP-1 RA. Unlike liraglutide and semaglutide, orfoglipron is a non-peptide molecule and a partial agonist of the GLP-1 receptor. Thus, it has greater oral bioavailability, may induce lesser desensitization of GLP-1 receptors, and will likely be cheaper to produce. In a Phase 2 clinical trial that enrolled 272 participants with overweight or obesity, orforglipron resulted in dose-dependent weight loss ranging from 9.4% (with the 12 mg dose) to 14.7% (with the 45 mg dose) at week 36. In contrast, the placebo group experienced a weight loss of 2.3% on average. Adverse events with orforglipron were similar to those seen with other GLP-1 RAs. Phase 3 trials and CVOTs will provide further data regarding the CV safety and efficacy of orforglipron.
Current recommendations
Both the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) have approved liraglutide (3.0 mg SQ once-daily) and semaglutide (2.4 mg SQ once-weekly) for chronic weight management in patients with overweight or obesity and at least one weight-related condition (such as hypertension, T2D, or hypercholesterolaemia). Semaglutide 2.4 mg QW is the only weight loss medication that has shown improvement in CV outcomes—and should be considered in all patients with overweight or obesity, and especially in patients with established CV disease. The use of these agents is recommended in conjunction with a reduced calorie diet and increased physical activity. The once-weekly dosing regimen of semaglutide may improve long-term adherence to therapy. Common side effects of GLP-1 RAs include nausea and diarrhoea, which are experienced by a significant proportion of the patients who are initiated on these drugs; however, most cases are mild and transient and tend to subside over time. Additionally, there is some indication that GLP-1 RAs may increase the risk of cholelithiasis. Starting with a low dose followed by slow up-titration can reduce gastrointestinal side effects. Notably, GLP-1 RAs are not associated with hypoglycaemia, even in patients without T2D.
Combined glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist
Tirzepatide
Tirzepatide is the first licenced dual GLP-1 and GIP RA for glucose lowering in T2D. Like GLP-1, GIP is an incretin, which is released in response to oral nutrients. Co-administration of GIP and GLP-1 RAs in humans has an additive incretin effect and also results in inhibition of glucagon release despite the fact that GIP alone increases glucagon release.57 The SURPASS (tirzepatide clinical development programme for treatment of T2D) programme was a combination of five individual clinical trials that established the safety and efficacy of tirzepatide at 5, 10 and 15 mg doses for glucose control in patients with T2D.58–62 Across the trials, tirzepatide use was associated with robust weight loss compared with any of the control arms tested.
Whilst tirzepatide is not yet licenced for weight management, this is being tested in the SURMOUNT clinical trial programme. The results from A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1) trial were recently published. This trial was conducted to assess the efficacy of weight loss with tirzepatide against placebo in 2539 patients with overweight or obesity without T2D, over a period of 72 weeks published.26 The same doses of tirzepatide used in the SURPASS programme, 5, 10, and 15 mg, were used in this weight management trial and were associated with 15%, 20%, and 21% reductions in body weight, respectively. Participants in the placebo arm experienced a weight loss of 3.1%, on average. Notably, 62% of participants had 22.5% body weight loss (on-treatment population; uncorrected for placebo). Additionally, tirzepatide significantly increased HDL and reduced systolic and diastolic blood pressure, triglycerides, and non-HDL cholesterol.63 Compared with placebo, tirzepatide increased the likelihood of mild-to-moderate gastrointestinal adverse events (particularly nausea, diarrhoea, and constipation). The other ongoing trials in the SURMOUNT programme are also assessing the safety and efficacy of tirzepatide against placebo in patients with overweight or obesity, and each trial has a distinct design. The SURMOUNT-2 trial enrolled patients with obesity and comorbidities including T2D and showed meaningful weight loss with tirzepatide, albeit of lesser magnitude than that seen in patients without T2D (10.8% with 10 mg and 12.8% with 15 mg at 72 weeks) similar to other trials that consistently demonstrated that people with T2D tend to have 20%–30% less weight loss.64 The SURMOUNT-3 trial is enrolling patients with weight-related comorbidities and will report the efficacy of tirzepatide as an add-on therapy to an intensive lifestyle intervention, and the SURMOUNT-4 trial is assessing the efficacy of tirzepatide for maintenance of weight loss.65–67
A Study of Tirzepatide on the Reduction on Morbidity and Mortality in Adults With Obesity (SURMOUNT-MMO) is an ongoing, Phase 3 randomized controlled trial designed to evaluate the effect of tirzepatide on morbidity and mortality in adults with obesity without T2D (NCT05556512). The trial is expected to enrol 15 000 participants, who will be randomized to either subcutaneous tirzepatide (with doses escalated up to the maximum tolerated) or placebo. The participants will be followed for up to 5 years for the primary outcome, a composite of time to first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or HF. The findings of SURMOUNT-MMO are expected in late 2027.
