MRIGTEAIS RG N REGIMENS AND DRUGS THERAPIES: EMERGING

Diabetes Care Volume 43, August 2020 1803

Vlado Perkovic,1 Robert Toto,2 Mark E. Cooper,3 Effects of Linagliptin on Johannes F.E. Mann,4,5 Julio Rosenstock,6 Darren K. McGuire,2 Steven E. Kahn,7 Cardiovascular and Kidney Nikolaus Marx,8 John H. Alexander,9 Bernard Zinman,10,11 Egon Pfarr,12 Outcomes in People With Normal Sven Schnaidt,13 Thomas Meinicke,13 Maximillian von Eynatten,12 Jyothis T. George,12 and Reduced Kidney Function: Odd Erik Johansen,14 and Christoph Wanner,15 Secondary Analysis of the on behalf of the CARMELINA investigators CARMELINA Randomized Trial Diabetes Care 2020;43:1803–1812 | https://doi.org/10.2337/dc20-0279

1Faculty of Medicine, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia 2University of Texas Southwestern Medical Cen- ter, Dallas, TX 3Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia 4Kuratorium fur¨ Dialyse Kidney Centre, Munich, Germany 5 OBJECTIVE Department of Nephrology, Friedrich-Alexander University of Erlangen-Nurnberg,¨ Erlangen, Germany Type 2 diabetes is a leading cause of kidney failure, but few outcome trials 6Dallas Diabetes Research Center, Dallas, TX proactively enrolled individuals with chronic kidney disease (CKD). We performed 7Division of Metabolism, Endocrinology and Nu- secondary analyses of cardiovascular (CV) and kidney outcomes across baseline trition, Department of Medicine, VA Puget Sound fi ‡ < < Health Care System and University of Washing- estimated glomerular ltration rate (eGFR) categories ( 60, 45 to 60, 30 to 45, ton, Seattle, WA 2 and <30 mL/min/1.73 m ) in Cardiovascular and Renal Microvascular Outcome 8Department of Internal Medicine I, University Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome Hospital Aachen, RWTH Aachen University, Aa- trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532). chen, Germany 9Duke Clinical Research Institute, Duke Health, RESEARCH DESIGN AND METHODS Durham, NC 10Lunenfeld-Tanenbaum Research Institute, Mount Participants with CV disease and/or CKD were included. The primary outcome was Sinai Hospital, Toronto, Ontario, Canada time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal 11Division of Endocrinology, University of Tor- onto, Toronto, Ontario, Canada stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome 12 ‡ Boehringer Ingelheim Pharma GmbH & Co. KG, of renal death, end-stage kidney disease, or sustained 40% decrease in eGFR from Ingelheim, Germany 13 baseline. Other end points included progression of albuminuria, change in HbA1c, Boehringer Ingelheim Pharma GmbH & Co. KG, and adverse events (AEs) including hypoglycemia. Biberach, Germany 14BoehringerIngelheim NorwayKS, Asker,Norway 15 RESULTS Division of Nephrology, Department of Med- icine, Wurzburg¨ University Clinic, Wurzburg,¨ Germany A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% Corresponding author: Vlado Perkovic, vlado albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as [email protected] compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI Received 9 February 2020 and accepted 6 April 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P 2020 values >0.05). Regardless of eGFR, albuminuria progression was reduced with Clinical trial reg. no. NCT01897532, clinicaltrials linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were .gov balanced among groups overall and across eGFR categories. This article contains supplementary material online at https://doi.org/10.2337/figshare.12129993. CONCLUSIONS © 2020 by the American Diabetes Association. Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV Readers may use this article as long as the work is properly cited, the use is educational and not for disease, there was no difference in risk for linagliptin versus placebo on CV and fi fi pro t, and the work is not altered. More infor- kidney events. Signi cant reductions in risk for albuminuria progression and HbA1c mation is available at https://www.diabetesjournals and no difference in AEs were observed. .org/content/license. 1804 Linagliptin and CV and Kidney Outcomes Diabetes Care Volume 43, August 2020

