Cardiovascular and diabetes outcomes among patients with obesity and type 2 diabetes after metabolic bariatric surgery or glucagon-like peptide 1 receptor agonist treatment.

BACKGROUND: With the increasing prevalence of obesity and type 2 diabetes, the availability of different treatment options remains essential. Studies comparing the outcomes of glucagon-like peptide 1 receptor agonists with those of metabolic bariatric surgery in patients with type 2 diabetes and obesity are lacking. METHODS: Using propensity score matching, based on data from several nationwide clinical registries, patients who underwent primary metabolic bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy) were matched with patients who received glucagon-like peptide 1 receptor agonists. Outcome measures included the occurrence of major cardiovascular events, microvascular complications, and potential side effects (alcohol/substance abuse, self-harm, and fractures). RESULTS: Over a mean follow-up of 7 years, major cardiovascular events occurred in 191 of 2039 patients (cumulative incidence 14.5%) in the surgery group compared with 247 of 2039 patients (19.6%) in the glucagon-like peptide 1 receptor agonist group (HR 0.75 (95% c.i. 0.62 to 0.91), P = 0.003). Patients in the surgery group had lower haemoglobin A1c values 5 years after treatment (mean difference 9.82 (95% c.i. 8.51 to 11.14) mmol/mol, P < 0.001) and fewer microvascular complications (retinopathy HR 0.88 (95% c.i. 0.79 to 0.99), P = 0.039; nephropathy HR 0.72 (95% c.i. 0.66 to 0.80), P < 0.001; and neuropathy or leg ulcers HR 0.82 (95% c.i. 0.74 to 0.92), P < 0.001), but a higher risk of alcohol/substance abuse (HR 2.56 (95% c.i. 1.87 to 3.50), P < 0.001), self-harm (HR 1.41 (95% c.i. 1.17 to 1.71), P < 0.001), and fractures (HR 1.86 (95% c.i. 1.11 to 3.12), P = 0.019). CONCLUSION: Compared with glucagon-like peptide 1 receptor agonist treatment, metabolic bariatric surgery is associated with superior metabolic outcomes and a lower risk of major cardiovascular events in patients with type 2 diabetes and obesity, but a higher risk of alcohol/substance abuse, self-harm, and fractures.

Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. METHODS: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. FINDINGS: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). INTERPRETATION: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available. FUNDING: Novo Nordisk.

A Blood Test for Alzheimer Disease, Repurposing GLP-1s, and Wildfire Smoke-Highlights From the AAIC.

This Medical News article is an interview about the latest findings presented at the recent Alzheimer's Association International Conference.

GLP-1 Medication Use for Type 2 Diabetes Has Soared.

This JAMA Data Brief discusses new data from the Medical Expenditure Panel Survey, or MEPS, Household Component, a household survey sponsored by the Agency for Healthcare Research and Quality.

Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic ß-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Anti-Obesity Medications in Patients With Heart Failure: Current Evidence and Practical Guidance.

Obesity is a significant risk factor for heart failure (HF) development, particularly HF with preserved ejection fraction and as a result, many patients with HF also have obesity. There is growing clinical interest in optimizing strategies for the management of obesity in patients with HF across the spectrums of both ejection fraction and disease severity. The emergence of anti-obesity medications with cardiovascular outcomes benefits, principally glucagon-like peptide-1 receptor agonists, has made it possible to study the impact of anti-obesity medications for patients with baseline cardiovascular conditions, including HF. However, clinical trials data supporting the safety and efficacy of treating obesity in patients with HF is currently limited to patients with HF with preserved ejection fraction, but do confirm safety and weight loss efficacy in this patient population as well as improvements in HF functional status, biomarkers of inflammation and HF stability. Here, we review the current data available surrounding the management of obesity for patients with HF, including the limitations of this evidence and ongoing areas for investigation, summarize the next phase of emerging anti-obesity medications and provide practical clinical advice for the multidisciplinary management of patients with both HF and obesity.

Evaluating the safety profile of semaglutide: an updated meta-analysis.

BACKGROUND: Semaglutide is increasingly used in the management of type 2 diabetes mellitus and obesity. Ensuring the safety of this medication is crucial for its clinical use. This meta-analysis evaluates the safety profile of semaglutide across patient populations and treatment durations. METHODS: Randomized controlled trials assessing the safety of semaglutide vs. placebo, with specified treatment durations were identified. The primary outcome was occurrence of any cardiovascular adverse events. Secondary outcomes included sudden cardiac death, adverse events leading to death, adverse events, gastrointestinal side effects, occurrence of hypoglycemia, and new-onset neoplasm. RESULTS: A total of 23 studies met the inclusion criteria with a combined sample size of 57,911 participants. The meta-analysis revealed that the adverse event associated with semaglutide is gastrointestinal in nature (nausea and vomiting). No significant differences were observed between semaglutide and comparator groups. CONCLUSION: Semaglutide appears to have a favorable safety profile across diverse patient populations and treatment durations, supporting its continued use in the management of type 2 diabetes mellitus and obesity. It is generally well-tolerated, with a low incidence of adverse events. Clinicians should be aware of these findings and monitor patients accordingly. Further long-term studies are warranted to assess the safety of semaglutide in clinical practice.