Retatrutide
Retatrutide is a weekly ‘triple agonist’, which acts on receptors of GIP, GLP-1, and glucagon. In a recently published study in patients with T2D and obesity, retatrutide showed clinically meaningful HbA1c reductions of 2.2% from a baseline HbA1c of 8.3% as well as robust body weight loss of 17% with the highest 12 mg dose at week 36.68 A simultaneous publication of a separate Phase 2 clinical trial also assessed the weight loss effects of retatrutide in patients with overweight or obesity but without T2D.69 In this trial, dose-dependent weight loss was noted with retatrutide, ranging from 8.7% in the 1 mg group to 24.2% in the 12 mg group. In contrast, the placebo group experienced weight loss of 2.1% on average. Retatrutide use resulted in an increase in mild-to-moderate gastrointestinal adverse effects, as well as an increase in heart rate—both of which were dose-dependent consistent with the GLP-1 RA class. Heart rate in the retatrutide group peaked at 24 weeks, after which it declined. While novel agents such as retatrutide result in very robust weight loss which is unprecedented for pharmacological agents, further studies are awaited to understand their impact on CV outcomes.
Current recommendations
Tirzepatide was recently approved by both EMA and FDA for the treatment of T2D, as an addition to diet and exercise. Whilst not yet licenced for weight management, findings from the SURMOUNT-1 trial suggest that tirzepatide may be the most effective weight loss agent to date. Moreover, there is no concern for increased risk of hypoglycaemia. However, the long-term safety and CV effects of this agent remain uncertain and will come to light once findings from the SURMOUNT-MMO trial and the ongoing SURPASS CVOT trial in T2D are reported.
Naltrexone/bupropion
Naltrexone/bupropion is a combination medication that acts centrally to promote satiety and increase energy expenditure, thereby resulting in weight loss.70 It exerts these actions by interfering with the firing of pro-opiomelanocortin (POMC) neurons in the hypothalamus. POMC is a pro-peptide that is broken down into three peptides: alpha-melanocyte stimulating hormone (alpha-MSH), beta-endorphin, and corticotropin. The alpha-MSH acts in the hypothalamus to increase satiety and energy expenditure. Beta-endorphins act on the μ-opioid receptors of POMC neurons and provide negative feedback, thereby limiting the amount of alpha-MSH released. Bupropion is a norepinephrine/dopamine re-uptake inhibitor that increases the firing of POMC neurons and subsequent release of alpha-MSH. Naltrexone is an opioid antagonist that prevents negative feedback by beta-endorphins, further promoting the release of alpha-MSH.70,71 When used in combination, the medications result in weight loss. Much of the evidence of the effects of naltrexone/bupropion on weight and cardio-metabolic parameters comes from a series of four Phase 3 randomized controlled trials (4563 patients) known as the Contrave Obesity Research trials and the LIGHT CVOT (8910 patients).27–31 A network meta-analysis showed that naltrexone/bupropion results in a 4.1% greater weight loss compared with lifestyle modification alone. The odds of achieving significant weight reductions of ≥5% or ≥10% were 5.0 and 5.2, respectively.47
Naltrexone/bupropion results in mild increases in heart rate and blood pressure, most prominent during early treatment.27–29,31 The combination results in favourable changes in lipid profile and glycaemic levels.27–29,31 Although the LIGHT trial was designed to assess CV outcomes, the trial was terminated early due to public release of confidential interim data that jeopardized the integrity and interpretation of the data and thus did not provide conclusive evidence. After 50% of the planned events, the primary outcome (composite of CV death, non-fatal stroke, or non-fatal myocardial infarction) occurred at a similar rate in the naltrexone/bupropion arm (2.3%) and the placebo arm (2.0%).31
Current recommendations
Naltrexone/bupropion is approved by the EMA and FDA for chronic weight management. The LIGHT trial did not indicate an increased risk of adverse CV; however, the results should be interpreted with caution given the early termination of the trial. Due to its tendency to cause a mild increase in blood pressure, naltrexone/bupropion should be avoided in patients with hypertension, especially if severe or uncontrolled. Gastrointestinal upset, including nausea, constipation, and vomiting, is seen in over 10% of patients taking naltrexone/bupropion. Other common side effects include tremors, dizziness, headache, and a feeling of jitteriness.
