New Data Suggests Nephroprotective Potential of Semgalutide in T2D Patients

Johannes Mann, MD

A post-hoc analysis of the SUSTAIN 1-7 trails indicated a suitable kidney profile for semaglutide in patients with type 2 diabetes. Furthermore, the findings showed that the GLP-1 receptor agonist may have nephroprotective effects.

The phase 3 SUSTAIN program evaluated the therapeutic effects of semaglutide within this patient population.

The findings from these studies, most notably in SUSTAIN 1-5 and SUSTAIN 7, showed that once-weekly semaglutide reduced hemeglobin A1c levels and bodyweight compared with placebo and other comparators. The therapy also demonstrated a safety profile similar to other GL1-1 receptor agonists.

In the SUSTAIN 6 trial, patients with a high cardiovascular disease risk experienced a reduction of the primary composite cardiovascular outcomes versus the placebo. Semaglutide also was associated with a decrease in macro-albuminuria, thus leading to a reduced risk of a secondary composite nepropathy outcome.

All trials included a fixed dose-escalation regimen of once-weekly subcutaneous semaglutide. The starting dose was 0.25 mg for 4 weeks and increased to final dose of either 0.5 mg or 1.0 mg.

A team led by Johannes Mann, MD, pooled data from the 7 trials to determine the effects of the GLP-1 receptor agonist’s on kidney function and safety in large population of type 2 diabetes patients. Thus, they assessed a total of 8416 enrolled patients, all of whom were ≥18 years of age.

Primary outcomes sought by the investigators were the effect of treatment estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), as well as kidney adverse events.

In the SUSTAIN 1-5 and SUSTAIN 7 trials, eGFR decreased from baseline to week 12 with all active treatments. For 0.5 mg of semaglutide, the estimated treatment difference versus placebo was -2.15 (95% CI, -3.47 to -0.83) mL/min per 1.73 m².

For 1.0 mg of semaglutide, the estimated treatment difference was -3.00 (95% CI; -4.31 to -1.68) mL/min per 1.73 m². The investigators noted that eGFR plateaued following week 12.

They did acknowledge, however, that from baseline to end of treatment, both doses of semaglutide were associated with a greater decline in eGFR compared with placebo across the 6 trials.

The investigators assessed the SUSTAIN 6 trial separately.

For both 0.5 mg and 1.0 mg doses, semaglutide was linked to an eGFR decline of –1.29 (95% CI, –2.07 to –0.51) mL/min per 1.73 m² and –1.56 (95% CI, -2.33 to –0.78) mL/min per 1.73 m², respectively, up to week 16.

There was no decline between week 16 and 104, or end of treatment. Overall decline between the investigative drug and placebo was similar throughout the entire treatment period.

They also found that this decline was diminished in patients with pre-existing chronic disease versus those without it.

In SUSTAIN 1–5, the UACR ratios at end of treatment to baseline were 0.917 with 0.5 mg of semaglutide, 0.836 with 1.0 mg of semaglutide, and 1.239 with placebo.

They observed greater reductions in UACR with semaglutide compared with placebo at the end of the treatment period.

For 0.5 mg, the estimated treatment ratio was 0.74 (95% CI, 0.64-0.85). For 1.0 mg, it was 0.68 (95% CI 0.59 to 0.78).

As for the SUSTAIN 6 trial, UACR ratios from end of treatment to baseline was 0.973 with 0.5 mg, 0.858 with 1.0 mg, and 1.302 with placebo.

Compared with placebo, greater reductions were observed in both treatment doses by the end of treatment—the estimated treatment ratios were 0.75 (95% CI, 0.66-0.85) and 0.66 (95% CI, 0.58-0.75) for 0.5 mg and 1.0 mg dosage, respectively.

And finally, they reported that kidney adverse events were balanced between treatment groups.

“Overall, this post-hoc analysis of data from the SUSTAIN 1–7 trials suggests that semaglutide has the potential to improve kidney outcomes with long-term treatment,” they concluded.

They referenced long-term data from the ongoing FLOW trial—which is aimed at primarly assessing the effects of semaglutide on kidney outcomes—as essential to supporting their hypothesis.

The study, “Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1–7 randomised controlled trials,” was published online in The Lancet.