Background: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown.
Methods: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50–75 ml per minute per 1.73m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5,000 or an eGFR of 25 to <50 ml per minute per 1.73m2 and a urinary albumin-to-creatinine ratio of >100 and <5,000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo.
The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes.
Prespecified confirmatory secondary outcomes were tested hierarchically.
Results: Among the 3,533 participants who underwent randomization (1,767 in the semaglutide group and 1,766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis.
The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 versus 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66–0.88; p = 0.0003).
Results: were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66–0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56–0.89).
The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73m2 in the semaglutide group (p < 0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68–0.98; p = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67–0.95, p = 0.01).
Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%).
Conclusions: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.)
![Figure 1: Primary and Confirmatory Secondary Outcomes. Shown are cumulative incidence plots of the primary outcome, major kidney disease events (a composite of the onset of kidney failure [dialysis, transplantation, or an estimated glomerular filtration rate {eGFR} of <15 ml per minute per 1.73m2 of body-surface area], ≥50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes) and several confirmatory secondary outcomes: kidney-specific components of the primary outcome (persistent ≥50% reduction in eGFR, persistent eGFR of <15 ml per minute per 1.73m2, initiation of long-term renal-replacement therapy, or death from kidney-related causes), death from cardiovascular causes, total eGFR slope, major cardiovascular events (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes), and death from any cause. Cumulative incidence estimates are based on the time from randomization to the first event, with death not included in the outcome modeled as a competing risk with the use of the Aalen-Johansen estimator. Data from participants without events of interest were censored at the end of each participant’s in-trial observation period. Estimates are based on a Cox proportional-hazards model with treatment as a categorical fixed factor and stratified according to sodium-glucose cotransporter 2 (SGLT2) inhibitor use at baseline. The eGFR data are least-squares means from a mixed model for repeated measures with treatment as a fixed factor; 𝙸 bars indicate the standard error. The annual rate of change in eGFR was analyzed with a linear random-effects model with randomization assignment, SGLT2 inhibitor use at baseline, time (as a continuous variable), and the interaction of randomization with time as fixed effects and including the participant effect as a random intercept and time as a random slope. On the basis of the available number of primary-outcome events, the nominal statistical-significance level was updated to 0.0322 with the use of the Lan-DeMets alpha-spending function. Events that are not related to eGFR were confirmed by the event adjudication committee. The eGFR was calculated with the serum creatinine level and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formula. The p-value cutoff for statistical-significance was 0.032 in Panels A, D, E, and F. Insets show the same data on an expanded y-axis.](/doc/longevity/glp/semaglutide/2024-perkovic-figure1-kidneydiseasesurvivalcurvesonsemaglutidevsplacebo.jpg)
Shown are cumulative incidence plots of the primary outcome, major kidney disease events (a composite of the onset of kidney failure [dialysis, transplantation, or an estimated glomerular filtration rate {eGFR} of <15 ml per minute per 1.73m2 of body-surface area], ≥50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes) and several confirmatory secondary outcomes: kidney-specific components of the primary outcome (persistent ≥50% reduction in eGFR, persistent eGFR of <15 ml per minute per 1.73m2, initiation of long-term renal-replacement therapy, or death from kidney-related causes), death from cardiovascular causes, total eGFR slope, major cardiovascular events (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes), and death from any cause.
Cumulative incidence estimates are based on the time from randomization to the first event, with death not included in the outcome modeled as a competing risk with the use of the Aalen-Johansen estimator. Data from participants without events of interest were censored at the end of each participant’s in-trial observation period. Estimates are based on a Cox proportional-hazards model with treatment as a categorical fixed factor and stratified according to sodium-glucose cotransporter 2 (SGLT2) inhibitor use at baseline. The eGFR data are least-squares means from a mixed model for repeated measures with treatment as a fixed factor; 𝙸 bars indicate the standard error. The annual rate of change in eGFR was analyzed with a linear random-effects model with randomization assignment, SGLT2 inhibitor use at baseline, time (as a continuous variable), and the interaction of randomization with time as fixed effects and including the participant effect as a random intercept and time as a random slope.
On the basis of the available number of primary-outcome events, the nominal statistical-significance level was updated to 0.0322 with the use of the Lan-DeMets alpha-spending function. Events that are not related to eGFR were confirmed by the event adjudication committee. The eGFR was calculated with the serum creatinine level and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formula.13 The p-value cutoff for statistical-significance was 0.032 in Panels A, D, E, and F. Insets show the same data on an expanded y-axis.