Orlistat
Orlistat lowers dietary fat absorption by ∼30% inhibiting gastrointestinal lipase.32,33,72 The effect of orlistat on weight and cardio-metabolic parameters has been assessed in >150 trials, either on its own or in combination with other obesity pharmacotherapy, glucose-lowering ,or lipid-lowering medications. In the network meta-analysis by Shi et al., orlistat was found to reduce weight by 3.2% more compared with usual care.47 The odds of losing ≥5% or ≥10% of baseline weight were 2.4 and 3.2, respectively.47 Orlistat is also safe and effective at reducing weight in adolescents.32
Trials have consistently demonstrated the ability of orlistat to reduce blood pressure, with no effect on heart rate.73 Additionally, orlistat reduces LDL and triglycerides, and increases HDL.73 In patients with pre-diabetes, orlistat lowered the risk of progression to overt T2D, and in patients with T2D, its use results in slightly better glycaemic control.74,75 It has also been shown to improve markers of CV risk, such as interleukin-6, plasminogen activator inhibitor, and C-reactive protein.76 To date, however, no clinical trials have assessed CV outcomes with orlistat. A recently published propensity-matched observational study of almost 37 000 patients demonstrated that orlistat use was associated with a reduced incidence of mortality, ischaemic heart disease, and HF.77
Current recommendations
The EMA and FDA have approved over-the-counter sale of orlistat for weight loss. It is also the only medication approved for weight loss in adolescents. Although no CVOTs have been conducted, improvements in CV risk factors and risk markers have been demonstrated. Gastrointestinal side effects are common. Oily rectal spotting, flatus with discharge, faecal urgency, and/or fatty stools occur in ∼16%–40% of users. Increased defaecation and faecal incontinence occur at a rate of ∼5%. The gastrointestinal side effects decrease over time. The use of multivitamins along with orlistat is recommended as it reduced the absorption of fat-soluble vitamins.78
Bariatric surgery
The two most frequently performed bariatric surgeries are Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy.79 These surgeries are most commonly performed using a laparoscopic approach. The RYGB procedure involves creation of a small pouch of the stomach, which is then directly linked to the small intestine, allowing for food to bypass most of the stomach. Sleeve gastrectomy involves vertical resection of a portion of the stomach. Numerous clinical trials have shown that bariatric surgery results in a weight loss of 15%–20% in excess of medical weight management or lifestyle intervention alone.34,80 This weight loss is achieved by 1 year of follow-up and has been shown to be sustained up to 5 years.34 Bariatric surgery also improves CV risk factors, including reductions in systolic and diastolic blood pressure, LDL, and triglycerides and an increase in HDL.81 Recent studies have also linked bariatric surgery to improved vascular regeneration and homeostasis.82 The Gastric Bypass to Treat Obese Patients With Steady Hypertension trial randomized 100 patients with hypertension to either bariatric surgery or medical therapy and showed a 45%–50% remission of hypertension with bariatric surgery, compared with 0% with medical therapy.35 Similarly, bariatric surgery results in complete remission of T2D in 35%–40% compared with 0% with medical weight management and <10% with lifestyle intervention.79
Although currently there is no Level 1 evidence to support better CV outcomes with bariatric surgery, large-scale cohort non-randomized studies have shown encouraging findings. In their retrospective analysis of 13 722 patients with T2D and obesity, Aminian et al.83 found a significantly lower incidence of extended MACE (defined as first occurrence of all-cause mortality, coronary events, cerebrovascular events, HF, nephropathy, and atrial fibrillation) in patients undergoing metabolic surgery, compared with matched non-surgical patients. Moreover, all seven components of the composite outcome showed statistically significant differences in favour of bariatric surgery. The Swedish Obese Subjects retrospective study assessed survival in 2007 undergoing bariatric surgery vs. 2040 control patients matched for variables such as BMI, age, and sex. Over a follow-up of 24 years, patients in the bariatric surgery group were at 33% lower risk of mortality compared with the control group.84 Similarly, a retrospective study with an average follow-up of 7.1 years showed a 40% lower risk of mortality in 7925 patients undergoing gastric bypass surgery, compared with 7925 age-, sex-, and BMI-matched controls.85 A recent observational study demonstrated that bariatric surgery is associated with significantly improved liver and CV outcomes in patients with concomitant obesity and non-alcoholic steatohepatitis, compared with non-surgical management.86 Meta-analyses of observational studies have shown consistent findings.87,88 The Bariatric Surgery for the Reduction of cArdioVascular Events Feasibility Trial is a pilot study currently underway to assess the feasibility of conducting a CVOT comparing bariatric surgery with medical weight management (NCT04226664).89