Results from recent cardiovascular (CV) presence of CKD, including advanced CKD. testing strategy, was time to first occur- outcome trials of glucose-lowering med- That trial confirmed the CV and kidney rence of a composite of adjudication- ications have helped to define the rela- safety of linagliptin. In this analysis, we confirmed kidney failure outcome (ESKD tive benefit and risks of these agents (1). report effects on primary CV and second- or renal death) or a sustained decrease This in turn has informed updated treat- ary kidney outcomes and on a compre- of $40% in eGFR from baseline. It was ment guidelines and recommendations hensive range of further pre- and post anticipated that at least 432 participants from multiple societies (2–4) with a pri- hoc–specified kidney outcomes as well as would experience the key kidney out- mary focus on the CV benefits of glucose- glycemic data, overall and in subgroups come event during the same period needed lowering therapies rather than glycemic defined by the presence or absence of to accrue the $611 3P-MACE. This would outcomes. Up to 40% of people with reduced kidney function. yield a power of 85% to test for superiority type 2 diabetes will develop chronic kid- of linagliptin versus placebo for the key ney disease (CKD) (5), and a substantial RESEARCH DESIGN AND METHODS secondary kidney outcome at a one-sided number will progress to advanced stages Design and Procedures a-level of 2.5%, assuming a hazard ratio ofCKD,includingend-stagekidneydisease The design and primary results have been (HR) of 0.75. (ESKD) (6). People with type 2 diabetes reported previously (21,22). In brief, CAR- To ensure the highest standard of as- and any level of CKD have a substantially MELINA was a multicenter, randomized, certainment for renal effects of linagliptin increased risk of death, CV events, heart double-blind clinical trial in adults with versus placebo, the following kidney out- failure (HF) events, and kidney failure type 2 diabetes (HbA1c 6.5–10.0% [48– comes were prospectively captured and (7,8), as well as a reduced quality of life 86 mmol/mol]) at high risk for CV and centrally adjudicated by experts masked to (9,10). In addition, individuals with di- kidney disease, defined as history of vas- study treatment assignment: 1)ESKD,2) abetes and CKD tend to be less well cular disease and urinary albumin-to- renal death, 3) sustained decrease of eGFR controlled with regards to CV risk factors creatinine ratio (UACR) .30 mg/g (or of $40%, and 4) sustained decrease of and have a lower likelihood of glycemic equivalent); estimatedglomerularfiltra- eGFR of $50% (for all definitions, see 2 goal attainment, while being at higher tion rate (eGFR) 45–75 mL/min/1.73 m Supplementary Section A). risk for hypoglycemia (11,12). This is and UACR .200mg/g (or equivalent); or particularly marked for those with ad- eGFR 15–45 regardless of UACR. It was Sensitivity Analysis of Key Secondary Kidney Outcome and Further Kidney Outcomes vanced kidney disease. There is thus a conducted at 605 centers in 27 coun- For the key secondary kidney outcome, substantial need to develop treatments tries. Investigators were encouraged to prespecified sensitivity analyses were that might preserve kidney function in use additional CV medications and med- conducted for participants with a min- diabetes and also treatments that im- ications for glycemic control (except DPP-4i, imum treatment duration of 30 days prove safely glycemic control in this glucagon-like peptide 1 [GLP-1] receptor (i.e., analyses that considered data from high-risk population. However, data re- agonists, and sodium–glucose cotrans- individuals being on investigational prod- garding the safety and efficacy of glucose- porter 2 [SGLT2] inhibitors) according to uct for at least 30 days; on-treatment set) lowering therapies in people with existing applicable standard of care throughout and by censoring at day 0 and day 30 after kidney disease are generally limited the trial. Participants who prematurely last dose of investigational product taken, because the vast majority of recent discontinued study medication were fol- CV outcome trials in type 2 diabetes lowed for ascertainment of CV and key respectively (i.e., analysis that considered did not proactively recruit those with secondary kidney outcome events. At- data from individuals until 0 or 30 days, CKD (13). Furthermore, although data tempts were made to collect vital status respectively, after last study medication from trials assessing different intensi- information on every randomized pa- intake). A robustness analysis of this out- ties of glucose-lowering therapy have tient at study completion, in compliance come was also assessed using variants of $ suggested that more intensive glucose with local law and regulations. The pro- eGFR(i.e.,withsustaineddecreaseof 50% $ lowering reduces albuminuria, effects tocol was approved by Institutional Re- or 30% in eGFR from baseline), dou- on major renal outcomes have been view Boards or Ethics Committees for bling of serum creatinine from baseline $ inconsistent (14–17). each participating site, and all partic- (equivalent to a 57% reduction in , Linagliptin is a dipeptidyl peptidase ipants provided written informed con- eGFR), or sustained eGFR 10 mL/min/ 2 4 inhibitor (DPP-4i) that undergoes en- sent for trial participation. 1.73 m . terohepatic cycling, with a large major- Additional prespecified and post hoc ity (85%) eliminated via biliary excretion Outcomes kidney outcomes (Supplementary Table (18), and does not need dose adjust- CV and Kidney Outcomes and Adjudication B1) include the composite of renal death ment in people with CKD. Analyses of of Kidney Events or ESKD, time to first doubling of serum pooled data from previous studies have The trial was event driven, and follow-up creatinine regardless of other renal events, supported the hypothesis that linaglip- continued until a minimum of 611 par- effect on geometric mean (gMean) UACR, tin may lower albuminuria (19) and might ticipants had experienced a primary CV albuminuria progression and regression, alsopreventprogressionofkidneydisease outcome event (time to first occurrence and effects on eGFR as assessed by a slope (20). The Cardiovascular and Renal Mi- of CV death, nonfatal myocardial infarc- analysis. Slope changes were further an- crovascular Outcome Study With Linaglip- tion, or nonfatal stroke [three-point ma- alyzed according to both acute change tin (CARMELINA) trial, for which primary jor adverse CV event (3P-MACE)]). The (defined as the effect over the first 12 results were reported previously (8,21), key secondary outcome, a kidney out- weeks of treatment) and chronic change enrolled a population enriched for the come that was part of the confirmatory (defined as the effect between week 12 of care.diabetesjournals.org Perkovic and Associates 1805

