CARMELINA: Linagliptin lowers albuminuria in T2D patients with nephrotic-range proteinuria

26 Jan 2021 bởiJairia Dela Cruz
CARMELINA: Linagliptin lowers albuminuria in T2D patients with nephrotic-range proteinuria

In patients with type 2 diabetes (T2D) and nephrotic-range proteinuria (NRP), treatment with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin helps reduce albuminuria burden and manage blood sugar at the same time, without increasing the risk of adverse cardiovascular or kidney events, according to data from the CARMELINA trial.

Specifically, there was a significant, albeit modest, increase in the proportion of patients whose albumin returned to normal levels, as well as ≥50-percent reduction in urinary albumin:creatinine ratio (UACR) from baseline, the investigators said. 

The observed improvements are consequential in patients with NRP, they added. For one, remission of proteinuria may lead to symptomatic improvement, being a marker of risk reduction in NRP. This population also has limited glucose-lowering therapy options, especially those with estimated glomerular filtration rate (eGFR) ˂45 mL/min/1.73 m2, for whom several medications are contraindicated or require dose reduction. [Am J Kidney Dis 2009;54:840-849; J Am Geriatr Soc 2013;61:1253-1261; Curr Opin Nephrol Hypertens 2014;23:306-313]

The present analysis included 646 T2D patients with NRP, representing 9.3 percent of the total CARMELINA population; 317 were treated with linagliptin 5 mg and 329 with placebo. Their median baseline UACR was 3,486 mg/g. NRP patients, compared with those who did not have the condition, were younger (mean, 62.3 vs 66.1 years) and had lower eGFR (mean, 39.9 vs 56.1 mL/min/1.73 m2).

Over a median follow-up of 2.2 years, the incidence of 3-point major adverse cardiac events (3P-MACE) were twofold higher among NRP vs no-NRP patients. Compared with placebo, linagliptin had a neutral effect on 3P-MACE (hazard ratio [HR], 1.02, 95 percent confidence interval [CI], 0.89–1.17), regardless of NRP. [Clin Kidney J 2021;doi:10.1093/ckj/sfaa225]

The same was true for kidney outcomes. The composite of renal death, end-stage kidney disease (ESKD), or sustained decrease of ≥40- or ≥50-percent in eGFR was 12.3- and 13.6-fold higher among patients with vs without NRP, and did not occur with significantly greater frequency on linagliptin vs placebo.

However, when assessed by NRP status, some heterogeneity was observed for linagliptin for the key kidney outcome (composite of renal death, sustained ESKD, or sustained decrease of ≥40 percent in eGFR; NRP: HR, 0.80, 95 percent CI, 0.63–1.01; No-NRP: HR, 1.25, 95 percent CI, 1.02–1.54; pinteraction=0.005).

“The potential heterogeneity of effect for the key kidney outcome we consider is a play of chance, as this was not observed for harder kidney outcomes excluding the eGFR component, or when using other creatinine-based measures in the same composite outcome (like doubling of creatinine or other eGFR cutoffs),” the investigators pointed out.

Meanwhile, linagliptin largely decreased glycated haemoglobin A1c (HbA1c), without increasing the risk of hypoglycaemia. It also led to more frequent regression to normoalbuminuria (HR, 1.20, 95 percent CI, 1.07–1.34) and reduction in UACR of ≥50 percent (HR, 1.15, 95 percent CI, 1.07–1.25). These effects were independent of NRP status (pinteractions>0.05).

“[T]he results presented here not only demonstrate cardiovascular and kidney safety for linagliptin in NRP and T2D, but also [show that the DPP-4 inhibitor] modestly reduces progression of albuminuria and increases regression to normoalbuminuria,” the investigators noted. “We also did not observe an increase in risk for HF in those with NRP and T2D, which differs from a previous trial with another DPP-4 inhibitor that indicated an increased risk of hospitalization for HF.” [Circulation 2014;130:1579-1588]

As such, the investigators believe that linagliptin may potentially delay insulin initiation, as well as be used to meet the KDIGO recommendation of an individualized HbA1c target, ranging from <6.5 to <8.0 percent in those with T2D and nondialysis-dependent chronic kidney disease. [Diabetes Care 2020;43:1803-1812; Kidney Int 2016;90:1175-1183; Kidney Int 2020;98:S1-S115]