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Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, AustraliaFolkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDivision of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected.
Individual patient–level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor linagliptin.
Setting & Participants
Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A1c, 7.0%-11.0% [53-97 mmol/mol]) or being on background glucose-lowering therapy (hemoglobin A1c, 6.5%-10.5% [48-91 mmol/mol]).
Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5 mg/d, and 1,961 received placebo.
The primary kidney disease outcome was defined as first occurrence during the study of 6 predefined safety end points: new onset of moderate elevation of albuminuria (urinary albumin-creatinine ratio [ACR] >30 mg/g with baseline values ≤ 30 mg/g), new onset of severe elevation of albuminuria (ACR > 300 mg/g with baseline values ≤ 300 mg/g), reduction in kidney function (serum creatinine increase to ≥250 μmol/L from a baseline value < 250 μmol/L), halving of estimated glomerular filtration rate (loss of baseline eGFR > 50%), acute renal failure (ascertained from diagnostic codes), or death from any cause.
Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
Cumulative exposure (person-years) was 1,751 for linagliptin and 1,055 for placebo. The primary composite outcome occurred in 448 (12.8%) and 306 (15.6%) participants in the linagliptin and placebo groups, respectively. Linagliptin treatment significantly reduced the hazard of kidney disease events by 16% compared with placebo (HR, 0.84; 95% CI, 0.72-0.97; P = 0.02).
Retrospective and hypothesis-generating study involving short- to midterm clinical trials.
Linagliptin was not associated with increased kidney disease risk in patients with type 2 diabetes. The potential of this drug to improve kidney disease outcomes warrants further investigation.
However, it is equally critical for any new agent to also be proved to be safe. Although specific aspects of toxicology, including renal handling of drugs likely to be administered for years, are routinely evaluated in the very early stages of drug development, it is only after sufficient clinical exposure that potential safety concerns might become apparent. As an example, systematic reviews and meta-analyses of clinical trials pointed out the potential for increased risks of myocardial infarction associated with the thiazolidinedione rosiglitazone.
Largely as a result of these types of concerns, regulatory requirements issued by the US Food and Drug Administration (FDA) in 2008 stipulate that new type 2 diabetes drugs should rule out an unacceptable increase in cardiovascular risk in phase 2 and phase 3 clinical trials prior to drug approval.
However, an approach to assess kidney disease end points for novel diabetes drugs is not generally applied. More commonly, specific renal data have been obtained from secondary analyses of cardiovascular outcome trials with several studies identifying effects on glomerular filtration rate (GFR), although this was not the primary end point of those trials.
Despite the value of acquiring these important data, such long-term renal safety evidence has often not been a priority of the clinical trial program, but has only become available several years after drug approval.
Linagliptin, a novel member of the dipeptidyl peptidase 4 (DPP-4) inhibitor class, has previously been shown to significantly improve glucose control without causing weight gain or increasing hypoglycemia risk.
In accordance with the guidance by the FDA, an early cardiovascular meta-analysis was performed that ruled out an unacceptable increase in cardiovascular risk for this drug and linagliptin was consequently approved in the United States in May 2011.
Unlike other members of the DPP-4 inhibitor class, linagliptin is not primarily cleared by the kidney and can be prescribed to patients with type 2 diabetes at one single dose irrespective of kidney function.
Such pharmacologic qualities support the use of linagliptin in a broad range of patients with type 2 diabetes, including those with increased prevalence and risk of renal microvascular complications, as well as in patients with declining kidney function.
The objective of this study was to explore kidney disease end points in a large set of patients with type 2 diabetes treated with linagliptin. Comprehensive assessments of safety events were performed by developing a systematic and innovative approach based on individual-patient data from a large clinical trials program.
Study Design and Data Source
This pooled kidney disease analysis included all randomized, double-blind, and placebo-controlled clinical trials of linagliptin of 12-week or longer duration for which database lock of either predefined interim or final analysis was completed before February 13, 2011. Individual-patient data from 2 phase 2 and 11 phase 3 trials were included in the data set only if they received either linagliptin at a dose of 5 mg once daily or placebo. Studies were conducted globally over periods of 12 to 76 weeks as monotherapy or in combination with other glucose-lowering agents in patients with inadequately controlled type 2 diabetes. Open-label extension periods of primary double-blind randomized clinical trials were not considered (Table S1, available as online supplementary material).
Detailed study designs and primary and secondary efficacy and safety results of the individual studies have been published previously (Table S1).