Current recommendations
Bariatric surgery is currently recommended for: (i) patients with a BMI ≥ 40 kg/m2; (ii) those with a BMI ≥ 35 kg/m2 and obesity-related complications such as T2D, CV disease, or sleep apnoea; and (iii) patients with BMI ≥ 30 kg/m2 and T2D that is difficult to control with medical treatments and lifestyle changes.90 Bariatric surgery is associated with a mortality rate of 0.1%–0.3%, with serious complications occurring in <5% of patients.91 Although this can be considered a relatively safe surgery, the immediate risks and costs are higher than other weight loss options, while long-term outcomes and cost-effectiveness remain unclear—which currently limits its use to morbid obesity.
Take home best practices for cardiologists
Obesity is now known to play a causative role in the development and progression of atherosclerotic CV disease, HF (particularly HFpEF), stroke, arrhythmias, and T2D. Realistic lifestyle intervention for weight loss such as a reduction of 500 calories/per day and walking 150 min per week should be offered to all overweight or obese patients as foundation therapy. Although the long-term CV benefit is debated, this intervention is safe, improves several cardio-metabolic risk factors and obesity-related co-morbidities, decreases hospitalizations, and enhances quality of life. Weight loss with lifestyle intervention alone is often not sufficient to meet individual targets, and patients usually gradually regain weight after the first year. Pharmacotherapy may be needed for additional and sustained weight loss. Select GLP-1 RAs (liraglutide 3.0 mg and semaglutide 2.4 mg) now have an indication for weight loss. Semaglutide 2.4 mg has shown not only double-digit weight loss, but also improvement in MACE in patients with overweight or obesity with established CV disease and no T2D. Moreover, in addition to reducing weight, it improves health-related quality of life and functional status in patients with HFpEF and obesity. The first dual GIP/GLP-1 RAs tirzepatide, and the triple agonist retatrutide, whilst not yet licenced for weight management, have shown tremendous weight loss efficacy (crossing 20% on average at higher doses) (Graphical Abstract). CV outcome data with these agents is awaited. Incretin therapies are associated with gastrointestinal side effects such nausea and vomiting; however, these are transient and can be minimized with gradual up-titration of doses. Importantly, weight loss pharmacotherapy should be continued on a chronic basis to maintain the weight loss. Bariatric surgery should be considered in patients with refractory or complicated morbid obesity.
As we move towards an era where the CV effects of weight loss interventions become clearer, there is a need for cardiologists to become familiar with them and have a more proactive role in managing obesity. As of 2019, only 2.9% of eligible obese patients receive appropriate pharmacotherapy. Given the common co-existence of obesity and CV disease, active involvement of cardiologists in managing weight can help overcome this inertia, especially with the weekly incretin therapies!
Supplementary data
Supplementary data are available at European Heart Journal online.
Declarations
Disclosure of Interest
M.D. is Director for Leicester NIHR Biomedical Research Centre and has acted as consultant, as advisory board member, as speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen, as advisory board member for Servier, and as speaker for Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, and Janssen. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. S.D.A. has received personal fees from Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis, Novo Nordisk, Servier, and V-Wave and has received grants and personal fees from Abbott Vascular and Vifor, outside the submitted work. J.R. has served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma, and Zealand and has received clinical research grants from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Novartis, Novo Nordisk, Oramed, Pfizer, and Sanofi. J.B. reports consulting fees from BI, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd., and Vifor. M.S.U. and M.E.H. have no potential conflicts of interest to declare.
Data Availability
No data were generated or analysed for or in support of this paper.
Funding
All authors declare no funding for this contribution.
