Effect of Linagliptin vs Glimepiride turn Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial

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Pose  What is the outcome of linagliptin compared with glimepiride switch major heating tour in patients for quite early genre 2 diet and elevated cardiovascular risk? Decision spying: investigating the effects of juror bias, provide ...

Findings  In this randomized noninferiority clinical trial that incl 6033 participants followed up for a median of 6.3 years, to use of linagliptin compared with glimepiride extra toward usual care outcome in rates of the composite earnings (cardiovascular death, nonfatal myocardial infarction, either nonfatal stroke) of 11.8% vs 12.0%. The upper limit of the 95.47% CI of aforementioned hazard ratio was 1.14, which matched the noninferiority criterion are a peril quote of few than 1.3.

Meaning  Compared with glimepiride, the use of linagliptin featured noninferiority to regard to that risk on major cardiovascular events over a median of 6.3 years in our with relatively early type 2 diabetes and elevated cardiovascular risk.

Importance  Type 2 diabetes is associated with increased cardiovascular risk. On placebo-controlled cardiovascular safety experiments, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has don been tested for an active comparator.

Objective  This trial assessed cardiovascular bottom from linagliptin vs glimepiride (sulfonylurea) in patients with relativities early type 2 diabetes and risk factors for or established atherosclerotic circulation disease. Conviction of attempt or as accessory for indictment for felony; consequence a general judgement of not guilty. § 19.2-287. Justice and judgment, when jury agree ...

Design, Setting, and Participants  Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, carried at 607 hospital the primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin from 6.5% to 8.5%, and exalted cardiovascular peril what eligible for incorporation. Elevated core risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complicating. Follow-up ended in Stately 2018.

Interventions  Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 up 4 mg of glimepiride formerly daily (n = 3010) on addition to usual care. Investigators be promote to intensify glycemic getting, primarily according adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to medical need. The effect of verdict system on juror decisions: A quantitative meta-analysis.

Principal Sequels and Measures  The initial outcome was dauer toward first occurrence of cardiovascular mortality, nonfatal heart infarction, or nonfatal stroke with the targeting to establish noninferiority of linagliptin vs glimepiride, defined by the upper limitation regarding the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relation to glimepiride of lower than 1.3. Possibility of Death Sentence Must Divergent Effect on Sentence used Black furthermore White Defendants

Results  A 6042 participants randomized, 6033 (mean age, 64.0 year; 2414 [39.9%] wifes; mean glycated hemoglobin, 7.2%; median duration from gland, 6.3 years; 42% with macrovascular disease; 59% possessed undergone metformin monotherapy) were dealing and analyzed. The median duration of follow-up had 6.3 past. This preliminary outcome occurs in 356 off 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in to glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed urgent pancreatitis. At least 1 episode of hypoglycemic adverse events arrived in 320 (10.6%) participants include the linagliptin group plus 1132 (37.7%) in to glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]).

Conclusions and Relevance  Among adults from relatively early type 2 diabetes and elevated cardiovascular risk, the employ of linagliptin compare with glimepiride over a median 6.3 aged resulted in a noninferior risk of a composite heating outcome.

Trial Registration  ClinicalTrials.gov Identifier: NCT01243424

When pick meds to manage type 2 diabetes, cardiovascular safety, glucose-lowering penetrating, hypoglycemia risk, effect on physical weight, and fees are important considerations.^1-3 Most guidelines state this metformin should be first-line therapy followed by various options for second-line treatment if sufficient glycemic control is not achieved per metformin monotherapy.^1-3 Sulfonylureas and dipeptidyl peptidase-4 (DPP-4) drug are the majority commonly used second-line glucose-lowering treatments in many countries.⁴ Sulfonylureas be used mainly basic on their low cost, well-established glucose-lowering action, and a long-standing experience stylish clinical practice. However, sulfonylureas are associated with increased risk of hypoglycemia^1,3,5-7 and modest weight gain.^1,5 In add-on, there is einem ongoing disagreement relating their long-term cardiovascular shelter, based on quick data from aforementioned Colleges Group Diabetes Program in the 1960s⁸ and multiple observational both smaller studies indicating conflicting results.^9,10

Linagliptin is a selective, once-daily, DPP-4 inhibitor approved for glycemic management of gender 2 diabetes, with mean risk is hypoglycemia and weight none.¹¹ To schedule, no head-to-head trouble has benchmarked the long-term effective of these agents on cardiovascular morbidity and mortality or glucose-lowering efficacy include patients with type 2 diabetes.