treatment and end of treatment). Post hoc knowntobefreeofthespecificoutcome Table D1). Premature discontinuation sensitivity analyses were performed to as- event. All analyses were performed us- of study medication was 23.9% and 27.4% sess if changes in albuminuria depended on ing the intention-to-treat principle, mod- in the linagliptin and placebo group, re- HbA1c changes. ified to exclude randomized participants spectively, with similar proportions across Several outcome analyses were per- whodidnottakeatleastonedoseofstudy eGFR categories (Supplementary Table formed to assess the impact of requiring medication (treated set). Handling of miss- D1). eventstobesustained. Sustainability was ingdataisdescribedinthestatisticalanalysis fi ful lled when at least two consecutive plan published elsewhere (21). CV and Kidney Outcomes by Baseline fi laboratory assessments met the de ni- A formal test of heterogeneity of the Kidney Function fi tion of the end point. The con rmatory treatment effect among subgroups was CV Outcomes assessment had to be performed at least performed for each subgroup analysis. A Incidence rates for the primary CV com- , 28 days after the initial assessment that two-sided P 0.05 was considered sig- posite outcome 3P-MACE and the other fi fi quali ed for the event (i.e., assessments ni cant for all analyses with no adjust- CV, HF, and mortality outcomes increased , performed 28 days after the initial drop mentsmadeformultipletesting.Iteratively with lower levels of baseline renal func- would not qualify for a sustained event). measured continuous parameters were tion (Supplementary Fig. E1). Consistent fi Theoutcomede nitionwasmetwithouta analyzed using mixed-effect models for neutraleffectsontheprimaryCVoutcome fi con rmatory assessment in case: 1)the repeated measures including random- 3P-MACE(HR 1.02 [95% CI0.89, 1.17]; P 5 decrease happened at trial end, 2) there ized treatment, region, week, treatment- 0.7398) as well as on further CV or HF wasanoccurrenceofdeathaftertheinitial by-week interaction, and linear covariates outcomes were observed across all renal decrease, or 3) the initial decrease hap- of baseline measurement and baseline- subgroups comparing linagliptin with pla- pened at the last available measurement by-week interaction in the model. Overall cebo (Fig. 1A and Supplementary Fig. F1), (for sustained albuminuria end points). safety assessments were conducted using with some evidence of heterogeneity descriptive statistics for AEs. Analyses observed for all-cause mortality (P for Efficacy and Safety were conducted with SAS version 9.4 interaction 0.0289 and 0.0547 in the Additional outcomes were change from (SAS Institute, Cary, NC). four- and two-eGFR category analyses, baseline in HbA1c and occurrence of respectively), which likely is a play of adverse events (AEs) and hypoglycemia. chance given the many subgroup anal- RESULTS The latter two were captured based on yses conducted without adjustment and investigator-reported events and coded Among 6,979 randomized and treated the lack of a consistent risk gradient by using the Medical Dictionary for Drug participants, a total of 4,348 (62.3%) declining GFR categories. Regulatory Activities version 20.1. had a baseline eGFR ,60 mL/min/1.73 2 m , including 3,000 (43.0%) with eGFR Kidney Outcomes 2 Subgroup Analysis ,45 mL/min/1.73 m . The proportions The key kidney composite outcome of Prespecified subgroup analyses were with normo-, micro-, and macroalbumi- 40% reduction in eGFR, ESKD, or renal done for participants by GFR categories nuria at baseline were 1,392 (19.9%), deathwasnot differentamong the groups according to Kidney Disease: Improv- 2,894 (41.5%), and 2,690 (38.5%), re- (HR 1.04 [95% CI 0.89, 1.22]; P 5 0.6164) ing Global Outcomes (KDIGO) (23): G # spectively. The baseline characteristics by (Fig. 1B), including across all kidney func- 2: .60; G3a: 45–60; G3b: 30–45; and GFR categories (Table 1 and Supplementary tion subgroups (Fig. 1B and Supplementary G $ 4: ,30 mL/min/1.73 m2,aswellas Table C1) were balanced across random- Fig. F1). As with the CV outcomes, higher dichotomously by eGFR .60 versus ized groups. Compared with participants rates of the kidney composite outcome #60 mL/min/1.73 m2. Because the pub- with preserved kidney function, those were observed with lower kidney func- lished evidence base is particularly scarce with lower eGFR tended to be older, have tion (Supplementary Fig. E1). Sensitivity 2 in those with eGFR ,45 mL/min/1.73 m , higher HbA1c and baseline blood pres- analyses considered minimum treatment post hoc analyses were also done for sure, longer duration of diabetes, and durations or various approaches to cen- participants with eGFR ,45 versus $45 higher levels of albuminuria. Overall, the soring after last dose of study drug taken mL/min/1.73 m2. median observation time and treatment (Supplementary Fig. F2), as well as un- exposure in the trial were 2.2 and 1.9 dertaking robustness analyses using other Statistical Analyses years, respectively, and were consistent cutoffs of eGFR reduction other than a Time-to-event outcomes were analyzed across groups according to GFR catego- 40% reduction, including doubling of se- using Cox proportional hazards regres- ries (Supplementary Table D1). Median rum creatinine and a 30% and 50% eGFR sion models, with randomized treatment observation time until occurrence of first decrease (Supplementary Fig. F3), and and geographical region as factors. For component of 3P-MACE was 2.1 years for found no difference between linagliptin end points including hospitalization for both linagliptin and placebo and for the and placebo. The same was true for dif- HF, the factor history of HF (yes or no) key secondary kidney outcome was 1.9 ferent definitions of various composite was included in addition. For subgroup and 1.7 years, respectively, with overall outcomes, including sustained ESKD or analyses, an additional factor for sub- follow-up data available of 98.7% (3P- renal death (linagliptin, 136 [of which group as well as a subgroup-by-treat- MACE) and 88.0% (key kidney outcome), 135 were ESKD] and incidence rate 1.8/ ment interaction term was included in respectively. Vital status was known in 100 patient-years vs. placebo, 154 [of the regression models. Censoring was 99.7% at study completion and did not which 152 were ESKD] and incidence applied the day a participant was last differ by GFR groups (Supplementary rate 2.0/100 patient-years) (HR 0.87 1806 Linagliptin and CV and Kidney Outcomes Diabetes Care Volume 43, August 2020