All patients provided written informed consent. Local ethics committees/institutional review boards reviewed and approved all study protocols. All studies were conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.
Setting and Participants
Eligibility criteria for each of the 13 trials were similar. Most relevant common inclusion criteria were age 18 years or older or 21 years or older, diagnosis of type 2 diabetes, and body mass index ≤ 40 or ≤45 kg/m2. At screening, hemoglobin A1c levels ranged either from 7.0% to 11.0% (53-97 mmol/mol) in treatment-naive participants or from 6.5% to 10.5% (48-91 mmol/mol) in participants previously treated with one or more glucose-lowering therapy. In the majority of trials, previous glucose-lowering therapies, if any, had to be unchanged for at least 8 weeks prior to informed consent. Most relevant common exclusion criteria at screening included the following: decreased hepatic function defined by serum levels of either alanine transaminase, aspartate transaminase, or alkaline phosphatase more than 3 times the upper limit of normal; myocardial infarction, stroke, or transient ischemic attack within the previous 3 or 6 months; any requirement for hemodialysis within the previous 3 months; and kidney transplantation.
Individuals whose blood glucose levels were not adequately controlled during each of the 13 trials received additional rescue therapy to ensure overall safety, as appropriate.
The pooled population consisted of all randomly assigned individuals (n = 5,466) who received at least one dose of study drug (treated set: linagliptin group, n = 3,505; placebo group, n = 1,961).
Kidney Disease End Points
Based on clinical guidelines or recommendations made by medical associations and regulatory bodies,
we defined the primary composite outcome as first occurrence of 6 individual and clinically relevant kidney disease end points: (1) new onset of moderate elevation of albuminuria (urinary albumin-creatinine ratio [ACR] > 30 mg/g at any time during study conduct with baseline values ≤ 30 mg/g), (2) new onset of severe elevation of albuminuria (ACR > 300 mg/g at any time during study conduct with baseline values ≤ 300 mg/g), (3) reduction in kidney function (serum creatinine increase to ≥250 μmol/L [≥2.8 mg/dL] from a baseline value < 250 μmol/L as defined by European Medicines Agency; increase observed at a minimum of 2 consecutive visits during study conduct with a between-visit time window of at least 4 weeks), (4) halving of estimated GFR (eGFR; loss of baseline eGFR > 50% as defined by the FDA, and observed at a minimum of 2 consecutive visits during study conduct with a between-visit time window of at least 4 weeks), (5) incidence of acute renal failure, and (6) death from any cause. Although similar end points have previously been interpreted as efficacy parameters in renal studies,
Because the majority of the linagliptin development program was conducted in the era before creatinine assay standardization, 1 of the 2 utilized central laboratories did not perform standardization to isotope-dilution mass spectrometry (IDMS) values for the measurement of serum creatinine. Therefore, serum creatinine values from this laboratory were standardized for appropriate use in the CKD-EPI equation (ie, reduction by 5%). Albuminuria was determined at each study visit by ACR from a spot urine sample at baseline and during the randomized treatment period. Normoalbuminuria was defined as baseline ACR ≤ 30 mg/g, moderate elevation of albuminuria was defined as baseline ACR > 30 to 300 mg/g, and severe elevation of albuminuria was defined as baseline ACR > 300 mg/g. All assessments of urine and blood were performed at a central laboratory (Quintiles Laboratories, Clearstone Central Laboratories [formerly MDS Pharma Services], and Covance Laboratories). Acute renal failure was defined as ID 20000003 of the standardized MedDRA query (Medical Dictionary for Regulatory Activities, version 14.0) broad search. Overall death was based on fatal adverse event outcome.
Overall safety assessments included adverse events, vital signs, and clinical laboratory variables. Based on relevant safety signals of recent cardiorenal outcomes trials in patients with type 2 diabetes and chronic kidney disease (CKD),
additional adverse events of special interest for this pooled kidney disease analysis included hypotension (identified by investigator from individual patient report form evaluation) and hyperkalemia (identified by central laboratory serum potassium levels > 5.0 mmol/L).
Statistical analyses were performed using SAS, version 9.2, software (SAS Institute Inc). Analyses were based on individual-patient data from the treated set. Descriptive statistics were used for demographic and baseline characteristics, as well as to determine primary and secondary outcomes (such as incidence, incidence rates per 1,000 person-years, and time at risk). Comparability between treatment groups for demographic and baseline characteristics was explored by applying stratified 2-sample t tests and Cochran-Mantel-Haenszel tests, respectively.