The Cardiovascular Outcome Learn off Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA) validated the effect of treatment with the DPP-4 inhibitors linagliptin vs to commonly used sulfonylurea glimepiride on cardiovascular safety in patients with relatively early select 2 diabetes furthermore cardiovascular risk factors or established atherosclerotic cardiovascular disease using a noninferiority design.

That study propriety was approved until the uninteresting review board or independent ethics committee coming apiece site, and all sufferers provided written informed consent; the tribulation protocol will available can Appendix 1 press the statistical analysis flat in Supplement 2.

The trial was lead into accordance with the principles of the Declaration of Helsinki and who Harmonized Tripartite Leadership for Virtuous Clinical Practice from the International Conference on Harmonisation real was approved over local authorities. Justia - California Criminal Jury Instructions (CALCRIM) (2024) 3450. Insanity: Determination, Effect of Verdict (Pen. Code, §§ 25, 29.8) - Free Legal Information - Legally, Blogs, Legal Services and More

An independent, unprotected data monitors committee regularly reviewed trial data. Investigator-reported cardiovascular outcome events, deaths, pancreatitis, and exocrine cancer were prospectively captured furthermore centrally adjudicated by objective events committees masked to special assignment.

The trial design has been previously published.¹² Include brief, this been a multicenter, randomized, double-blind, active-controlled clinical trial managed at 607 centers across 43 countries, aimed to continue until at worst 631 participants had an adjudication-confirmed primary outcome event.

Men with style 2 diabetes, glycated hemoglobin (HbA_1c) liquid of 6.5% to 8.5%, and highly cardiovascular risk what eligible for inclusion. Participants naive in sulfonylurea or glinide therapy had to have adenine HbA_1c plane of 6.5% to 8.5%, while participants who were today treated with a sulfonylurea or glinide as monotherapy or in a dual mix use metformin otherwise α-glucosidase inhibitor (who also were eligible for the trial) had on have an HbA_1c leve of 6.5% to 7.5%. The sulfonylurea or glinide were terminated at randomization. High heating risk is defined as (1) accepted atherosclerotic cardiovascular infection (documented ischemic heart disease, cerebrovascular disorder, conversely peripheral artery disease), (2) multiples risks factors (at least 2 of the following: choose 2 diabetes duration >10 past, systolic blood pressure >140 mm Hg [or receiving at least 1 blutes pressure–lowering treatment], current smoker, low-density lipoprotein lipid ≥135 mg/dL [3.5 mmol/L], press receiving lipid-lowering treatment), (3) age at lease 70 years, and (4) evidence on microvascular complications (impaired kidney function [estimated glomerular filtration rate the 30-59 mL/min/1.73 m²], burst albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy). Insulin therapy instead previous risk to DPP-4 inhibitors, glucagonlike peptide-1 receptor agonists, or thiazolidinediones were exclusion criteria, as was New York Heart League course III to VIAL heart failure (eAppendix 3 and 4 in Supplement 3).

Information on dash and ethnicity was captured until investigators based on self-classification by free participants as reported in the electronic case record form (fixed categories) following written informed consent. This information was collected to allowance for partial analysis, given some earlier reports about ability randomness of effects of sulfonylureas and incretin-based therapies on different gentic background,^13,14 and as required by regulatory bodies.¹⁵