Table 1—Baseline characteristics by eGFR categories <30, 30 to <45, 45 to <60, and ‡60 mL/min/1.73 m2 eGFR ,30 eGFR 30–,45 eGFR 45–,60 eGFR $60 Overall N (%) 1,062 (15.2) 1,938 (27.8) 1,348 (19.3) 2,631 (37.7) 6,979 (100) Age, years 66.7 (9.5) 68.8 (8.6) 66.9 (8.6) 62.8 (8.6) 65.9 (9.1) Male 568 (53.5) 1,121 (57.8) 885 (65.7) 1,816 (69.0) 4,390 (62.9) Region Europe (including South Africa) 345 (32.5) 788 (40.7) 552 (40.9) 1,249 (47.5) 2,934 (42.0) Latin America 409 (38.5) 563 (29.1) 426 (31.6) 912 (34.7) 2,310 (33.1) North America 210 (19.8) 419 (21.6) 268 (19.9) 283 (10.8) 1,180 (16.9) Asia 98 (9.2) 168 (8.7) 102 (7.6) 187 (7.1) 555 (8.0) eGFR (MDRD), mL/min/1.73 m2 23.4 (4.2) 37.2 (4.1) 51.4 (4.4) 81.6 (16.7) 54.6 (25.0) ,30 1,062 (100) 0 0 0 1,062 (15.2) ,15 21 (2.0) 0 0 0 21 (0.3) UACR, mg/g, median (25th–75th percentile) 585 (77–2,039) 125 (24–719) 223 (60–731) 126 (46–412) 162 (44–728) UACR (mg/g)* ,30 159 (15.0) 535 (27.6) 214 (15.9) 484 (18.4) 1,392 (19.9) 30–300 293 (27.6) 688 (35.5) 566 (42.0) 1,347 (51.2) 2,894 (41.5) .300 609 (57.3) 714 (36.8) 568 (42.1) 799 (30.4) 2,690 (38.5)

HbA1c, % 7.9 (1.0) 7.9 (1.0) 8.0 (1.0) 8.0 (1.0) 8.0 (1.0)

HbA1c, mmol/mol 62.5 (10.8) 62.4 (10.7) 63.7 (11.0) 64.3 (11.2) 63.4 (11.0) Diabetes duration, years 17.3 (9.8) 16.6 (9.7) 15.4 (9.5) 12.0 (8.4) 14.8 (9.5) BMI, kg/m2 31.5 (5.6) 31.6 (5.4) 31.3 (5.3) 30.9 (5.1) 31.3 (5.3) SBP/DBP, mmHg 143 (20)/76 (11) 141 (19)/76 (11) 141 (18)/78 (10) 139 (16)/79 (10) 141 (18)/78 (10) HF 253 (23.8) 512 (26.4) 374 (27.7) 734 (27.9) 1,873 (26.8) Insulin 823 (77.5) 1,288 (66.5) 769 (57.0) 1,171 (44.5) 4,051 (58.0) Metformin 180 (16.9) 717 (37.0) 821 (60.9) 2,090 (79.4) 3,808 (54.6) Sulfonylurea 231 (21.8) 543 (28.0) 438 (32.5) 1,030 (39.1) 2,242 (32.1) Any antihypertensives 1,035 (97.5) 1,877 (96.9) 1,307 (97.0) 2,472 (94.0) 6,691 (95.9) ACE inhibitors or ARBs 797 (75.0) 1,583 (81.7) 1,145 (84.9) 2,133 (81.1) 5,658 (81.1) Statins 764 (71.9) 1,432 (73.9) 982 (72.8) 1,840 (69.9) 5,018 (71.9) Data are n (%) or mean (SD) unless otherwise indicated. ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; SBP, systolic blood pressure. *Data missing for three (0.0%) participants: two (0.1%) linagliptin and one (0.0%) placebo.

