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Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE

Long-Term Efficacy and Safety of LinagliptininPatientsWithType2 Diabetes and Severe Renal Impairment A 1-year, randomized, double-blind, placebo-controlled study

1 5 JANET B. MCGILL, MD CHRISTOPHE SAUCE, MS Standards of diabetes care recom- 2 6 LANCE SLOAN, MD MAXIMILIAN VON EYNATTEN, MD 3 6 mend reducing the risk, or slowing the JENNIFER NEWMAN, BS HANS-JUERGEN WOERLE, MD 4 progression, of CKD by optimizing gly- SANJAY PATEL, MB CHB cemic control (7). However, most drugs available to treat hyperglycemia are af- d fi fected by kidney function and should OBJECTIVE This placebo-controlled study assessed long-term ef cacy and safety of the therefore be either avoided or used at re- dipeptidyl peptidase-4 inhibitor linagliptin in patients with and severe renal duced doses in patients with CKD (8,9). impairment (RI). Consequently, there is a great need to fo- RESEARCH DESIGN AND METHODSdIn this 1-year, double-blind study, 133 cus on optimal diabetes management in patients with type 2 diabetes (HbA1c 7.0–10.0%) and severe RI (estimated glomerular filtration patients with type 2 diabetes and CKD. rate [eGFR] ,30 mL/min/1.73 m2) at screening were randomized to linagliptin 5 mg (n =68)or Dipeptidyl peptidase-4 (DPP-4) inhib- placebo (n = 65) once daily, added to existing background therapy. The primary efficacy end itors are one of the latest therapeutic classes fi point was HbA1c change from baseline to week 12. Ef cacy and safety end points were assessed of glucose-lowering . Within after 1 year. this class, linagliptin uniquely has a pri- marily nonrenal route of elimination, with RESULTSdAt week 12, adjusted mean HbA1c decreased by 20.76% with linagliptin and 20.15% with placebo (treatment difference, 20.60%; 95% CI 20.89 to 20.31; P , 0.0001). only ;5% of the dose being excreted via 2 HbA1c improvements were sustained with linagliptin ( 0.71%) over placebo (0.01%) at 1 year the kidneys (10,11). This contrasts with (treatment difference 20.72%, 21.03 to 20.41; P , 0.0001). Mean doses decreased by other DPP-4 inhibitors, such as , 26.2 units with linagliptin and 20.3 units with placebo. Overall adverse event incidence was , , and similar over 1 year (94.1 vs. 92.3%). Incidence of severe hypoglycemia with linagliptin and that are predominantly cleared by renal ex- placebo was comparably low (three patients per group). Linagliptin and placebo had little effect cretion (12). Thus, linagliptin needs no 2 2 2 on renal function (median change in eGFR, 0.8 vs. 2.2 mL/min/1.73 m ), and no drug- dose adjustment in patients with impaired related renal failure occurred. renal function (13,14). Dose adjustment is CONCLUSIONSdIn patients with type 2 diabetes and severe RI, linagliptin provided clin- recommended for sitagliptin, saxagliptin, ically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, and vildagliptin in patients with creatinine stable body weight, and no cases of drug-related renal failure. The potential for linagliptin to clearance ,50 mL/min, including those spare insulin and provide long-term renal safety warrants further investigations. with ESRD requiring dialysis (12). Previous clinical studies have shown that linagliptin achieves clinically meaningful improvements in glycemic control in pa- iabetes, predominantly type 2, is rising worldwide (2,3). Diabetes has been tients with type 2 diabetes either as mono- Dreaching epidemic proportions, with identified as the leading cause of CKD, which therapy (15–17) or in combination with global prevalence estimated to increase may progress to end-stage renal disease (18), metformin/ from 8.3%, affecting 366 million adults in (ESRD) or increase the risk of death (3,4). (19), or a (20). Those 2011, to 9.9% or 552 million adults, by 2030 This association represents an increasing bur- studies demonstrated the overall safety (1). Concurrent with this increase, the prev- den for patients and healthcare systems, par- and tolerability of linagliptin (21). The ob- alence of chronic kidney disease (CKD) is ticularly in developing countries (5,6). jective of this study was to investigate the long-term efficacy, safety, and tolerability of ccccccccccccccccccccccccccccccccccccccccccccccccc linagliptin compared with placebo when administered in combination with existing From the 1Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis, St. Louis, Missouri; 2Texas Institute for Kidney and Endocrine Disorders, Lufkin, Texas; 3Boehringer In- glucose-lowering background therapy in gelheim, Ridgefield, Connecticut; 4Boehringer Ingelheim, Bracknell, U.K.; 5Boehringer Ingelheim, Reims, patients with type 2 diabetes and severe France; and 6Boehringer Ingelheim, Ingelheim, Germany. renal impairment (RI) over 52 weeks. Corresponding author: Janet B. McGill, [email protected]. Received 13 April 2012 and accepted 21 July 2012. DOI: 10.2337/dc12-0706 RESEARCH DESIGN AND This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 METHODS .2337/dc12-0706/-/DC1. A complete list of the members of the study can be found in the Supplementary Data online. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly Study population cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ Eligible study participants were women licenses/by-nc-nd/3.0/ for details. (nonfertile or using a medically approved care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online October 1, 2012 Linagliptin use with severe renal insufficiency birth control method) and men aged 18– during the first 12 weeks of treatment missing baseline HbA1c values or without 80 years, previously diagnosed with type (unless dose adjustment was required for any on-treatment HbA1c value, resulting 2 diabetes, who were treated with safety reasons). During the following in 65 patients per treatment group (25% glucose-lowering agents, including insu- 40-week treatment period, background planned dropout rate). lin, sulfonylurea, glinides, , therapy could be adjusted according to The primary efficacy end point, and a-glucosidase inhibitors. Existing glucose parameters. change from baseline to week 12 in glucose-lowering therapy must have re- Rescue therapy (any changes in treat- HbA1c, was tested using a superiority hy- mained unchanged for $8 weeks before ment or doses of glucose-lowering back- pothesis of linagliptin to placebo at the study entry. Participants fulfilled the cri- ground therapy during weeks 1–12 and/ two-sided 5% level of significance. A pro- teria for severe RI (CKD stage 4/5) at or addition of insulin during weeks 1–52) tocol-defined interim analysis was per- screening, having an estimated glomeru- could be initiated based on failure to meet formed after all study participants lar filtration rate (eGFR) calculated by the prespecified glycemic response criteria: a completed the first 12 weeks. Type I error Modification of Diet in Renal Disease confirmed fasting plasma glucose (FPG) rate was controlled for the primary end study equation of ,30 mL/min/1.73 m2 level .240 mg/mL (.13.3 mmol/L) dur- pointanalyzedat12weeks. (while not receiving chronic dialysis). In ing weeks 1–12, a confirmed FPG level The change from baseline to weeks 12 addition, participants had an HbA1c .7 .200 mg/dL (.11.1 mmol/L) during and 52 in HbA1c was assessed using and #10% (.53 and #86 mmol/mol) weeks 12–52, or a randomly determined ANCOVA with treatment and glucose- and a BMI #45 kg/m2. Exclusion criteria glucose level .400 mg/dL (.22.2 mmol/ lowering background drugs as fixed- at screening included the following: myo- L) at any time. Patients who failed to meet classification effects and continuous cardial infarction (MI), stroke, or transient these criteria despite rescue therapy were HbA1c and renal function at baseline as ischemic attack within the previous 6 discontinued from the study. linear covariates. This analysis was per- months; any requirement for acute dialysis Routine laboratory analyses and de- formed on the full analysis set (FAS) using within the previous 3 months; renal trans- terminations of HbA1c and plasma glucose last observation carried forward (LOCF) plantation; impaired hepatic function; and were performed by a central laboratory to impute missing data. The FAS included use of any other DPP-4 inhibitor or anti- (Clearstone Facilities; Canada, U.S., randomized participants who received $1 obesity drug within the previous 3 months. Singapore, and/or France). dose of treatment and who had both a The study was carried out according baseline and $1 on-treatment HbA1c to the Declaration of Helsinki and the Study end points measurement. ANCOVAs were also used International Conference on Harmoniza- The primary efficacy end point was the to assess changes in FPG at weeks 12 and tion Good Clinical Practice principles. change from baseline to week 12 in HbA1c 52 in the FAS (LOCF) and the change The protocol was approved by the in- to determine the superiority of linagliptin in body weight at week 52 in the FAS dependent ethics committee or institu- over placebo. Secondary efficacy end observed cases. tional review board at each participating points included changes from baseline to Logistic regression with baseline site. All participants provided written week 52 in HbA1c,FPG,glucose-lowering HbA1c, treatment (linagliptin or placebo), informed consent. background therapy, and body weight. glucose-lowering background therapy, Safety and tolerability end points in- baseline renal function, and