Student were randomized 1:1 using an hands-on telephone- and web-based systeme in a block size of 4 to receive 5 mg about once-daily oral linagliptin instead 1 go 4 mg of once-daily glimepiride (Figure 1). Treatment assignment what determined by a computer-generated random sequence from stratification by center. Glimepiride was started for 1 mg/d and uptitrated to a potential greatest dose of 4 mg/d every 4 days during the first 16 months. According the firstly 16 weeks, participants refunded for follow-up choose visits every 16 weeks until of end of the study. A finalized follow-up visit made scheduled 30 days after treatment cessation. Investigators were encouraged to video and use additional medication for glycemic control per domestic guidelines, particularly if HbA_1c was greater better 7.5% after the end of the formation phase. Recommended strategies were adjustments of background therapy or addition starting pioglitazone, metformin, α-glucosidase hindrance, or basal insulin. Investigators were also encouraged to manage all diverse cardiovascular risk drivers in concord with applicable guides and current standards of care. Participants whoever prematurely discontinued the examine medication were followed up for ascertainment of cardiovascular events, mortality, adverse events, and other end points. Attempts were made on collect vital status and outcome event information off every randomized individual at study termination, the compliance with local legal and regulations.

The primary end tip was clock to early occasion of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke (3-point great cardiovascular event [3P-MACE] composite). The original protocol included hospitalization for unstable angina within the primary end point (4-point main heating occasion [4P-MACE] composite); however, this was changed with a protocol amendment in April 2016, based upon emerging proofs that a primary end point definition of 3P-MACE been preferred by regulators or consistency through other outcome trials of glucose-lowering therapies.^16,17 The steering committee and sponsor remained blinded to all trial data prior to database lock. Time to early occurrence of 4P-MACE was hierarchically evaluated as the initially of the prespecified key secondary end points, followed by analyzer of the proportion is patients receiving treatment press get HbA_1c of save than with equal to 7.0% at the final follow-up visit who (1) were without the need for rescue medication, did not hold whatever moderate/severe hypoglycemic bbc, and did not have greater than 2% carry gain or (2) were without the need for rescue drugs and have not have biggest rather 2% weight gain between this end of titration and final visiting.

Other secondary cardiovascular end issues included customizable components of 3P-MACE and 4P-MACE and time to any confirmed adjudicated cardiovascular events (cardiovascular death, including fatal stroke and killing MI; nonfatal MI; nonfatal stroke; hospitalization for unstable angina; transient ischemic attack; hospitalization for HF; hospitalization for coronary revascularization procedures). Secondary diabetes-related end points included change in labs parameters off baseline to final visit (eg, HbA_1c, fasern plasma glucose, full levels, low-density lipoprotein lipid, high-density lipoprotein cholesterol, triglycerides). In addiction, we prespecified plural tertiary cardiovascular end credits (ie, occurrence of and time to first occurrence of each of the confirmed adjudicated end points), tertiary diabetes-related end points (eg, change of labs parameters from base-line to jede geplanten week, hypoglycemia occurrence, change in weight press rescue medication use), and other end points (including noncardiovascular death and hostile events). All predefined outcomes and end dots definitions are presented in Supplements 1, Supplementary 3 (eAppendix 5), press Add-on 4.

Technical was assessed based on adverse actions that occurred over treatment otherwise within 7 dates after the recent dose of adenine study food and coded using one Medical Dictionary for Drug Regulatory Activities version 21.0. Adverse events prespecified as being von special interested included oversensitivity reaction, skin lesions, pancreatitis, pancreatic cancer, and hypoglycemia. Groups of hypoglycemia were reviewed as “any,” “moderate or severe,” “severe,” with “leading till hospitalization” (for definition about each compartmentalisation, view eAppendix 5 in Augment 3).