[0.69, 1.10]) (Supplementary Fig. F4) magnitude of effect was attenuated. Of function (Fig. 3A and Supplementary and ESKD, renal death, or sustained note, the reduction in albuminuria pro- Table H1) with average (95% CI) reduc- 2 eGFR ,10 mL/min/1.73 m (HR 0.84 gression with linagliptin was not depen- tion in HbA1c of 20.35% (20.45, 20.25)/ [95% CI 0.67, 1.05]) (Supplementary dent on change in HbA1c (Supplementary 23.83 mmol/mol (24.92, 22.75) in the Fig. F5). Fig. G3). No significant difference in the advanced CKD subgroup with eGFR ,45 Albuminuria burden was modestly re- annual rate of change in eGFR was ob- mL/min/1.73 m2 and 20.36% (20.45, duced with linagliptin, as evident by sig- served (slope difference 20.175 mL/min/ 20.28)/23.99mmol/mol (24.92,23.06) nificant reductions in risk of progression to 1.73 m2/year [95% CI 20.472, 0.122]; P 5 for those with baseline eGFR $45 mL/ albuminuria, with consistent effects (inter- 0.2485) (Fig. 2B), despite a small acute min/1.73 m2. These improvements in action P value 5 0.35) across GFR cat- effect observed with linagliptin relative to glycemic control occurred despite re- egories G # 2toG$ 4(Fig.2A)by placebobyweek12(slopedifference duced use of other glucose-lowering reductioningMeanchanges in albumin- 20.22 mL/min/1.73 m2/4 weeks [95% treatments during follow-up overall and uria from similar baseline (e.g., adjusted CI 20.38, 20.07]; P 5 0.0040) (Fig. 2C across all predefined renal subgroups in the gMean at week 36 for linagliptin 130.36 and Supplementary Figs. G4 and G5), linagliptin arm (Supplementary Table H2), vs. 150.19 mg/g for placebo [gMean ratio driven by changes in the G # 2 group. including by GFR groups ,45 (HR 0.76 [95% 0.87 (0.81, 0.93)] and at week 84 for Annual rate of slope change between CI 0.65, 0.86]) versus $45 mL/min/1.73 m2 linagliptin 128.81 vs. 145.76 mg/g for week 12 and end of treatment was not (0.77 [0.68, 0.88]) (Fig. 3B). Fewer partic- placebo [gMean ratio 0.88 (0.82, 0.95)]) impacted by linagliptin treatment (0.09 ipants initiated or increased insulin dose 2 and by reduced proportions of partic- mL/min/1.73 m /year [95% CI 20.22, among participants randomized to lina- ipants who had albuminuria progression 0.41]; P 5 0.5638, relative to placebo) gliptin compared with placebo regardless or increased proportions with albumin- (Fig. 2C). of GFR (Supplementary Table H2), with an uria regression (Supplementary Figs. G1 Effects on Glycemia and Hypoglycemia HR of 0.69 (95% CI 0.59, 0.81) (P,0.0001) 2 and G2 and Supplementary Table G1); HbA1c was significantly reduced with li- in those with eGFR ,45 mL/min/1.73 m however, in the sustained analysis, the nagliptin, regardless of baseline kidney and 0.76 (0.65, 0.88) (P 5 0.0004) care.diabetesjournals.org Perkovic and Associates 1807

Figure 1—Effect of linagliptin vs. placebo by renal function on CV outcomes, mortality, and hospitalization for HF (HHF) (A) and kidney outcomes (B). *P value of subgroup-by-treatment interaction test. NC, not calculated. in those with eGFR $45 mL/min/1.73 m2, hypoglycemia (Fig. 3D and Supplementary ,45 mL/kg/1.73 m2, any hypoglycemia, respectively (Fig. 3C). Consistent with the Figs. I1 and I2), although the absolute risk hypoglycemia with plasma glucose ,54 overall trial results, the improvement for for hypoglycemia increased in both groups mg/dL or severe hypoglycemia (analyzed linagliptin in HbA1c across eGFR catego- with declining baseline eGFR. For example, together), or severe hypoglycemia in the ries occurred without an increased risk for in the advanced CKD subgroup with eGFR placebo group occurred 1.9-, 2.3-, and 1808 Linagliptin and CV and Kidney Outcomes Diabetes Care Volume 43, August 2020

Figure 2—A:Timetofirst occurrence of albuminuria progression (change from normo- to micro- or macroalbuminuria or from micro- to macroalbuminuria) for linagliptin vs. placebo by eGFR subgroups. *P for interaction. B: Overall effects on eGFR (MDRD) slope from baseline to last value on treatment and by eGFR category G # 2to$ G4 for linagliptin (Lina) vs. placebo (pbo). C: Overall change from baseline in eGFR (MDRD) over time for linagliptin vs. placebo and comparison of acute vs. chronic slope differences. MMRM, mixed model for repeated measures; OC, observed case. *Adjusted mean eGFR slope based on MMRM including terms for time as a linear covariate, treatment, region, and baseline eGFR as categorical covariates, and treatment-by-time interaction, baseline eGFR-by-treatment interaction, baseline eGFR-by-time interaction, and baseline eGFR-by-treatment-by-time interaction. care.diabetesjournals.org Perkovic and Associates 1809

2 Figure3—A: HbA1c overtimebyeGFR45 mL/min/1.73m subgroupsforlinagliptinvs.placebo.*Baselinevaluesaredescriptive;post-baselinedata from mixed model repeated measures adjusting for treatment, region, baseline HbA1c value, week, treatment-by-week interaction, and baseline HbA1c value-by-week interaction. B: New introduction of any glucose-lowering medications by eGFR 45 mL/min/1.73 m2 subgroups for linagliptin vs. placebo.C:Timetoinitiationoflong-termuseofinsulinorlong-termdoseincreaseininsulinbyeGFR45mL/min/1.73m2 subgroupsforlinagliptinvs. placebo. D: Occurrence of hypoglycemia by eGFR 45 subgroups for linagliptin vs. placebo. IRR, incidence rate ratio. *Severe defined as requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. 1810 Linagliptin and CV and Kidney Outcomes Diabetes Care Volume 43, August 2020