The hazard ratio (HR) for the time to first event of interest of the primary composite outcome was calculated using the Cox proportional hazards model with the primary exposure treatment group. Adjustments were performed for individual studies. Subgroup analyses of the primary composite outcome were performed by age, race, and concomitant antihypertensive treatment (with or without angiotensin-converting enzyme [ACE] inhibitor and/or angiotensin receptor blocker [ARB] therapy at baseline). Interaction tests were conducted in order to exclude the heterogeneity of the treatment effect regarding age, race, antihypertensive treatment, kidney function at baseline, and individual studies. These interaction analyses were performed using an additional Cox regression model including the respective factor, as well as the interaction term of the respective factor with treatment.
Statistical analysis of the secondary outcomes was based on the individual components of the primary composite outcome.
Cox proportional hazards model analyses were also performed to calculate HRs of adverse events of special interest (ie, hypotension and hyperkalemia). Renal and safety parameters were reported using descriptive statistics.
Demographic and Baseline Characteristics
This pooled kidney disease analysis included a total of 5,466 treated individuals: 3,505 received linagliptin, 5 mg, once daily and 1,961 received placebo. Median treatment exposure was 171 (range, 1-531) days for linagliptin and 172 (range, 1-531) days for placebo. Cumulative exposure was 1,751 person-years for linagliptin and 1,055 person-years for placebo. Overall, participants in the linagliptin group (8.3%) were less likely to discontinue treatment compared with those receiving placebo (12.6%).
Demographic and baseline clinical and biochemical characteristics (Table 1) and background glucose-lowering and cardiovascular therapies (Table 2) were well balanced between the 2 treatment groups.
The primary composite outcome occurred in 448 (12.8%) individuals in the linagliptin group and 306 (15.6%) individuals in the placebo group (Table 3). Linagliptin treatment significantly reduced the hazard of the first occurrence during the study of the primary composite outcome by 16% as compared with placebo (HR, 0.84; 95% confidence interval [CI], 0.72-0.97; P = 0.02; Fig 1). Sensitivity analyses ruled out a significant study by treatment interaction (P for heterogeneity = 0.6).
Table 3Incidence, Incidence Rates, and Time at Risk of Primary and Secondary Outcomes
Kidney function at baseline was identified as a potential confounder for the primary composite outcome. Sensitivity analysis showed that adjustment for kidney function at baseline did not influence the association between reduced renal risk and linagliptin treatment (HR, 0.83; 95% CI, 0.72-0.97; P = 0.02).
Moreover, the observed risk reduction for kidney disease end points with linagliptin was consistent across examined subgroups, including those defined by race and concomitant use of renin-angiotensin system (RAS) inhibitors, with borderline evidence of heterogeneity in the age subgroup (Table 3; Fig 1B).
Secondary analyses of the individual components of the primary composite outcome showed that the majority of kidney disease end points occurred more frequently in the placebo group (Table 3). The overall most frequent event reported was new onset of moderate elevation of albuminuria, with an incidence rate of 9.3% and 10.9% in the linagliptin and placebo groups, respectively. Linagliptin treatment significantly reduced the hazard of new onset of moderate elevation of albuminuria by 18% (HR, 0.82; 95% CI, 0.69-0.98; P = 0.03; Fig 2). The second most reported event was new onset of severe elevation of albuminuria, occurring in 2.4% and 3.2% in the linagliptin and placebo groups, respectively (HR, 0.86; 95% CI, 0.61-1.20; P = 0.4; Fig 2).
Rare kidney disease end points such as reduction in kidney function, halving of eGFR, or acute renal failure were comparable between the linagliptin and placebo groups (Table 3).
Five (0.1%) and 4 (0.2%) deaths occurred during the study periods in the linagliptin and placebo groups, respectively. None of these was considered drug related by the investigators.
Safety and Tolerability
Overall, clinical adverse events occurred in 2,151 (61.4%) participants in the linagliptin group and 1,242 (63.3%) in the placebo group. The proportion of participants having drug-related adverse events was 12.9% in the linagliptin group and 13.4% in the placebo group. Hypotensive episodes, as reported by investigators, occurred in 11 (0.3%) participants in the linagliptin group and 7 (0.4%) in the placebo group (HR, 1.12; 95% CI, 0.43-2.95; P = 0.8). Elevated serum potassium levels were documented in 28 (0.8%) participants in the linagliptin group and 24 (1.2%) in the placebo group (HR, 1.02; 95% CI, 0.59-1.77; P = 0.9).