treatment– Study design cluded the frequency and intensity of baseline renal function interaction as cova- This randomized, double-blind, placebo- adverse events (AEs), withdrawals be- riates was used to assess the percentage of controlled, parallel group study was carried cause of AEs, physical examinations, 12- patients who attained the HbA1c target out at 53 sites in six countries (Australia, lead electrocardiograms, vital signs, and (,7.0% [,53 mmol/mol]) in the FAS. Lo- Hong Kong, Israel, New Zealand, Ukraine, clinical laboratory assessments through- gistic regression with treatment, glucose- and U.S.). It comprised a 2-week, open- out the 52 weeks. Hypoglycemic events lowering background therapy, and baseline label, placebo run-in period, followed by a and severe hypoglycemic episodes were renal function as covariates was also used to 52-week double-blind treatment period, recorded (22). Additionally, an indepen- analyze the percentage of patients who and a 1-week follow-up period. dent clinical event committee (CEC) pro- used rescue therapy on the FAS (observed Study participants who met the eligi- spectively reviewed, in a blinded fashion, cases). All values measured after intake of bility criteria at screening and at the end of all reports of treatment-emergent fatal rescue were set to missing. the 2-week placebo run-in period were events and suspected cardiovascular Changes in glucose-lowering back- randomized (1:1) to receive double-blind (CV) events and evaluated whether pre- ground therapy and safety were analyzed treatment with either linagliptin (5 mg/ specified criteria for adjudication end in the treated set (TS) using descriptive day) or placebo in addition to their points (CV death, stroke, MI, and hospi- statistics. The TS included randomized glucose-lowering background therapy talization for unstable angina) were met. participants who received $1doseof for 52 weeks. This allocation was strati- treatment. fi # . # ed by HbA1c ( 8vs. 8% [ 64 vs. Statistical analyses .64 mmol/mol]) and glucose-lowering Assuming that the SD of change from RESULTS background therapy. Study investigators baseline in HbA1c was 1.0% in both treat- and participants were blinded to treat- ment groups, a total of 50 patients in each Patient disposition ment assignment for the duration of the group were required to achieve a power of A total of 133 patients were randomized to study and to results of interim analyses. 93% to detect a 0.7% difference in HbA1c receive either linagliptin or placebo To assess the glucose-lowering effect change from baseline to week 12. An ad- in addition to their glucose-lowering back- of adding linagliptin, stable doses of exist- ditional 15 patients per group were added ground therapy (68 vs. 65 patients, re- ing background therapy were maintained to account for patients with potentially spectively). The primary efficacy analysis

2 DIABETES CARE care.diabetesjournals.org McGill and Associates was performed for 128 patients (FAS). Of age, BMI, and baseline HbA1c were kidney disease, 14.3% of patients had those, 106 patients (linagliptin, 56; pla- 64.4 6 10.3 years, 32.0 6 5.8 kg/m2, eGFR in the range of 30–60 mL/min/ cebo, 50) had data available from baseline and 8.2 6 1.0% (66 6 11 mmol/mol), 1.73 m2 at baseline (assessed $2 weeks to week 12, and data for the remaining respectively. Overall, most patients were after screening). The classification of patients were imputed using LOCF either white(73.7%).Thereweremoremen 92.7% of patients in the linagliptin group because they were missing or their data (60.2%) than women (39.8%), with a remained severe RI at baseline (Table 1). were recorded after intake of rescue med- higher proportion of men in the linagliptin In addition, slightly different formulae ication. The 1-year study was completed by group than in the placebo group (66.2 vs. were used to calculate eGFR at the initial 97 (72.9%) patients (linagliptin, 72.1; pla- 53.8%, respectively). More than half of pa- screening by the central laboratory and at cebo, 73.8%) (Fig. 1). The primary reasons tients were aged $65 years (55.6%), clas- baseline evaluations by the linagliptin for discontinuation were AEs (linagliptin, sified as obese (BMI $30 kg/m2, 66.2%), study program. Patients were randomized 11.8; placebo, 16.9%) and refusal to con- and had an HbA1c $8% ($64 mmol/mol; based on the central laboratory calculation tinue medication (linagliptin, 10.3; pla- 54.7%). Most patients (96.1%) had type 2 of eGFR, which did not take race into cebo,1.5%).Onepatientinthe diabetes for .5 years and were receiving account, whereas baseline eGFR values linagliptin group refused to continue due glucose-lowering background monother- were classified on the linagliptin program