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

Abstract

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.

Keywords: albuminuria; cardiovascular disease; chronic kidney disease.

Graphical abstract

Figure 1

KDIGO heatmap for prognosis of CKD. Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red: very high risk. Figure reprinted from Kidney International Supplements, volume 3, KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease, pp 1-163. Copyright (2023), with permission from Elsevier. CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes.

Figure 2

Kidney disease composite outcome by KDIGO risk category at baseline. Kidney disease composite end point was defined as persistent macroalbuminuria, persistent doubling of the serum creatinine level and estimated glomerular filtration rate per modification of diet in renal disease <45 ml/min per 1.73 m², the need for kidney replacement therapy, or death due to kidney disease. CI, confidence interval; HR, hazard ratio; KDIGO, Kidney Disease: Improving Global Outcomes.

Figure 3

eGFR slope from baseline to end of treatment by KDIGO risk category. CI, confidence interval; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes.

Figure 4

Change from baseline to end of treatment in UACR by KDIGO risk category. CI, confidence interval; KDIGO, Kidney Disease: Improving Global Outcomes; UACR, urine albumin-to-creatinine ratio.

Figure 5

Participants progressing to (a) a higher KDIGO risk category or (b) a lower KDIGO risk category at end of treatment (2 years). ∗Statistically significant (P < 0.05). ^† OR is obtained for OW semaglutide versus placebo by logistic regression. ^‡ Adjusted baseline characteristics include: age, gender, diabetes duration, antidiabetic medication, smoking status, previous myocardial infarction/stroke/transient ischemic attack, geographic region and estimated glomerular filtration rate at baseline. Data from 2804 of the 3297 subjects randomized in SUSTAIN 6 were available for this post hoc analysis. CI, confidence interval; KDIGO, Kidney Disease: Improving Global Outcomes; OR, odds ratio; OW, once weekly.

Figure 6

Contributors to change in KDIGO risk category at end of treatment. Baseline and week 104 measurements of eGFR-CKD-EPI and UACR were used to calculate KDIGO category for each participant. The proportion of participants who experienced a change in KDIGO risk category due to changes in UACR, eGFR or both are displayed. (a) Percentages are based on the total number of participants in each treatment group for each KDIGO risk category. Cells with darker shading are indicative of a larger proportion of participants experiencing a change in KDIGO risk due to change in UACR, eGFR, or both at end of treatment. CKD-KPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; UACR, urine albumin-to-creatinine ratio.