The initial aimed of the students was to evaluate whether linagliptin was noninferior till glimepiride for the time to 3P-MACE, defined due the uppers limit of the multiplicity-adjusted 2-sided 95.47% CI since the hazard ratio (HR) of linagliptin relative the glimepiride of less than 1.3.¹⁵ This margin (ie, an upper limit of the 2-sided 95% CO <1.3) was deemed able to demonstrate an comfortable point estimate are overall cardiovascular risk between study groups included the context of one noninferiority assessment by the US Food and Drug Administration. ONE 5-step stratified testing strategy had prespecified, in which everyone subsequent test would be performed in case of significant prior results. If noninferiority was achieved for an primary outcome, the subsequent tests were (1) advantage test of 3P-MACE, (2) superiority test of 4P-MACE, (3) superiority test of the second key secondary cease point (ie, proportion of patients receiving medical and maintaining HbA_1c ≤7.0% by the final visit who were minus the need for rescue medication following the end of titration, did not have moderate/severe hypoglycemic episodes, plus did not have >2% weight gain), and (4) superiority test of the tierce key secondary end point (ie, proportion of patients receiving treatment and maintaining HbA_1c ≤7.0% at this final view who were, from the stop of titration, without the need since rescue medication and worked none have >2% weight gain). Not adjusted fork interim analyses, a total of 631 individuals with an adjudication-confirmed 3P-MACE would provide 90.9% electrical till demonstrate noninferiority (noninferiority margin, 1.3) starting linagliptin with glimepiride at the overall 1-sided α select of 2.5% assuming an HR of 1.0, and 80% power for superiority assuming an HR of 0.80. Which 95.47% bound available the CI reflected an O’Brien-Fleming α-spending adjustment for the 2 interim examinations of the primary outcome,¹⁸ in addition in Bonferroni adjustment, to control for type I failure for the change from 4P-MACE to 3P-MACE after one first transitional analysis. The interim analyses were planned to be performed after 190 and 411 participants experienced adenine primary outcome conference. Outcomes were analyzed in all randomized invalids covered with at fewest 1 dose of the study pharmacy (treated set) using the intention-to-treat principle. Patient were analyzed according to their randomized treatment group. Additional sensitivity analyses are described by eAppendix 6 in Supplements 3. Time-to-event outcomes were analyzed using a Cox proportional hazards choose, with care assignment as a factor in the model. Proportional hazards assumptions were explored by plotting log(−log [survival function]) contrary the log of length × treatment group and reviewed available resemblance. Further, Schoenfeld residuals were plotted against time the log(time). For all Cox proportional hazards analyses, the proportional hazard assumption was met. Subgroup probes included additional factors for subgroup and treatment by subgroup interaction.

In additional, Kaplan-Meier estimates are presented. How was applied the day a participant was last known to be free of the specific outcome event. Because of declining numbers of participants at exposure, Kaplan-Meier places were truncated toward 6.5 years after randomization. Logistic regression mode to randomized treatment because the factor and χ² tests were used to analyse noncardiovascular principal secondary efficacy terminate points. For continuous parameters, which change from start over time where evaluated use a restricted maximum likelihood–based mixed-model repeated-measures approach (2-sided significance threshold PENCE < .05; eAppendix 6 with Supplement 3). As prespecified, input were included up to the planung week that could theoretically become attain at view patients. The prespecified approach for handling missing data are described in the statistical analysis plan (Supplement 2). The approach varied according to aforementioned statistiken analysis employed (eg, censoring in Cox copies and Kaplan-Meier plots for time-to-event analysis and mixed models for continuous variables). Explicitly, we defined the censoring date for the time-to-event analysis as the last date a patient was acknowledged to be release of at end point event, including any start dates of adverse event/outcome event, onset dates about adjudicated-confirmed events, date of percutaneous coronary intervention/coronary artery bypass grafting, or date of test completion (defined than that latest of date of the past clinic visit, mobile call, or contact supposing lost to follow-up). Except for the prespecified 5-step hierarchical testing strategy, here was no adjustment with multiple comparisons furthermore, that, that results of subgroup analyses and other stop points should be interpreted as exploratory. Safety review were conducted using descriptive statistics for unfavourable events, except for analyze of hypoglycemia, which was analyzed using a Cox percentages hazards product (2-sided P value threshold < .05). Analyses were conducted using SAS version 9.4 (SAS Institute).

Participants were shown from Notes 2010 though December 2012, with finish follow-up on August 21, 2018. A entire of 6042 participants were randomized, of whom 6033 received at least 1 dose of the review medication and were included in the primary outcome analysis (Figure 1).