to perceived lack of efficacy. The others apy (76.7%), with 63.9% treated with in- formula, which included race as a factor. who refused to continue gave no cause. sulin alone and 18.0% with insulin Other reasons for discontinuation were combination therapy. The most common Efficacy lack of therapeutic effect (linagliptin, 1.5; concomitant medications (linagliptin vs. Adjusted mean HbA1c change from base- placebo, 1.5%) and loss to follow-up (lina- placebo) were antihypertensive agents line over time is shown in Fig. 2A.At gliptin, 1.5; placebo, 4.6%). Mean expo- (94.1 vs. 100.0%), lipid-lowering agents weeks 12 (primary end point) and 52 (sec- sure to study treatment was 313 and 299 (77.9 vs. 80.0%), and acetylsalicylic acid ondary end point), linagliptin was supe- days in the linagliptin and placebo groups, (67.6 vs. 69.2%). The most frequent con- rior to placebo in lowering HbA1c (Fig. respectively. Median exposure was 364 comitant diagnoses were hypertension 2B). Treatment differences for linagliptin days in both groups. (94.1 vs. 100.0%), diabetic nephropathy versus placebo were 20.60% (95% CI (88.2 vs. 95.4%), diabetic retinopathy 20.89 to 20.31; P , 0.0001) at week Demographics and baseline (63.2 vs. 53.8%), and metabolic syn- 12 and 20.72% (95% CI 21.03 to characteristics drome (54.4 vs. 61.5%). All patients had 20.41; P , 0.0001) at week 52. Similar Patient demographics and baseline clinical protocol-defined severe RI at screening. results were seen in subgroups with base- characteristics were generally well-balanced However, due to common fluctuations in line HbA1c #8and.8% (#64 and .64 between groups (Table 1). Mean 6 SD renal function seen in advanced stages of mmol/mol) (Fig. 2C). The proportion of patients with baseline HbA1c $7% who reached the target of HbA1c ,7% (,53 mmol/mol) at week 52 tended to be higher with linagliptin than with placebo (18.0 vs. 9.8%, respectively; odds ratio 2.886, 95% CI 0.769–10.836; P = 0.2225). Both the linagliptin and placebo groups demonstrated similar decreases from baseline to week 12 in FPG (ad- justed mean change, 20.49 vs. 20.39 mmol/L; treatment difference, 20.10; 95% CI 21.35–1.16; P = 0.8802). A sim- ilar result was seen at week 52 (adjusted mean change, 20.30 vs. 20.38 mmol/L; treatment difference, 0.07; 95% CI, 20.82–0.97; P = 0.8698). The proportion of patients with $1 change in daily glucose-lowering back- ground therapy from baseline to week 52 was similar between groups (47.1 vs. 50.8%). In the linagliptin group, 81.3% of patients with changes in background therapy had $1 dose decrease, and 34.4% had $1 dose increase. In the pla- cebo group, 42.4% of patients with changes had $1 dose decrease, and 60.6% had $1 dose increase. Back- ground insulin therapy was adjusted in 28 patients in the linagliptin and placebo Figure 1dFlow chart of participants. The first participant was enrolled on 11 December 2008, groups (51.9 vs. 50.9% of insulin-treated and the last participant completed assessments on 5 January 2011. qd, once daily. patients). The mean percentage change in care.diabetesjournals.org DIABETES CARE 3 Linagliptin use with severe renal insufficiency

Table 1dDemographic and baseline clinical characteristics in the TS Safety and tolerability Over the 1-year treatment period, the Linagliptin (n = 68) Placebo (n = 65) overall incidence of AEs was similar be- tween the linagliptin and placebo groups Age (years) 64.0 6 10.9 64.9 6 9.6 (94.1 vs. 92.3%, respectively; Table 2). ,65 years [n (%)] 29 (42.6) 30 (46.2) The proportion of patients experiencing $65 years [n (%)] 39 (57.4) 35 (53.9) drug-related AEs was also similar between Sex [n (%)] the linagliptin and placebo groups (45.6 Men 45 (66.2) 35 (53.8) vs. 44.6%). Hypoglycemia (42.6 vs. Women 23 (33.8) 30 (46.2) 40.0%) and hyperglycemia (4.4 vs. 3.1%) Race [n (%)] were the most common drug-related White 53 (77.9) 45 (69.2) AEs in the linagliptin and placebo groups, Asian 8 (11.8) 11 (16.9) respectively. The most commonly reported Black/African American 6 (8.8) 7 (10.8) AEs (.5% in any group) are summarized Other 2 (3.1) 1 (1.5) in Table 2. The majority of AEs were of Body weight (kg) 89.9 6 19.0 85.7 6 17.6 mild or moderate intensity in both BMI (kg/m2) 32.3 6 5.8 31.7 6 5.9 groups. BMI ,30 kg/m2 [n (%)] 18 (26.5) 27 (41.5) Over the 1-year treatment period, BMI $30 kg/m2 [n (%)] 50 (73.5) 38 (58.5) small numbers of patients experienced eGFR (mL/min/1.73 m2) 22.1 6 6.3 25.1 6 6.9 severe hypoglycemia in either group (li- eGFR [n (%) in each category]a nagliptin, 3 [4.4%]; placebo, 3 [4.6%]) 30–60 mL/min/1.73 m2 5 (7.4) 14 (21.5) (Table 2). Symptomatic hypoglycemia 15–30 mL/min/1.73 m2 55 (80.9) 45 (69.2) was experienced by a similar proportion ,15 mL/min/1.73 m2 8 (11.8) 6 (9.2) of patients in both groups (linagliptin, 24 Duration of type 2 diabetes, .5 years [n (%)] 64 (97.0) 59 (95.2) [33.5%]; placebo, 22 [33.8%]). Asymp- b 6 6 HbA1c (%) 8.2 1.1 8.2 0.9 tomatic hypoglycemia occurred in more n b HbA1c [ (%) in each category] patients in the linagliptin group (38 ,7% (,53 mmol/mol) 5 (7.6) 1 (1.6) [55.9%] vs. 23 [35.4%]). This resulted $7and,8% (53–64 mmol/mol) 29 (43.9) 23 (37.1) in a higher overall incidence of hypogly- $8and,9% (64–75 mmol/mol) 21 (31.8) 25 (40.3) cemia in patients treated with linagliptin $9% ($75 mmol/mol) 11 (16.7) 13 (21.0) than with placebo (43 [63.2%] vs. 32 FPGb (mmol/L) 8.3 6 4.4 8.9 6 3.6 [49.2%], respectively). Overall, the ma- Glucose-lowering background therapy [n (%)] jority of patients with hypoglycemia Insulin were receiving insulin as monotherapy Monotherapy 39 (57.4) 46 (70.8) or in combination with another glucose- Combination therapy 15 (22.1) 9 (13.8) lowering agent(s) (linagliptin, 36 [83.7%]; Mean baseline dose [units (SD)] 67.7 (50.7) 62.9 (57.7) placebo, 27 [84.4%]). The difference in Sulfonylurea overall incidence of hypoglycemia be- Monotherapy 9 (13.2) 7 (10.8) tween patients treated with linagliptin Combination therapy with any other OAD(s) 4 (5.9) 2 (3.0) and those treated with placebo was only Glitazone d 1(1.5) notably different during the first 12 weeks a-Glucosidase inhibitor + glinide 1 (1.5) d of treatment when background therapy fi fi Data are expressed as mean 6 SD unless stated otherwise. OAD, oral antidiabetes drug. aAt screening, all 133 was xed ( rst 12 weeks, 33 [48.5%] vs. patients included in the study had confirmed severe RI. bFAS. 17 [26.2%]; last 40 weeks, 34 [50.0%] vs. 29 [44.6%]). Renal function over time was assessed daily insulin dose was 29.4% in the lina- daily dose increased 5.0% in the placebo as a safety parameter. Average eGFR gliptin group and 20.5% in the placebo group. values did not decrease by a clinically group. This represented a mean (6 SE) The proportion of patients requiring meaningful degree with either linagliptin absolute change in dose of 26.2 (4.7) rescue therapy was lower with linagliptin or placebo (median difference from base- units with linagliptin and 20.3 (2.1) than placebo (24.2 vs. 48.4%, respec- line to the last value on treatment 20.8 vs. units with placebo. Details of mean tively). The odds for use of rescue therapy 22.2 mL/min/1.73 m2). Time course of change over time in background insulin were significantly lower with linagliptin mean 6 SE eGFR over 1 year is presented therapy are provided in Supplementary than placebo (odds ratio, 0.345; 95% CI in Fig. 2D. The incidences of AEs related Fig. 1. In addition, changes in back- 0.160–0.747; P = 0.0069). to renal and urinary disorders were simi- ground sulfonylurea therapy occurred in Over the 1-year treatment period, lar between the linagliptin and placebo five patients in each treatment group bodyweightdecreasedinbothgroups. groups (25.0 vs. 21.5%, respectively). (38.5 vs. 55.5% of sulfonylurea-treated At week 52, adjusted mean changes from No renal failure related to linagliptin patients, respectively). By study end, no baseline in body weight were 21.83 kg was reported. Mean trough concentra- patients were receiving sulfonylurea ther- with linagliptin versus 20.29 kg with pla- tions of linagliptin were similar across apy in the linagliptin group, but mean cebo (treatment difference, 21.53 kg; visits (ranging from ;7to10nmol/L). 95% CI 24.11–1.04; P = 0.2370). The incidence of CEC-adjudicated CV

4 DIABETES CARE care.diabetesjournals.org McGill and Associates

d 6 Figure 2 Time course of adjusted mean SE change from baseline in HbA1c over 52 weeks (A) in the FAS (LOCF). Change from baseline to week 6 # . 12 and to week 52 in adjusted mean SE HbA1c in all patients (B) and in patients with baseline HbA1c 8% and baseline HbA1c 8% (C) in the FAS (LOCF). Time course of mean 6 SE eGFR over 1 year in the TS (D). *P , 0.01, **P , 0.001, ***P , 0.0001 vs. placebo. White bars/circles, linagliptin; black bars/circles, placebo. MDRD, modification of diet in renal disease. events was similar in both groups (Table 2). over 52 weeks. Throughout the study, many oral glucose-lowering agents are Three deaths in each group were reported linagliptin was well tolerated, with a safety cleared by the kidney. Therefore, in patients during the study. None were suspected to and tolerability profile similar to placebo with severe RI, most of these therapies are be treatment related. in this vulnerable patient population. In either not recommended or contraindicated particular, linagliptin was associated with (e.g., a-glucosidase inhibitors, metformin, CONCLUSIONSdThis 1-year ran- very low risk of severe hypoglycemia, stable -like