2.5-fold more frequently, respectively, context, the present results expand the (i.e., in the G # 2 group), which did not lead to relative to those with eGFR $45 mL/ evidence base among DPP-4i specifically an overall GFR difference. Similar results were min/1.73 m2 (Fig. 3D). for linagliptin and demonstrate its CV observed in the Trial Evaluating Cardiovas- AEs safety in CKD, including those with an cular Outcomes With Sitagliptin (TECOS) , 2 In line with the overall safety results, the eGFR 45 mL/min/1.73 m .Ofnote, (34) and Examination of Cardiovascular frequency of occurrence of investigator- despite a previous trial indicating an in- Outcomes with Alogliptin versus Standard reported AEs, serious AEs, and AEs lead- creased risk of hospitalization for HF with of Care (EXAMINE) (28). Potential reasons ing to study drug discontinuation for another DPP-4i, saxagliptin, and suggest- for a mild acute GFR reduction in those patients treated with linagliptin versus ing that this might be particularly true for with normal or better preserved renal fi placebo in CARMELINA did not differ people with CKD (27,30), CARMELINA also function could be remission of hyper l- among treatment groups by renal func- demonstrates that linagliptin does not tration, possibly related to an early na- – tion, but those with the lowest renal increase the risk of HF overall (8,22) or in triuretic effect mediated by stromal cell a function generally had a higher fre- the subset of participants with reduced derived factor-1 (36), or indirectly via quency of AEs (Supplementary Table I1). kidney function. the two- to threefold increase in GLP-1, In addition, the present results dem- which induces natriuresis by reducing the onstrate that the glucose-lowering efficacy Na/H exchange transporter isoform 3– CONCLUSIONS of linagliptin was preserved in partic- dependent sodium reabsorption in the The CARMELINA trial was deliberately ipants with reduced kidney function. The proximal tubule or via modulation of $1 enriched for participants with reduced glycemic benefits also translated into a of the .40 other substrates metabo- kidney function. As a result of this en- reduced need for other glucose-lowering lized by DPP-4, including high-mobility richedpopulation,thistrialcapturedmore therapies, including insulin, without group protein box 1 (37), which this trial renal outcomes than most CV outcome increasing risk for hypoglycemia. Although cannot provide a definitive answer for. trials of glucose-lowering therapies and SGLT2 inhibitors are now advocated to be While the data on GLP-1 receptor ago- foundnooveralleffectonthemaincom- used relatively early in type 2 diabetes, nists are more mixed, with some sugges- posite renal outcome comprised of the because they have been shown to prevent tion of possible renal benefit reported composite of renal death, ESKD, or sus- or slow down the progression of CV and HF (38,39),theLiraglutideEffectandActionin tained $40% reduction in eGFR from events and CKD (2–4,31), their glucose- Diabetes: Evaluation of Cardiovascular Out- baseline. It also demonstrated that li- lowering efficacy diminishes with reduced come Results (LEADER) trial observed the nagliptin did not increase CV risk among eGFR; in this context, linagliptin may have largest number of major renal outcomes in people with reduced kidney function, an important role, as it improves glycemic trials of the GLP-1 receptor agonist class and including participants with an eGFR ,45 control and reduces the need for insulin did not demonstrate clear benefitfor mL/min/1.73 m2 for whom few data without increasing the risk of hypoglyce- either persistent doubling of creatinine have previously been collected. Finally, mia (2–4,31) and, in comparison with other (184 events; HR 0.89 [95% CI 0.67, 1.19]) linagliptin treatment was associated with DPP-4i, does not require any dose adjust- or ESKD (120 events; HR 0.87 [95% CI improvements in glycemic control, with- ment with declining renal function. 0.61, 1.24]) (38). Notably, the com- out increasing hypoglycemia risk, as well A neutral effect on the main renal com- pleted outcome trials with GLP-1 re- as albuminuria, across all levels of kidney posite outcome was observed, despite a ceptor agonists were not powered for function. The former led to a reduction in significant though modest reduction in kidney outcomes and did not specifically the need for other glucose-lowering ther- albuminuria burden. Of note, in an ex- enroll patients with CKD, as CARMELINA apies, including insulin addition and upti- ploratory analysis, this reduction in albu- did. Although reduction in albuminuria tration, both overall and in people with minuria was not driven by changes in has been proposed as an independent reduced kidney function. glycemic control, which is interesting surrogateforhardkidneyoutcomes(40),a These results from CARMELINA are and aligns with some mechanistic data potentialreason for the lack of clear effect important, as people with reduced kidney suggesting that linagliptin has nongly- onmajor renal outcomes in CARMELINA is function have limited glucose-lowering cemic kidney effects (e.g., via attenua- that the albuminuria reduction was smaller therapy options, as a number of agents tion of podocyte injury or inhibition of than those observed with other renopro- are contraindicated or require dose myofibroblast transformation [32] or in- tective therapies, specifically angiotensin reduction (12,24,25). This is particularly hibition of endothelial-to-mesenchymal receptor blockade (41) or SGLT2 inhibitors true for those with eGFR ,45 mL/min/ transition and restoration of miRNA-29s (42,43). Alternatively, it can be argued 1.73 m2. Furthermore, people with re- [33]); however, this trial cannot address that the observation time may also have duced kidney function are at increased mechanisms potentially underlying this been too short to demonstrate benefit riskofdrug-relatedadverseeffects(25),so observation. These results, therefore, both in CARMELINA, particularly in light of the it is particularly important to obtain spe- expand and are broadly consistent with modest albuminuria reduction observed. cific safety data in this population (12,13). previous large trials of DPP-4i, in which The strengths of this analysis include Most glucose-lowering trials of DPP-4i modest effects on albuminuria were ob- the large number of participants with (26–29) have included modest numbers served, without any clear benefits on reduced kidney function. The trial was of participants with CKD, and very few with excretory kidney function (34,35), although a conducted to a high standard and achieved advanced CKD, in contrast to CARME- modest acute reduction in GFR during the planned number of CV and renal LINA, in which recruitment of people with the first 4 weeks in those with the least outcomes, and these renal outcomes CKD was a prespecified goal (22). In this reduced renal function at baseline occurred were prospectively captured, centrally care.diabetesjournals.org Perkovic and Associates 1811