Mean changes in eGFR, ACR, blood pressure, and body weight from baseline to week 24 in the linagliptin and placebo groups are presented in Table 4. Table S2 provides additional information on blood pressure changes during interventions as categorized by the International Society of Hypertension recommendations. No significant differences were observed for changes in blood pressure among normo- and hypertensive patients when treated with either linagliptin or placebo.
Table 4Change in Renal and Selected Safety Parameters From Baseline to Week 24
In this pooled kidney disease analysis, a comprehensive assessment of kidney disease end points for a glucose-lowering drug was performed based on available data from an early clinical development program. Such safety evaluations have previously been requested to improve informed treatment decision making and to weigh overall risks and benefits of novel glucose-lowering agents as early as possible in drug development. A recent example of early drug safety evaluation was the FDA guidance issued in 2008 requesting that all new oral glucose-lowering drugs for treating type 2 diabetes have to explore cardiovascular safety prior to regulatory approval.
However, similar guidance on renal safety has not generally been requested, although type 2 diabetes is associated with considerable renal burden. This is noteworthy because there is a large body of evidence that supports the view that macro- and microvascular changes often occur simultaneously and share common risk factors and underlying mechanisms.
Therefore, it would be of relevance for new diabetes drugs to provide early safety information on renal complications in addition to assessing cardiovascular safety. This consideration is further supported because individuals with diabetes per se are known to be at significant increased risk of developing CKD. As the leading cause of kidney failure in the United States, diabetes accounts for nearly 45% of new cases.
To further define the potential impact of a glucose-lowering drug on renal risk and outcomes, a novel and systematic approach was developed to assess kidney disease end points in patients with type 2 diabetes treated with the DPP-4 inhibitor linagliptin.
In order to address this important gap, linagliptin was chosen as an appropriate candidate because it does not require dose adjustment due to nonrenal clearance and thus can be given as a single oral dose in patients with type 2 diabetes at any stage of decreased kidney function.
Overall, our pooled kidney disease analysis included 13 randomized controlled clinical trials made up of more than 5,000 individuals with type 2 diabetes. We found that linagliptin treatment was not associated with an increase in renal risk. Moreover, linagliptin treatment reduced significantly the hazard of kidney disease end points by 16% when compared with placebo. This is an intriguing finding and generates the novel hypothesis that this agent may have potential to slow CKD progression in type 2 diabetes, as recently reported through its effects on the “surrogate” albuminuria.
The primary aim of our pooled kidney disease analysis was to rule out an increased renal risk with linagliptin. It is important to exclude potential deleterious effects as a result of drug-drug interactions, particularly as they pertain to the kidney. For example, a recent trial targeting dual blockade of the RAS by combining the novel renin inhibitor aliskiren with the established classes of either ACE inhibitors or ARBs in patients with type 2 diabetes supports such a possibility.
Of note, in our analysis, linagliptin was not associated with an increased risk of hypotension or hyperkalemia. Furthermore, this lack of a deleterious effect of linagliptin was observed in this cohort, in which 45% of participants were concomitantly treated with a RAS inhibitor at baseline. Hence, our analysis indicates that there is no increased renal or hemodynamic risk with the combined blockade of the RAS and DPP-4 system.
As outlined, the data are consistent with a potential beneficial effect of linagliptin on the onset and progression of kidney disease in type 2 diabetes. In line with findings from this pooled kidney disease analysis and a previous analysis that has identified an albuminuria-lowering effect of linagliptin, which appears to be at least partially independent of its glucose-lowering action,
Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.
In the present study, more than 500 individuals with eGFRs < 60 mL/min/1.73 m2 were included. Kidney function at baseline did not influence the association between reduced renal risk and linagliptin treatment, indicating a possible renal effect of linagliptin even at advanced stages of CKD. Moreover, the risk reduction for kidney disease end points with linagliptin was seen in participants with or without concomitant treatment with RAS inhibitors at baseline. Although treatments based on blockade of the RAS have generally been associated with a reduction in albuminuria and improved kidney disease outcome in patients with type 2 diabetes,
further research is now underway to explore glucose-dependent and -independent effects of linagliptin in the kidney. Specifically, the MARLINA-T2D trial (Efficacy, Safety and Modification of Albuminuria in Type 2 Diabetes Subjects With Renal Disease With Linagliptin; ClincalTrials.gov study number NCT01792518) is designed and powered to explore the albuminuria-lowering potential of linagliptin in patients with type 2 diabetes and prevalent albuminuria already treated with ACE inhibitors or ARBs. This 24-week, randomized, controlled study was initiated in early 2013 and results are expected in 2015.
