Clinical Context
Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease worldwide, affecting approximately 40% of patients with type 2 diabetes. Despite advances in glucose and blood pressure control, many patients progress to kidney failure requiring dialysis or transplantation. Until recently, SGLT2 inhibitors were the only glucose-lowering agents proven to slow DKD progression in dedicated renal outcomes trials.
The FLOW trial (Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes) represents a watershed moment in nephrology: the first dedicated renal outcomes trial of a GLP-1 receptor agonist. While previous cardiovascular outcomes trials (SUSTAIN-6, PIONEER-6, SELECT) showed signals of kidney benefit with semaglutide, these were secondary endpoints. FLOW was designed and powered specifically to determine whether semaglutide could protect kidneys in patients with established DKD.
The trial was stopped early for overwhelming efficacy—an unusual occurrence that signals profound clinical benefit. This subgroup analysis examines whether semaglutide’s kidney protection is additive to SGLT2 inhibitors, addressing a critical question for the many patients already receiving these agents.
Study Summary (PICO Framework)
Summary:
In adults with type 2 diabetes and chronic kidney disease, stratified by baseline use of SGLT2 inhibitors, weekly semaglutide significantly reduced the risk of kidney failure, ≥50% decline in eGFR, kidney death, or cardiovascular death by 24% compared to placebo, though benefits were significant only in participants not already on SGLT2 inhibitors.
| PICO | Description |
|---|---|
| Population | Adults with type 2 diabetes and chronic kidney disease (eGFR 25-75 mL/min/1.73m² with UACR ≥300 mg/g, or eGFR 25-50 with UACR 100-300 mg/g). N=3,533 total; 550 on SGLT2i, 2,983 not on SGLT2i at baseline. |
| Intervention | Semaglutide 1.0 mg subcutaneously once weekly (titrated from 0.25 mg). |
| Comparison | Matching placebo administered weekly, with standard of care continued in both groups. |
| Outcome | Primary composite (kidney failure, ≥50% eGFR decline, kidney death, or CV death) reduced by 24% overall (HR 0.76; 95% CI 0.66-0.88). In non-SGLT2i users: HR 0.73 (p<0.001). In SGLT2i users: HR 1.07 (p=0.755, not significant). |
Clinical Pearls
1. Semaglutide is now a proven kidney-protective agent. FLOW establishes semaglutide as the first GLP-1 RA with dedicated evidence of renal protection. The 24% reduction in the primary composite outcome is clinically meaningful and comparable in magnitude to SGLT2 inhibitor trials (CREDENCE, DAPA-CKD). This expands treatment options for patients who cannot tolerate SGLT2 inhibitors.
2. The combination question remains unanswered. The lack of significant benefit in patients already on SGLT2 inhibitors is intriguing but must be interpreted cautiously. Only 550 patients (15.6%) were on SGLT2i at baseline, limiting statistical power for this subgroup. The point estimate (HR 1.07) doesn’t suggest harm, but neither does it demonstrate additive benefit. Larger studies or longer follow-up may clarify whether combining these agents provides incremental kidney protection.
3. Trial stopped early for efficacy—a rare event. Data safety monitoring boards stop trials early only when continued enrollment would be unethical because the answer is clear. This speaks to the robustness of semaglutide’s benefit and accelerated patient access to an effective therapy.
4. Multiple mechanisms likely contribute. Semaglutide’s kidney protection probably involves several pathways: improved glycemic control, weight loss, blood pressure reduction, decreased inflammation, and direct effects on renal hemodynamics. Unlike SGLT2 inhibitors, GLP-1 RAs do not cause the characteristic acute eGFR dip, which may be advantageous in patients with advanced CKD.
Practical Application
Patient selection: Consider semaglutide for kidney protection in patients with type 2 diabetes and CKD (eGFR 25-75 with albuminuria) who are not on SGLT2 inhibitors—either due to intolerance, contraindications, or preference. For patients already on SGLT2i, the decision to add semaglutide should be based on other benefits (glucose control, weight loss, cardiovascular protection) rather than proven additive renal protection.
Dosing in CKD: No dose adjustment is required for semaglutide based on kidney function. Start at 0.25 mg weekly and titrate monthly to the target dose of 1.0 mg (as used in FLOW) or 2.4 mg for obesity indications. The primary limitation in advanced CKD is gastrointestinal tolerance, not pharmacokinetics.
Monitoring: Check eGFR and UACR at baseline and periodically (every 3-6 months) to track kidney function. Unlike SGLT2i, semaglutide doesn’t cause acute eGFR decline, so any deterioration should prompt evaluation for other causes.
Combining with SGLT2 inhibitors: Until more data emerge, a reasonable approach is to ensure patients are on an SGLT2 inhibitor first (given the stronger evidence base), then add semaglutide for additional glycemic control, weight management, or cardiovascular protection. Both classes are now guideline-recommended for cardiorenal protection in type 2 diabetes.
How This Study Fits Into the Broader Evidence
FLOW joins the landmark renal outcomes trials that have transformed DKD management. The CREDENCE trial (canagliflozin) and DAPA-CKD trial (dapagliflozin) established SGLT2 inhibitors as first-line kidney-protective agents. FIDELIO-DKD and FIGARO-DKD added finerenone (a nonsteroidal mineralocorticoid receptor antagonist) as another option.
Current ADA and KDIGO guidelines recommend maximally tolerated ACE inhibitor or ARB therapy, plus an SGLT2 inhibitor, for patients with type 2 diabetes and CKD. FLOW positions semaglutide as an alternative or additional therapy, particularly valuable for patients who cannot use SGLT2 inhibitors.
The cardiovascular benefits of semaglutide demonstrated in SELECT (20% reduction in MACE) complement these renal findings, making semaglutide an attractive choice for patients with multiple cardiorenal risk factors.
Limitations to Consider
The subgroup analysis of SGLT2i users is hypothesis-generating, not definitive, due to limited sample size and post-hoc nature. The trial used semaglutide 1.0 mg, not the 2.4 mg dose approved for obesity; whether higher doses provide greater kidney protection is unknown. Additionally, the population had relatively preserved kidney function (mean eGFR ~47); extrapolation to more advanced CKD requires caution.
Bottom Line
The FLOW trial establishes semaglutide as the first GLP-1 receptor agonist proven to protect kidneys in patients with type 2 diabetes and CKD. For patients not on SGLT2 inhibitors, semaglutide reduces the risk of kidney failure and cardiovascular death by approximately 24%. Whether it provides additive benefit to SGLT2 inhibitors remains uncertain, but semaglutide now represents a valuable kidney-protective option for patients with diabetic kidney disease.
Source: Johannes F. E. Mann, et al. “Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial.” Nature Medicine. Read article here.