adjudicated, and prespecified along with Laboratories, and Vitae Pharmaceuticals; and for the integrity of the data and the accuracy of subgroup analyses by baseline kidney func- has a policy of having honoraria paid to his the data analysis. tion. The trial also had some limitations. employer.R.T.is a consultant toAmgen, Boehringer Prior Presentation. Parts of this study were Ingelheim, ZS Pharma, Inc., Relypsa, Inc., Novo presented at the American Society of Nephrol- The median follow-up was only 2.2 years, Nordisk, Reata Pharmaceuticals, AstraZeneca, ogy’s Kidney Week 2018, San Diego, CA, 23–28 with 1.9 years for the key kidney outcome, and Bayer. M.E.C. has served on advisory boards October 2018, and the 79th Scientific Sessions of and beyond the key kidney outcome, we or spoken at scientific meetings (or both) for the American Diabetes Association, San Fran- only report secondary analysis. In addition, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly cisco, CA, 7–11 June 2019. the trial excluded people with a baseline and Company, Merck Sharp & Dohme, Mundi- pharma, Novartis, Novo Nordisk, Reata Pharma- , 2 References eGFR 15 mL/min/1.73 m and those ceuticals, Sanofi, andServierLaboratories.J.F.E.M. 1. McGuire DK, Marx N, Johansen OE, Inzucchi receiving dialysis, so the generalizability has received personal fees from AstraZeneca, SE, Rosenstock J, George JT. FDA guidance on Bayer, Boehringer Ingelheim, MEDICE, Novartis, of the present results to a broader pop- antihyperglyacemic therapies for type 2 diabe- Novo Nordisk, and Vifor Pharma. J.R. has served ulation is uncertain, although smaller tes: one decade later. Diabetes Obes Metab on scientific advisory boards and received hon- studies specific tothese populations have 2019;21:1073–1078 oraria or consulting fees from Eli Lilly and 2. Davies MJ, D’Alessio DA, Fradkin J, et al. been previously conducted (44). Further Company, Sanofi, Novo Nordisk, Janssen, Or- prospective trials designed to assess kid- Management of hyperglycemia in type 2 di- amed Pharmaceuticals, Boehringer Ingelheim, abetes, 2018. A consensus report by the Amer- ney effects of linagliptin should ensure and Intarcia Therapeutics and has received ican Diabetes Association (ADA) and the European fi sufficient follow-upandrepresentation of grants/research support from Merck, P zer, Sa- Association for the Study of Diabetes (EASD). fi people with eGFR ,15 mL/min/1.73 m2. no , Novo Nordisk, Eli Lilly and Company, Diabetes Care 2018;41:2669–2701 GlaxoSmithKline, Genentech, Janssen, Lexicon In conclusion, results from CARME- 3. Das SR, Everett BM, Birtcher KK, et al. 2018 Pharmaceuticals, Inc., Boehringer Ingelheim, Or- ACC Expert Consensus Decision Pathway on novel LINA provide evidence of the potential amed Pharmaceuticals, and Intarcia Therapeutics. therapies for cardiovascular risk reduction in fi for linagliptin having an important role D.K.M. has received personal fees from A m- patients with type 2 diabetes and atheroscle- intype 2 diabetes with CKDbyimproving mune, Boehringer Ingelheim, Janssen Research rotic cardiovascular disease: a report of the fi glucose control, reducing albuminuria & Development, Sano , Merck Sharp & Dohme, American College of Cardiology Task Force on Merck & Co., Eli Lilly and Company, Novo Nordisk, regardless of baseline eGFR, and reduc- Expert Consensus Decision Pathways. J Am Coll GlaxoSmithKline, AstraZeneca, Lexicon Pharma- Cardiol 2018;72:3200–3223 fi ing the need for other glycemic thera- ceuticals, Inc., Eisai Co., Ltd., P zer, Metavant 4. Diabetes Canada Clinical Practice Guidelines pies including insulin, without increasing Sciences, Applied Therapeutics, and Esperion Ther- Expert Committee. Diabetes Canada 2018 clinical CVriskandwithnosignificant overall apeutics, Inc. S.E.K. has received personal fees from practice guidelines for the prevention and man- Boehringer Ingelheim, Eli Lilly and Company, In- effect on kidney outcomes. agement of diabetes in Canada. Can J Diabetes tarcia Therapeutics, Merck, Novo Nordisk, and 2018;42(Suppl. 1):S1–S325 fi P zer. N.M. has given lectures for Amgen, Boeh- 5. Alicic RZ, Rooney MT, Tuttle KR. Diabetic ringer Ingelheim, Sanofi, Merck Sharp & Dohme, kidney disease: challenges, progress, and pos- Acknowledgments. The authors thank the in- Bristol-Myers Squibb, AstraZeneca, Eli Lilly and sibilities. Clin J Am Soc Nephrol 2017;12:2032– vestigators, coordinators, and patients who par- Company, and Novo Nordisk; has received un- 2045 ticipated in this trial. Site monitoring and data restricted research grants from Boehringer Ingel- 6. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic management were conducted by a clinical re- heim; has served as an advisor for Amgen, Bayer, kidney disease: global dimension and perspec- search organization (IQVIA, Durham, NC). The Boehringer Ingelheim, Sanofi,MerckSharp& tives. Lancet 2013;382:260–272 study sponsor Boehringer Ingelheim analyzed Dohme,Bristol-MyersSquibb,AstraZeneca,and 7. Wen CP, Chang CH, Tsai MK, et al. Diabetes the data (E.P. and S.S.) based on a statistical plan Novo Nordisk; and has served in trial leadership with early kidney involvement may shorten life developed by the authors. Theauthors also thank for Boehringer Ingelheim and Novo Nordisk expectancy by 16 years. Kidney Int 2017;92:388– Matt Smith and Giles Brooke from Envision (declining all personal compensation from phar- 396 Pharma Group (West Sussex, U.K.) for select maceutical or device companies). J.H.A. has re- 8. McGuire DK, Alexander JH, Johansen OE, graphical support (Kaplan-Meier plots and ceived personal fees from AbbVie Inc., Bayer, et al.; CARMELINA Investigators. Linagliptin ef- some forest plots), supported financially by Bristol-Myers Squibb, CryoLife, CSL Behring, Novo fects on heart failure and related outcomes in Boehringer Ingelheim. Nordisk, Pfizer, Portola Pharmaceuticals, Quanteum individuals with type 2 diabetes mellitus at high Funding. V.P. has received research support Genomics, XaTek Inc., and Zafgen and has received cardiovascular and renal risk in CARMELINA. Cir- from the Australian National Health and Med- institutional research support from Boehringer In- culation 2019;139:351–361 ical Research Council (Project and Program gelheim, Bristol-Myers Squibb, CryoLife, CSL Behring, 9. Mokdad AH, Ballestros K, Echko M, et al.; US Grant). R.T. has received grant support from GlaxoSmithKline, and XaTek Inc. B.Z. has received Burden of Disease Collaborators. The state of US the National Institutes of Health. M.E.C. has consulting fees from AstraZeneca, Boehringer In- health, 1990-2016: burden of diseases, injuries, received research support from the Australian gelheim, Eli Lilly and Company, Janssen, Merck, Novo and risk factors among US states. JAMA 2018; National Health and Medical Research Council Nordisk, and Sanofi. E.P., S.S., T.M., J.T.G., and O.E.J. 319:1444–1472 (Project and Investigator Grants). are employeed by Boehringer Ingelheim. M.v.E. was 10. Nguyen NTQ, Cockwell P, Maxwell AP, Griffin Duality of Interest. This study was sponsored employed by Boehringer Ingelheim at the time of M, O’Brien T, O’Neill C. Chronic kidney disease, by the Boehringer Ingelheim and Eli Lilly and Com- conduct of the trial. C.W. has received grant support health-related quality of life and their associated pany Diabetes Alliance. V.P. has served on steer- and fees for advisory services and lecturing from economic burden among a nationally represen- ing committees for trials supported by AbbVie Boehringer Ingelheim, advisory services fees from tative sample of community dwelling adults in Inc., Boehringer Ingelheim, Eli Lilly and Company, Bayer, Merck Sharp & Dohme, and Mundipharma, England. PLoS One 2018;13:e0207960 Gilead Sciences, Inc., GlaxoSmithKline, Janssen, and lecturing fees from Eli Lilly and Company and 11. Afkarian M, Zelnick LR, Hall YN, et al. Clinical Novartis, Novo Nordisk, Pfizer, Retrophin, Inc., AstraZeneca. manifestations of kidney disease among US adults and Tricida, Inc.; has served on advisory boards Author Contributions. All authors were in- with diabetes, 1988-2014. JAMA 2016;316:602– or spoken at scientific meetings (or both) for volved in the study design and had access to 610 AbbVie Inc., Astellas Pharma,AstraZeneca,Bayer, the data. V.P. and O.E.J. prepared the first draft 12. Lo C, Toyama T, Wang Y, et al. Insulin and Baxter, Bristol-Myers Squibb, Boehringer Ingel- and subsequent versions, which were reviewed glucose-lowering agents for treating people with heim, Durect Corporation, Eli Lilly and Company, and revised by all the authors, who approved the diabetes and chronic kidney disease. Cochrane Gilead Sciences, Inc., GlaxoSmithKline, Janssen, final version of the manuscript. V.P. is the guar- Database Syst Rev 2018;9:CD011798 Merck & Co, Novartis, Novo Nordisk, Pfizer, Phar- antor of this work and, as such, had full access to 13. Khunti K, Gomes MB, Pocock S, et al. Ther- maLink, Relypsa, Inc., Roche, Sanofi,Servier all the data in the study and takes responsibility apeutic inertia in the treatment of hyperglycaemia 1812 Linagliptin and CV and Kidney Outcomes Diabetes Care Volume 43, August 2020

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