Cardiovascular outcomes with semaglutide by severity of chronic kidney disease in type 2 diabetes: the FLOW trial.

BACKGROUND AND AIMS: In the FLOW trial, semaglutide reduced the risks of kidney and cardiovascular (CV) outcomes and death in participants with type 2 diabetes mellitus (T2D) and chronic kidney disease (CKD). These prespecified analyses assessed the effects of semaglutide on CV outcomes and death by CKD severity. METHODS: Participants were randomised to subcutaneous semaglutide 1 mg or placebo weekly. The main outcome was a composite of CV death, non-fatal myocardial infarction (MI) ornon-fatal stroke (CV death/MI/stroke) as well as death due to any cause by baseline CKD severity. CKD was categorised by eGFR < or ≥60 mL/min/1.73 m2, UACR < or ≥300 mg/g or KDIGO risk classification. RESULTS: 3533 participants were randomised with a median follow-up of 3.4 years. Low/moderate KDIGO risk was present in 242 (6.9%), while 878 (24.9%) had high and 2412 (68.3%) had very high KDIGO risk. Semaglutide reduced CV death/MI/stroke by 18% (HR 0.82 [95% CI 0.68-0.98]; P = .03), with consistency across eGFR categories, UACR levels and KDIGO risk classification (all P-interaction >.13). Death due to any cause was reduced by 20% (HR 0.80 [0.67-0.95]; P = .01), with consistency across eGFR categories and KDIGO risk class (P-interaction .21 and .23, respectively). The P-interaction treatment effect for death due to any cause by UACR was .01 (<300 mg/g HR 1.17 [0.83-1.65]; ≥300 mg/g HR 0.70 [0.57-0.85]). CONCLUSIONS: Semaglutide significantly reduced the risk of CV death/MI/stroke regardless of baseline CKD severity in participants with T2D.

Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis.

BACKGROUND: Semaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk. METHODS: Participants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45-<60 versus ≥ 60 mL/min/1.73 m2) or damage (urine albumin:creatinine ratio [UACR] ≥ 30-≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated. RESULTS: Independently of treatment, participants with reduced kidney function (eGFR ≥ 45-<60 and < 45 mL/min/1.73 m2: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30-≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [pINT] > 0.05). Semaglutide reduced HbA1c regardless of baseline eGFR and UACR (pINT>0.05); reductions in BW were affected by baseline eGFR (pINT<0.001) but not UACR (pINT>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup. CONCLUSIONS: MACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage. TRIAL REGISTRATIONS: NCT01720446; NCT02692716.

Effects of Once-Weekly Semaglutide on Kidney Disease Outcomes by KDIGO Risk Category in the SUSTAIN 6 Trial.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended by Kidney Disease: Improving Global Outcomes (KDIGO) as risk-based treatment for hyperglycemia, weight management, and cardiovascular (CV) risk reduction in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). The aim of this post hoc analysis was to assess treatment effects of once weekly semaglutide on kidney disease outcomes by KDIGO risk category and on changes in KDIGO risk category, compared with placebo. Methods: Participants with T2D and established CV disease or at high CV risk treated with once weekly semaglutide or placebo in SUSTAIN 6 (NCT01720446) were stratified by baseline KDIGO risk category (low [n = 1596], moderate [n = 831], high [n = 445], very high [n = 366]). Treatment effect was analyzed for a kidney disease composite end point (macroalbuminuria, serum creatinine doubling and estimated glomerular filtration rate [eGFR] < 45 ml/min per 1.73 m2, kidney replacement therapy, or death due to kidney disease) from baseline to 2 years. Results: The treatment effect of semaglutide versus placebo was consistent across KDIGO categories for the kidney disease composite end point (hazard ratio [95% confidence interval (CI)]: 0.35 [0.07-1.72], 0.42 [0.25-0.72], 0.87 [0.45-1.71], and 0.72 [0.42-1.23] for low, moderate, high, and very high risk categories, respectively; P interaction = 0.28). Participants receiving semaglutide were more likely to move to a lower KDIGO risk category (odds ratio: 1.69; 95% CI: [1.32-2.16]) and less likely to move to a higher KDIGO risk category versus placebo (odds ratio: 0.71; 95% CI: [0.59-0.86]). Conclusion: Once weekly semaglutide versus placebo reduced risks of kidney disease end points and improved risk categories irrespective of baseline KDIGO risk.

Lifestyle modification program, LIFE is LIGHT, in patients with type 2 diabetes mellitus and obesity: Results from a 48-week, multicenter, non-randomized, parallel-group, open-label study.

BACKGROUND: Obesity is a potential risk factor for development of type 2 diabetes mellitus (T2DM). To achieve long-term weight reduction in patients with T2DM and obesity using comprehensive lifestyle management program (LMP). MATERIALS AND METHODS: This 48-week interventional, multicenter, parallel-group, open-label study included patients aged ≥18 years with T2DM and a body mass index (BMI) of 27-40 kg/m2. The primary objective was to demonstrate a clinically significant weight reduction (≥5%) from baseline in intensive lifestyle modification (ILM) and standard treatment (ST) groups. RESULTS: The ILM group (N = 100) received recommendations for dietary and physical activity, and behavioral counseling. The ST group (N = 30) was managed in accordance with routine T2DM clinical practice. The patients in ST group were older (60.6 ± 8.9 vs. 54.6 ± 10.2 years in ILM group); overall more than 60% were women. At Week 48, the mean reduction in body weight was 5.8% (95% confidence interval [CI]: -6.9, -4.6) and 1.2% (95% CI: -2.6, 0.2) (p < 0.001) in the ILM and ST group, respectively. At Week 48, a weight loss of ≥5% was achieved by 50% of patients in the ILM group versus 13.3% in the ST group (p = 0.002). The decreases in BMI, waist-to-hip ratio and glycated hemoglobin (HbA1c) was significantly greater in the ILM versus ST group with between-group differences of -1.63 (p ≤ 0.001), -0.03 (р ≤ 0.001) and -0.69% (p = 0.002), respectively. CONCLUSION: A clinically significant weight reduction (≥5%) was demonstrated in patients with obesity and T2DM with use of a comprehensive LMP, along with improvements in BMI, waist-to-hip ratio, and HbA1c.