peptide-1 receptor agonists, domized, double-blind, placebo-controlled body weight, and no cases of drug-related and some first-generation ) study was designed and powered to in- renal failure. or may require significant dose reduction vestigate the long-term safety, tolerability, Glycemic control is fundamental to (e.g., second-generation sulfonylureas, re- and efficacy of an oral glucose-lowering diabetes management (7). Several large clin- paglinide, and DPP-4 inhibitors) (8,9). Al- agent exclusively in patients with type 2 ical trials have demonstrated an association though advanced CKD does not affect the diabetes and severe RI. The results show between hyperglycemia and the progres- metabolism of , these that the addition of the oral DPP-4 in- sion of microvascular complications, such agents must also be used with caution be- hibitor linagliptin (5 mg once daily) to as CKD, in patients with type 2 diabetes cause of the increased risk of fluid retention background glucose-lowering therapy (23–25). However, antihyperglycemic and heart failure (26). provided a clinically meaningful HbA1c re- treatment options are limited in patients In this study, adding linagliptin to duction after 12 weeks that was sustained with type 2 diabetes and CKD because glucose-lowering background therapy care.diabetesjournals.org DIABETES CARE 5 Linagliptin use with severe renal insufficiency

Table 2dSafety results over 1 year in the TS (15,17,18,20). These studies have shown linagliptin to improve HbA1c in patients Linagliptin (n = 68) Placebo (n = 65) with renal function ranging from normal to severe RI. Overall incidence of AEs [n (%)] Comparisons of the efficacy of other Any AE 64 (94.1) 60 (92.3) DPP-4 inhibitors are limited due to differ- Serious AEs 25 (36.8) 27 (41.5) ences in study design and patient popula- Drug-related AEs 31 (45.6) 29 (44.6) tions; however, the HbA1c improvements AEs leading to discontinuation 9 (13.2) 11 (16.9) in patients with type 2 diabetes and mod- Deaths 3 (4.4) 3 (4.6) erate or severe RI with linagliptin were Most common AE (occurring in .5% in either similar, or greater, than those seen with group by preferred term) [n (%)] other DPP-4 inhibitors. Placebo-corrected Hypoglycemia 43 (63.2) 32 (49.2) HbA1c reductions were 20.4 to 20.7% Hyperglycemia 19 (27.9) 23 (35.4) for vildagliptin after 52 weeks (27) and Hyperkalemiaa 21 (30.9) 16 (24.6) 0.4 and 0.7% for saxagliptin after 12 and RIb 11 (16.2) 4 (6.2) 52 weeks, respectively (28,29). Mean Diarrhea 10 (14.7) 6 (9.2) HbA1c change from baseline with sitaglip- Urinary tract infection 6 (8.8) 8 (12.3) tin was 0.7% after 54 weeks in an active- Constipation 8 (11.8) 4 (6.2) comparator extension study (30). This is Blood creatinine phosphokinase increased 7 (10.3) 7 (10.8) noteworthy given that linagliptin, in con- Edema peripheral 7 (10.3) 7 (10.8) trast to other DPP-4 inhibitors, does not Upper respiratory tract infection 5 (7.4) 7 (10.8) require dose adjustment in patients with Pruritus 3 (4.4) 6 (9.2) severe RI, whereas a recent study reported Nasopharyngitis 6 (8.8) 3 (4.6) that sitagliptin was frequently used at in- Anemia 3 (4.4) 5 (7.7) appropriate doses in patients with type 2 Back pain 4 (5.9) 5 (7.7) diabetes and RI, and only 15% of patients Cough 3 (4.4) 5 (7.7) with moderate to end-stage RI received Muscle spasms 5 (7.4) 2 (3.1) recommended doses (31). Nausea 5 (7.4) 1 (1.5) HbA1c is a function of both fasting Acute renal failurea 5(7.4) 4(6.2) and postprandial glucose levels (32). Arthralgia 4 (5.9) 4 (6.2) The FPG reductions observed with lina- Fall 3 (4.4) 4 (6.2) gliptin over placebo do not seem to fully Headache 2 (2.9) 4 (6.2) account for the HbA1c change, suggesting Angina pectoris 4 (5.9) 3 (4.6) that postprandial glucose reductions, Bronchitis 4 (5.9) 2 (3.1) which can occur with incretin-based ther- Influenza 4 (5.9) 1 (1.5) apies, must have made more substantial Pain in extremity 4 (5.9) 3 (4.6) contributions than FPG reductions. This Incidence of hypoglycemia by intensity [n (%)]c contention is supported by previous ob- Asymptomatic hypoglycemiad 38 (55.9) 23 (35.4) servations of linagliptin’spositiveeffects Mild hypoglycemiae 14 (20.6) 11 (16.9) on postprandial glucose (15,18). Moderate hypoglycemiaf 10 (14.7) 11 (16.9) Long-term improvements in glycemic Severe hypoglycemiag 3(4.4) 3(4.6) control with linagliptin were associated Frequency of CV events confirmed by a with a trend toward decreases in back- CEC [n (%)] ground insulin therapy in the current Nonfatal stroke 1 (1.5) 1 (1.5) study. This could help optimize diabetes Nonfatal MI 4 (5.9) 2 (3.1) management but warrants further studies CV death, MI, stroke, and hospitalization to determine the extent of this effect. for unstable angina 7 (10.3) 9 (13.8) Linagliptin use was also associated aNo events in either group were deemed as drug-related. bOne event in the linagliptin group and none in the with a numerically smaller decline in placebo group was deemed drug-related. c$2 hypoglycemic events were experienced by 48.5 and 33.8% of eGFR than placebo despite slightly worse linagliptin- and placebo-treated patients, respectively. dEvent not accompanied by typical symptoms of kidney function at baseline. However, hypoglycemia but with a measured plasma glucose concentration #3.9 mmol/L. eMeasured plasma glucose many factors can impact progressive renal $ # f , g concentration 3.0 and 3.9 mmol/L. Measured plasma glucose concentration 3.0 mmol/L. Event re- disease in this population, and longer- quiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. term clinical studies are needed to explore the potential effects of linagliptin on renal function. Along with a previous finding provided a clinically significant placebo- used either alone or in combination with that linagliptin exposure did not vary in corrected reduction of 0.7% in HbA1c oral diabetes medications was associated patients with normal, mild, or moderate after 52 weeks in patients with type 2 di- with placebo-corrected HbA1c reductions RI (33), the pharmacokinetic data from abetes and severe RI. This finding is in line ranging from 0.5–0.9% in patients with this study confirm that linagliptin is not with previous 24-week studies that re- uncontrolled type 2 diabetes and normal expected to accumulate at any degree of ported that linagliptin (5 mg once daily) renal function or mild to moderate RI impaired renal function.

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Glycemic control becomes problem- specifically for dose calculation. In addi- 3. Atkins RC. The epidemiology of chronic atic in advanced CKD because of the risk tion, renal function with linagliptin re- kidney disease. Kidney Int Suppl 2005; of hypoglycemia secondary to reduced mained stable over time, and overall 94:S14–S18 renal gluconeogenesis and clearance of insulin doses were reduced. Investigations 4. Molitch ME, DeFronzo RA, Franz MJ, insulin as well as of some antihypergly- to evaluate these observations further are et al.; American Diabetes Association. Nephropathy in diabetes. Diabetes Care cemic agents and/or their metabolites currently underway. 2004;27(Suppl. 1):S79–S83 (34). This study showed that symptom- 5. American Diabetes Association. Economic atic hypoglycemic events and severe hy- costs of diabetes in the U.S. In 2007. poglycemic episodes occurred at similar AcknowledgmentsdThis study was spon- Diabetes Care 2008;31:596–615 rates in the linagliptin and placebo sored by . J.B.M. has 6. Khuwaja AK, Khowaja LA, Cosgrove P. groups. The higher rate of asymptomatic served as a speaker and consultant for Boeh- The economic costs of diabetes in de- hypoglycemic events is most likely ex- ringer Ingelheim and Merck. L.S. has received veloping countries: some concerns and plained by the protocol-fixed background honoraria for public speaking from Boehringer recommendations. Diabetologia 2010;53: – – treatment in the first 12 weeks of this Ingelheim. J.N., S.P., C.S., M.v.E., and H.-J.W. 389 390; author reply 391 392 are employees of Boehringer Ingelheim. No study. 7. American Diabetes Association. Standards other potential conflicts of interest relevant to of medical care in diabetesd2011. Diabetes Patients with type 2 diabetes and this article were reported. Care 2011;34(Suppl. 1):S11–S61 CKD have high risk for CV disease. The J.B.M. contributed to the design of the study 8. Bakris GL. Recognition, pathogenesis, and U.S. Food and Drug Administration re- and interpretation of the data. L.S. contributed treatment of different stages of nephropathy quires evidence that therapies for diabetes to the design of the study and participated in in patients with type 2 diabetes mellitus. do not cause unacceptable increases in CV the conduct of the study and the collection and Mayo Clin Proc 2011;86:444–456 risk (35). Retrospective analyses of data interpretation of data. J.N. participated in the 9. Shrishrimal K, Hart P, Michota F. Man- from DPP-4 inhibitors have not suggested collection of data. S.P. participated in the aging diabetes in hemodialysis patients: any increased CV risk (36). In a prespeci- conduct of the study and the collection, anal- observations and recommendations. Cleve – fied and prospective meta-analysis, lina- ysis, and interpretation of data. C.S. planned Clin J Med 2009;76:649 655 and performed the statistical analysis of the gliptin was associated with a reduced 10. Blech S, Ludwig-Schwellinger E, Gräfe- data. M.v.E. participated in the analysis and Mody EU, Withopf B, Wagner K. The CV event rate (37). In the current study, interpretation of the data. H.