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Effects of Semaglutide on Chronic Kidney Disease in Patients With Type 2 Diabetes
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of >100 and <5000) 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 1.73 m2), 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 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 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 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 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 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 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 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 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.).
Additional Info
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Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
N. Engl. J. Med 2024 May 24;[EPub Ahead of Print], V Perkovic, KR Tuttle, P Rossing, KW Mahaffey, JFE Mann, G Bakris, FMM Baeres, T Idorn, H Bosch-Traberg, NL Lausvig, R PratleyFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Flow study – semaglutide in type 2 diabetes with CKD
Type 2 diabetes is the largest driver of chronic kidney disease in the world. For decades we have controlled blood pressure, reduced blood glucose, and blocked the renin–angiotensin system as the main strategies to reduce CKD progression. Recently, SGLT2 inhibitors have shown great protection against CKD among individuals with and without diabetes.
But what about GLP-1 RA agents like semaglutide — do these medications benefit patients with diabetes and CKD? The Flow study was designed to answer this question.
This study's entry criteria were based on the estimated glomerular filtration rate (eGFR) and urinary albumin–creatinine ratio (UACR). The eGFR is a measurement of the speed of filtration and the UACR is a measure of the quality of the filter. A good filter should keep good things such as albumin and eliminate waste products like creatinine. So, a high UACR means a lot of albumin is leaking out, which means the filter is of bad quality. In this study, the authors enrolled patients with an eGFR between 25 and 50 mL/min/1.73 m2; however, these patients had to have UACR greater than 100. They also enrolled patients with an eGFR of greater than 50 to 75 mL/min/1.73 m2, but these patients had to have a higher UACR — greater than 300.
The study included 3533 patients randomized to receive semaglutide 1.0 mg subcutaneously or placebo every week. The study was stopped early due to efficacy; the median follow-up was 3.4 years.
The primary composite outcome of renal and cardiovascular events and death were all significant and are listed below:
Kidney + cardiovascular + death outcome: 24% lower (HR, 0.76; 95% CI, 0.66–0.88; P = .0003)
Kidney only outcome: 21% lower (HR, 0.79; 95% CI, 0.66–0.94)
Cardiovascular-only outcome: 18% lower (HR, 0.82; 95% CI, 0.68–0.98; P = .029)
Death outcomes: 29% and 20% lower
Serious adverse events: no difference between semaglutide and placebo
This study showed that the GLP-1 RA semaglutide is associated with significant benefits in patients with type 2 diabetes and CKD. There were about 15% of patients on SGLT2 inhibitor therapy, with no difference in outcomes observed between patients who received this therapy and those who did not. This finding makes sense as semaglutide has a different mechanism of action from SGLT2 inhibitors.
Semaglutide corrects GLP-1 signaling, which is reduced in patients with type 2 diabetes, back to normal. There are GLP-1 receptors on kidney cells and the immune cells in the kidney. Therefore, these cells need GLP-1 signaling. The authors of this study pointed out that GLP-1 signaling “reduces the cellular expression of proinflammatory and profibrotic mediators.” This might be the reason why semaglutide had good benefits for the kidneys. In addition, the cardiovascular system has GLP-1 receptors, and this may explain the reduced cardiovascular events as well.
The outcomes are clear regardless of the exact mechanism of semaglutide; once-weekly semaglutide reduced the risk of renal, cardiovascular, and mortality events.
Type 2 diabetes (T2D), which affects more than 570 million people globally, is the most frequent cause of chronic kidney disease (CKD) in most countries. Both T2D and CKD markedly increase the risk for major adverse kidney and cardiovascular (CV) outcomes. Although renin–angiotensin system (RAS) inhibitors, SGLT2 inhibitors, and the nonsteroidal mineralocorticoid receptor antagonist finerenone have demonstrated benefits on both kidney and CV outcomes, the residual risk for these events among patients with T2D and CKD remains high. Meta-analyses of CV outcomes trials suggest that GLP-1 receptor agonists reduce the risks of kidney disease progression, major adverse CV events, and CV death.