A major strength of the present study is the large sample size, which provides greater power to detect significant differences than individual randomized controlled trials. Nonetheless, we acknowledge that this pooled kidney disease analysis was of clinical trials not primarily designed to investigate kidney disease end points. However, safety assessments were standardized across trials and laboratory assessments of albuminuria and kidney function were conducted by a central laboratory. Another limitation is the use of a primary composite outcome that combines different kidney disease end points. However, all of our selected kidney disease end points are likely part of broader pathologic pathways to kidney failure in patients with diabetes. Finally, average durations of the included trials were relatively short, which could explain the overall low observation rate of significant kidney disease progression and hard kidney disease outcome events. To address the high unmet medical need in patients with type 2 diabetes and CKD, the recently initiated CARMELINA trial (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus; ClinicalTrials.gov study number NCT01897532) will investigate the long-term effect of linagliptin on major cardiovascular and kidney disease outcomes in adults with type 2 diabetes at risk of macro- and microvascular events.
In conclusion, it is suggested that emerging data from clinical development programs should be systematically used to assess kidney disease end points in patients with type 2 diabetes treated with new glucose-lowering agents. Analogous to the current efforts to better assess cardiovascular safety, renal safety analyses could provide reliable and valid information on kidney disease in the early stages of drug development. In our analysis, a novel approach for kidney disease assessments has been developed using the large clinical trials program of the novel DPP-4 inhibitor linagliptin. Linagliptin was not associated with an increased renal risk but was associated with a significant reduction in clinically relevant kidney disease end points in patients with type 2 diabetes.
Part of this work was presented as an abstract at the American Society of Nephrology’s Kidney Week 2012, San Diego, CA, October 30 to November 4, 2012 (poster TH-PO530).
Support: Audrey Koïtka-Weber, PhD, provided scientific consulting and medical writing services for this study; this assistance was funded by Boehringer Ingelheim, the manufacturer of linagliptin. Boehringer Ingelheim was the funding source and sponsor for all clinical trials. The sponsor was involved in study design, data collection, data analysis, and interpretation of data. Each author had full access to the data. The manuscript was prepared by the authors under the supervision of Dr Cooper, with the sponsor-funded scientific writing assistance of Dr Koïtka-Weber. The decision to submit the manuscript was the responsibility of Dr Cooper.
Financial Disclosure: Dr Cooper has received speaker honoraria from Boehringer Ingelheim, Servier, and Eli Lilly and is an advisory member for Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, and Novo-Nordisk. Dr Perkovic is supported by a Heart Foundation of Australia Cardiovascular Research Network Fellowship; has received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Servier; serves on Steering Committees for trials supported by Abbott, Baxter, Boehringer Ingelheim, Janssen, and Pfizer; and is a consultant for Abbott, Astellas, Baxter, and Vitae Pharmaceuticals. Dr McGill has received grants from Sanofi, Novartis, Takeda, Mannkind, and Andromeda; has served as a speaker and consultant for Merck and Janssen; and is a consultant for Boehringer Ingelheim, Sanofi, Mannkind, and Novo Nordisk. Dr Groop has received speaker honorariums from Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Merck Sharp and Dohme, Novartis, and Novo Nordisk and research grants from Eli Lilly and Roche and is an advisory member for Boehringer Ingelheim and Novartis. Dr Rosenstock has served on scientific advisory boards and received honorarium or consulting fees from Pfizer, Roche, Sanofi, Novo Nordisk, Eli Lilly, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Johnson & Johnson, Novartis, Boehringer Ingelheim, and Lexicon and grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, Lexicon, and Boehringer Ingelheim. Dr Wanner has received speaker honoraria from Abbvie, AstraZeneca, Bristol-Myers Squibb, MSD, Mitsubishi, Roche, and Sanofi-Genzyme; serves on Steering Committees for trials supported by Abbvie and Boehringer Ingelheim; and is a consultant for Abbvie, Baxter, Keryx and Mitsubishi. Mr Hehnke and Drs Woerle and von Eynatten are employees of Boehringer Ingelheim.
Contributions: research idea and study design: MEC, MvE; statistical analysis: UH; data analysis/interpretation: MEC, VP, JBM, P-HG, CW, JR, UH, H-JW, MvE; supervision or mentorship: MEC. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. MEC takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.