-J.W. participated metabolism and disposition of the oral mortality and risk of CV events were in the design and conduct of the study and the dipeptidyl peptidase-4 inhibitor, lina- similar between the linagliptin and interpretation of the data. All of the authors gliptin, in humans. Drug Metab Dispos placebo groups, but the sample size were fully responsible for all content and edi- 2010;38:667–678 was small. A large prospective ongoing torial decisions, were involved at all stages of 11. Heise T, Graefe-Mody EU, Huttner€ S, Ring trial (CAROLINA; clinicaltrials.gov: manuscript development, and have approved A, Trommeshauser D, Dugi KA. Pharma- fi NCT01243424) will evaluate the effect the nal version. J.B.M. is the guarantor of this cokinetics, pharmacodynamics and tolera- of linagliptin on CV outcomes. work and, as such, had full access to all the bility of multiple oral doses of linagliptin, a Our study is limited by the exclusion data in the study and takes responsibility for dipeptidyl peptidase-4 inhibitor in male the integrity of the data and the accuracy of the of patients with ESRD requiring chronic type 2 diabetes patients. Diabetes Obes data analysis. Metab 2009;11:786–794 dialysis, which could affect the extrapola- Parts of this study were presented at the 71st 12. Deacon CF. Dipeptidyl peptidase-4 in- tion of data to this population. However, as Scientific Sessions of the American Diabetes fi hibitors in the treatment of type 2 diabetes: linagliptin undergoes high-af nity binding Association, San Diego, California, 24–28 June a comparative review. Diabetes Obes Metab to DPP-4, no impact of hemodialysis on 2011 (abstract 413-PP) and at the 47th Annual 2011;13:7–18 drug exposure is expected. Additionally, it Meeting of the European Association for the 13. Deacon CF, Holst JJ. Linagliptin, a xanthine- has been shown that linagliptin concen- Study of Diabetes, Lisbon, Portugal, 12–16 based dipeptidyl peptidase-4 inhibitor with trations were not significantly increased in September 2011 (abstract 821). an unusual profile for the treatment of type patients with ESRD compared with other The authors thank the patients and staff 2 diabetes. Expert Opin Investig Drugs – degrees of RI (14). Therefore, it is unlikely who participated in this study. The authors 2010;19:133 140 also thank Christian Friedrich of Boehringer that differences in linagliptin exposure be- 14. Graefe-Mody U, Friedrich C, Port A, et al. – Ingelheim for providing helpful comments Effect of renal impairment on the phar- tween CKD stages 1 4 patients and ESRD during the development of the manuscript. macokinetics of the dipeptidyl peptidase- patients (CKD stage 5) could affect the Medical writing assistance, supported finan- fi 4 inhibitor linagliptin(*). Diabetes Obes ef cacy or safety of linagliptin. cially by Boehringer Ingelheim, was provided Metab 2011;13:939–946 In conclusion, this placebo-controlled, by Audrey Koïtka-Weber and Nick Brown 15. Del Prato S, Barnett AH, Huisman H, double-blind trial evaluated the safety and (Envision Scientific Solutions) during the Neubacher D, Woerle H-J, Dugi KA. Effect efficacy of a DPP-4 inhibitor exclusively in preparation of this manuscript. of linagliptin monotherapy on glycaemic patients with type 2 diabetes and severe control and markers of b-cell function in RI. These results confirm that linagliptin patients with inadequately controlled type References 2 diabetes: a randomized controlled trial. provides clinically meaningful improve- – ments in glycemic control without un- 1. Whiting DR, Guariguata L, Weil C, Shaw J. Diabetes Obes Metab 2011;13:258 267 IDF diabetes atlas: global estimates of the 16. Forst T, Uhlig-Laske B, Ring A, Ritzhaupt acceptable side effects in this vulnerable A, Graefe-Mody U, Dugi KA. The oral patient population. This supports the use prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311–321 DPP-4 inhibitor linagliptin significantly of linagliptin as an effective once-daily 2. Grassmann A, Gioberge S, Moeller S, lowers HbA1c after 4 weeks of treatment treatment option in patients with type 2 Brown G. ESRD patients in 2004: global in patients with type 2 diabetes mellitus. diabetes and severe RI, without the in- overview of patient numbers, treatment Diabetes Obes Metab 2011;13:542–550 convenience of dose adjustments or more modalities and associated trends. Nephrol 17. Kawamori R, Inagaki N, Araki E, et al. frequent assessments of renal function Dial Transplant 2005;20:2587–2593 Linagliptin monotherapy provides superior care.diabetesjournals.org DIABETES CARE 7 Linagliptin use with severe renal insufficiency

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