A promising FLOW of repurposed pharmacological therapies in people with CKD in type 2 diabetes

Over the past decade, there has been an abundance of pharmacological therapies shown to improve outcomes in people with cardiovascular, renal and/or metabolic (CaReMe) diseases. Practitioners caring for CaReMe patients now have at their disposal multiple drugs across several classes with robust clinical outcome data from multinational randomised controlled trials. For patients with chronic kidney disease (CKD) in type 2 diabetes, these now include renin–angiotensin system (RAS) blockers and, more recently, sodium–glucose cotransporter 2 inhibitors (SGLT2is) and non-steroidal mineralocorticoid receptor antagonists (MRAs). 

Common to these drugs is that their current wide applications have extended well beyond their original intended use, which was primarily for treatment of hypertension or hyperglycaemia. Similarly, the emergence of several weight-loss pharmacotherapies for the treatment of obesity has attracted major interest for their impact on obesity-related complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and novel combinations with other peptide hormones, such as glucose-dependent insulinotropic polypeptide (GIP), have demonstrated reductions in total body weight of between 10% and 25% in phase 3 randomised trials.¹ 

Improvements in glycaemic regulation, cardiometabolic risk factors (such as hypertension or hyperlipidaemia) and even diabetes remission accompany weight loss with these drugs. In the recent STEP-HFpEF trial, marked improvements in heart failure symptoms and exercise capacity were observed in patients with obesity-related heart failure with preserved ejection fraction treated with the GLP-1 RA semaglutide², and in the SELECT trial reductions in downstream major adverse cardiovascular events were shown in non-diabetic people with overweight/obesity with semaglutide.³ Naturally, clinical triallists would go on to explore the potential for beneficial effects in people with CKD in type 2 diabetes, which were identified from exploratory secondary analyses of the original landmark GLP-1 RA trials.⁴

The FLOW trial (Effects of Semaglutide on CKD in Patients with Type 2 Diabetes) was a multicentre, international, double-blind, randomised clinical trial comparing major kidney disease outcomes in patients with CKD in type 2 diabetes assigned to semaglutide versus placebo.⁵ Included participants were adults with predominantly proteinuric CKD in type 2 diabetes: total, n=3533; mean age, 67±9 years; 30% females; mean BMI, 32±6 kg/m²; mean HbA_1c, 7.8±1.3 %; mean eGFR, 47±15 mL/min/1.73 m²; median urinary albumin-to-creatinine ratio, 568 mg/g; and over two thirds had macroalbuminuria, with 68% classified as very high risk according to KDIGO definitions. Randomisation to study arms was stratified by baseline SGLT2i use (~16% of participants were taking these agents at study entry) and almost all subjects were on stable maximum tolerated doses of RAS blockers. 

The active treatment arm comprised an 8-week semaglutide dose-escalation period to achieve the target maintenance dose of 1 mg/week, which was less than half the 2.4 mg/week dose used in the seminal weight-loss trials using semaglutide, and in the STEP-HFpEF and SELECT studies.^2,3 Over the median trial follow-up duration of 3.4 years – stopped early, after a pre-specified interim analysis – significantly fewer participants in the semaglutide than placebo arm experienced the primary major kidney disease events outcome (a composite of kidney failure, sustained ≥50% reduction in eGFR, or death from kidney or cardiovascular disease). This amounted to almost a quarter lowering of the relative risk of the primary outcome in the semaglutide versus placebo arm (HR, 0.76; 95% CI, 0.66–0.88; P=0.0003), hazard ratios which were consistent across all kidney-specific and cardiovascular components of the primary outcome. 

Importantly, these effects were observed despite relatively modest reductions in body weight (−5.5 kg), HbA_1c (−0.87 %) and blood pressure (−3.8 mmHg) with semaglutide, owing to the lower 1 mg/week maintenance dose in the study. Adverse events (mostly gastrointestinal side effects) leading to discontinuation were slightly more common in the semaglutide than placebo arm (13% vs 12%, respectively), although fewer participants in the semaglutide arm experienced a serious adverse event than placebo.⁵

Once again, FLOW has shown us the potential for wide-ranging and heterogenous benefits of CaReMe pharmacotherapies. In the case of semaglutide, originally solicited as an efficacious, safe and well-tolerated weight-loss drug, FLOW suggests renoprotective effects independent of reductions in body weight and at lower doses than for treatment of obesity. 

As with SGLT2is, the pleiotropic effects of semaglutide and other GLP-1 RA and related weight-loss agents targeting the gut–brain axis will be the subject of intense research interest. Speaking of which, although the overall use of SGTL2is was modest in the trial, a recent post hoc analysis of FLOW has shown that the benefits of semaglutide occurred irrespective of concomitant SGLT2i use, and suggested the combination of semaglutide and SGLT2i could be additive (although the trial was underpowered to confirm this assertion).⁶ Like we have already seen in heart failure, there is promise of our entering an era of combination therapy with four pillars of treatment for kidney failure: RAS blockers, SGLT2is, GLP-1 RAs and MRAs, which have been estimated to have a marked cumulative impact on reducing mortality in CKD in type 2 diabetes.⁷

A digest of the study can be read here.

References

1. Melson E, Ashraf U, Papamargaritis D, Davies MJ (2024) What is the pipeline for future medications for obesity? Int J Obes (Lond) 1 Feb [Epub ahead of print]
2. Kosiborod MN, Abildstrom SZ, Borlaug BA et al (2023) Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 389: 1069–84
3. Lincoff AM, Brown-Frandsen K, Colhoun HM et al; SELECT Trial Investigators (2023) Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 389: 2221–32
4. Rossing P, Baeres FMM, Bakris G et al (2023) The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 38: 2041–51
5. Perkovic V, Tuttle KR, Rossing P et al; FLOW Trial Commmittees and Investigators (2024) Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med 24 May [Epub ahead of print]
6. Mann JFE, Rossing P, Bakris G et al (2024) Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med 24 Jun [Epub ahead of print]
7. Neuen BL, Heerspink HJL, Vart P et al (2024) Estimated lifetime cardiovascular, kidney, and mortality benefits of combination treatment with SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal MRA compared with conventional care in patients with type 2 diabetes and albuminuria. Circulation 149: 450–62