The FLOW trial is the first dedicated outcomes trial testing the efficacy and safety of a GLP-1 receptor agonist in a population of patients with T2D and CKD. Overall, 3533 participants (95% of whom were at high/very high risk of progression based on KDIGO criteria) were randomized (1:1) to subcutaneous semaglutide 1.0 mg once weekly or placebo. Participants were required to be on maximal tolerated RAS blockade (60% were on an ARB and 35% were on an ACE inhibitor) and, at baseline, 15% were on an SGLT2 inhibitor and 80% were on lipid-lowering therapy. Almost 23% had a prior history of myocardial infarction or stroke, and 19% had a history of heart failure. After a median follow-up period of 3.4 years, the composite primary outcome (a persistent decline in eGFR of ≥50%, persistent eGFR <15 mL/min/1.73 m2, renal replacement therapy, and renal or CV death) was reduced by 24% (HR, 0.76; 95% CI, 0.66–0.88; P = .0003). The number needed to treat over 3 years to prevent one primary outcome was 20 (95% CI, 14–40). In addition, three key supportive secondary outcomes tested in a hierarchical fashion were significant. The annual eGFR slope was significantly lower (meaning less of a decline) in semaglutide- than placebo-treated participants (−2.19 vs −3.36 mL/min/1.73 m2/year; difference in annual slope, 1.16 mL/min/1.73 m2/year; 95% CI, 0.86–1.47 mL/min/1.73 m2/year; P < .001). The rate of major CV events was 18% lower (212 vs 254; HR, 0.82; 95% CI, 0.68–0.98; P = .029), and the rate of death due to any cause was 20% lower (227 vs 279; HR, 0.80; 95% CI, 0.67–0.95; P = .010). The benefits were largely consistent across clinically relevant prespecified subgroups.
Currently, RAS blockade, SGLT2 inhibitors, and finerenone are recommended as guideline-directed therapies to reduce the risk of progression among patients with T2D and CKD, with the option to use a GLP-1 receptor agonist to improve glycemic control and decrease CV risk. The results of the pivotal FLOW trial, which demonstrate that semaglutide substantially reduces the risk of adverse kidney and CV outcomes as well as CV and all-cause mortality, suggest that semaglutide should be included as a fourth pillar in the management of high-risk patients with T2D and CKD. Because of the significant benefits on CV and all-cause mortality, it could be argued that semaglutide should be used earlier in the treatment regimen and independent of the prevailing HbA1c level.
GLP-1 receptor agonists improve glycemia, promote weight loss, and reduce MACE events in people with type 2 diabetes. Ancillary studies had already suggested GLP-1 agonists could also benefit people with type 2 diabetes and chronic kidney disease (CKD), but a dedicated trial with hard clinical outcomes on CKD was missing. The FLOW trial fills this gap. This randomized trial enrolled 3533 participants with type 2 diabetes and CKD — defined as creatinine-based eGFR (eGFRcr) of 50 to 75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) between 300 and 5000 mg/g or an eGFRcr between 25 and 50 mL/min/1.73m2 with UACR between 100 and 5000 mg/g — to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. Median follow-up was 3.4 years. The trial terminated early on recommendation following prespecified interim analysis. The primary composite outcome (dialysis, transplantation, eGFRcr <15 mL/min/1.73m2, 50% reduction in eGFRcr, or death from kidney-related or cardiovascular causes) was 24% lower in the semaglutide group than in the placebo group (HR, 0.76; 95% CI, 0.66–0.88; P = .0003). Results were similar for kidney-specific outcomes (HR, 0.79; 95% CI, 0.66–0.94) and for death from cardiovascular causes (HR, 0.71; 95% CI, 0.56–0.89).
This trial has particularly important implications for clinical practice. People with type 2 diabetes and CKD are at increased risk of MACE and end-stage renal disease, with a strong competitive effect of mortality on end-stage renal disease. Finding benefit not only for the primary outcome but also for the prespecified kidney-specific outcomes and cardiovascular mortality positions semaglutide as a first-line option for people with type 2 diabetes and albuminuric CKD. Around 13.2% of trial participants permanently discontinued semaglutide, primarily due to gastrointestinal disorders. Serious adverse effects were otherwise lower in the semaglutide group (fewer serious infections or cardiovascular outcomes).
Important questions remain regarding use of other renal protective therapies, and, since only 15% of the participants were on SGLT2 inhibitors (SGLT2i) and the beneficial effect of GLP-1 on people using SGLT2i was not apparent in the subgroup analysis, it remains to be proved whether GLP-1 agonists are beneficial in people already on SGLT2i. The order of priority in case combination therapy is not desirable or possible also remains to be studied. Additionally, whether GLP-1 agonists are beneficial in CKD populations not included in this trial, such as people with type 2 diabetes and lower levels of UACR or those with non-diabetic albuminuric CKD, is unknown. However, it is exciting to be able to offer our patients with type 2 diabetes and CKD a new pharmacological intervention proven to have a significant impact on major outcomes.