Daniel M. Keller, PhD

November 02, 2012

SAN DIEGO, California — Linagliptin appears to have nephroprotective effects when used in the treatment of type 2 diabetes mellitus (T2DM). Maximilian von Eynatten, MD, executive medical director for Boehringer Ingelheim in Ridgefield, Connecticut, reported results of a meta-analysis of 13 phase 3 studies here at Kidney Week 2012, which showed an overall reduction in the risk of reaching a composite renal endpoint.

Linagliptin is an oral, once-daily dipeptidyl peptidase-4 inhibitor indicated for the treatment of T2DM using a single fixed dose independent of renal function. Chronic kidney disease affects more than 40% of adults with diabetes, occurring despite improvements in glycemic control.

The meta-analysis included all completed phase 3, randomized, double-blind, placebo-controlled trials of at least 12 weeks' duration in the linagliptin development program. Drug exposure was a mean of 7 months and ranged from 12 weeks to 2 years.

All of the trials involved patients with a diagnosis of inadequately controlled T2DM (N = 5466). The linagliptin (n = 3505) and placebo (n = 1961) groups were fairly well matched for demographic, laboratory, and T2DM disease parameters, as well as renal/cardiovascular history and medications.

The composite primary renal safety endpoint consisted of new-onset microalbuminuria; macroalbuminuria; chronic kidney disease (CKD; first occurrence of serum creatinine of 2.83 mg/dL or greater); worsening of CKD, defined as a loss in estimated glomerular filtration rate (GFR) of more than 50% above baseline; acute renal failure; and all-cause mortality.

Lower Kidney Risk With Linagliptin

Patients taking linagliptin were 16% less likely to reach the composite renal endpoint compared with patients on placebo (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.72 - 0.97; P < .05). The incidence of the renal endpoint was 266.8/1000 patient-years vs 308.9/1000 patient-years on linagliptin vs placebo, respectively.

"That came as a surprise on our end because what you want to show when you are keen on safety is that you have the same risk," Dr. von Eynatten told Medscape Medical News. "That patients have a lower risk with linagliptin actually was a surprising finding, and when we looked into the individual events, we found more or less that for each of the 6 individual events there was a lower event rate with linagliptin as compared to placebo."

Many T2DM patients are prescribed an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker at least in part for their nephroprotective effects. Dr. von Eynatten said that in a subgroup analysis, "even in patients with or without [renin-angiotensin-aldosterone system (RAAS)] inhibition, you still have the same overall observation that there is a tendency towards a renal benefit with linagliptin. Is this evidence? No, because it's not a dedicated clinical trial."

Dr. von Eynatten concluded that the study findings support the hypothesis of a potential direct effect of linagliptin on reducing the onset and progression of renal disease in T2DM. Although RAAS inhibition lowers the risk for progression of kidney disease, "a huge amount of patients still progress," he said, and the results have generated a hypothesis of a potential for combining RAAS inhibition with linagliptin.

New But Expected Data, Suggest Experts

Timothy Mathew, MBBS, FRACP, medical director of Kidney Health Australia in Adelaide, commented to Medscape Medical News that "there has been no suggestion to my knowledge that [the drug] has a renoprotective effect, which is what this study is showing. So this to me is new information."

Dr. Mathew, who was not involved in the study, questioned whether the effect is unique to linagliptin or is a class effect of the gliptins. He also pointed out that a disadvantage of gliptins is that they are not very strong in their average hemoglobin A1c reduction, but on the other hand, they have a lower risk for hypoglycemia.

George Bakris, MD, professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medical School in Illinois, told Medscape Medical News that he is not at all surprised at the results. Dr. Bakris was also not involved in the study.

"It's well known that glycemic control reduces microalbuminuria. Microalbuminuria is not considered a renal endpoint as a stand-alone any more. It's considered a marker of inflammation," he said. "Good glycemic control reduces inflammation; hence, good glycemic control should reduce microalbuminuria. There's not 1 study that I've seen that doesn't show that. So this is to be expected, and these analyses are largely driven by that conversion and improvement."

Dr. Bakris disagreed with the expectation of a neutral finding concerning renal safety with linagliptin that Dr. von Eynatten expressed. "I would have predicted improvement in microalbuminuria. I actually would have predicted improvement from macro- to micro-[albuminuria], and glucose would have been improved," Dr. Bakris said. "Everything else I would have predicted would have been neutral." Because the study defined chronic kidney disease in terms of albuminuria, "of course it got better," he said. "So, is this drug good in people with kidney disease? Yes. Is it protecting you? Well, it's protecting you as much as glucose control would protect you."

He noted that an advantage of linagliptin is that other gliptin drugs require dose reductions when the GFR drops because they are renally excreted. "This one is not [renally excreted]. So it is a no-brainer in a sense — you can give it to somebody with a GFR of 30 [mL/min/1.73 m2] or you can give it to somebody with a GFR of 90 [mL/min/1.73 m2], and the dose is the same, and even on dialysis. So that's a good thing," he said.

The study was supported by Boehringer Ingelheim. Dr. von Eynatten is an employee of the company. Dr. Mathew was not involved in the study but has been on the Boehringer Ingelheim advisory board in Australia dealing with linagliptin. Dr. Bakris was not involved in the study; he consults for Merck and Johnson & Johnson.

Kidney Week 2012: American Society of Nephrology 45th Annual Meeting. Abstract TH-PO530. Presented November 1, 2012.