Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA‐T2D trial

Abstract

AimsThe MARLINA‐T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard‐of‐care in individuals with type 2 diabetes and albuminuria.MethodsA total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48–86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) 30–3000 mg/g despite single agent renin‐angiotensin‐system blockade were randomized to double‐blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time‐weighted average of percentage change from baseline in UACR over 24 weeks, respectively.ResultsBaseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo‐adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [CI], −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P < .0001). The placebo‐adjusted gMean for time‐weighted average of percentage change in UACR from baseline was −6.0% (95% CI, −15.0 to 3.0; P = .1954). The adverse‐event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups.ConclusionsIn individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo‐adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.

Safety and efficacy of antihyperglycaemic agents in diabetic kidney disease

“…For another commonly utilized agent, 360 patients with T2D, eGFR equal or above 30 mL/min/1.73 m 2 and UACR between 30 and 3000 mg/g were randomized to either receive linagliptin or placebo for 24 weeks in the MARLINA‐T2D study . At the end of the study, HbA1c below 7.0% was achieved by more individuals in the linagliptin group that in placebo: 36.2% compared to 9.3%, although the percentage change in UACR between these two had only a difference of 0.9%, proving to have an insignificant lowering effect in albuminuria, at least in the time frame of the study .…”

Empagliflozin reduces albuminuria—a promise for better cardiorenal protection from the EMPA-REG OUTCOME trial

“…The recently published MARLINA study (21), displayed a placebo-adjusted 6% reduction with linagliptin, which was not statistically or clinically significant, but a secondary analysis of the large saxagliptin study SAVOR-TIMI-53 (22) did report a significant reduction in UACR, however without influencing renal or cardiovascular outcome. More studies investigating the renoprotective potential in the DPPIV class are ongoing.…”

Diabetic nephropathy: newer therapeutic perspectives

“…MARLINA-T2D trial was designed to investigate linagliptin in patients with T2DM and CKD [36]. This study, which involved 360 participants who were followed over 24 weeks, was also designed to test superiority of linagliptin over placebo in terms of albuminuria.…”