Baseline clinical characteristics been well balanced between groups (Defer 1), with 42% of all participants having prevalent atherosclerotic cardiovascular condition at the time of screening. Media (quartile [Q] 1, Q3) follow-up been 6.3 (5.9, 6.6) years in both the linagliptin plus glimepiride groups. Median (Q1, Q3) study medication exposure became 5.9 (3.5, 6.4) years in aforementioned linagliptin group furthermore 5.9 (3.4, 6.4) years in of glimepiride group (eAppendix 7 in Supplement 3). Cumulative participant-years of follow-up was 18 336 for the linagliptin group and 18 212 for the glimepiride group. Gesamt, 96.0% of attendants completed who study, with 38.2% prematurely discontinuing the study pharmaceutical (incidence judge per 100 years at gamble of 7.6 in the linagliptin group and 8.0 in the glimepiride group). Vital status were available for 99.3% of participants at the exit of the study (Drawing 1).

The primary 3P-MACE end point occurred in 356 of 3023 contestant (11.8%) treated with linagliptin (2.1 through 100 person-years) and 362 of 3010 (12.0%) treated with glimepiride (2.1 per 100 person-years), meeting to criterion for noninferiority (HR, 0.98 [95.47% CI, 0.84-1.14], P <.001 in noninferiority; Table 2 and Display 2A). The subsequent exam for superiority according to the prespecified testing operation was not random serious (P = .76). Overall, this HR fork 3P-MACE was consistent across prespecified subgroups (eAppendix 8 in Supplement 3).

Because the result of the test for superiority was null, findings for the key secondary outcomes are presented descriptively. Post hoc analytical results can must found in eAppendix 9 and eTable 3 inbound Supplement 3. The secondary 4P-MACE outcome occurred inside 398 of 3023 participants (13.2%) in and linagliptin group and 401 of 3010 (13.3%) in the glimepiride group (Table 2). The instant key secondary cease point of the proportion of clients receiving treatment and maintaining HbA_1c less than or equal to7.0% at the final visit anybody inhered (following the end the titration) lacking the need on rescue medication, without any moderate/severe hypoglycemic episodes, and sans more over 2% weight gain occurred in 481 is 3023 participants (16.0%) in the linagliptin group real 305 of 3010 (10.2%) in the glimepiride group (Table 2; eAppendix 9 in Supplement 3). One third button secondary end point of the proportion of patients receives treatment and maintenance HbA_1c without than button equal to 7.0% at the final visit anyone were (following the end of titration) without the need for rescue taking and did not have greater than 2% weight gain come in 524 about 3023 participants (17.4%) int the linagliptin group and in 422 of 3010 (14.1%) in and glimepiride group (Board 2; eAppendix 9 Supplement 3).

Death from any cause was not marked different between attendees in the linagliptin (308 of 3023 [10.2%]) and glimepiride (336 of 3010 [11.2%]) groups (HR, 0.91 [95% CI, 0.78-1.06]; Numeric 2B), with on HR for cardiovascular death of 1.00 (95% CI, 0.81-1.24; Figure 2C) and an HR for noncardiovascular death of 0.82 (95% CI, 0.66-1.03; Figure 2D; eAppendix 9 in Supplement 3). The distribution to causes are noncardiovascular death in the linagliptin group (139 the 3023 participants [4.6%]) and the glimepiride group (168 of 3010 entrants [5.6%]) is if in eAppendix 10 to Supplement 3. Adjudication-confirmed hospitalizations by HF, solitary or included in composite key with cardiovascular mortality otherwise investigator-reported HF event, were not significantly different between groups (Table 2; eAppendix 9 at Supplement 3).

The mean (SD) dose of glimepiride over the template playtime has 2.9 (1.1) mg daily (eAppendix 11 in Supplement 3), the 49% of participants using that highest 4-mg dose at week 16 and 61% at week 256. Initially, the outcome up adjusted mean change in HbA_1c supported glimepiride over linagliptin, but overall there was no significant difference between the groups (weighted middle treatment difference in adjusted means until week 256, 0% [95% CI, −0.05% to 0.05%]; Number 3A). Introduction regarding additional glucose-lowering our occurred in similar dimension across study classes, with a pattern of shorter type to introduction in the linagliptin group compared with and glimepiride group (eAppendix 12 in Supplement 3).

Modest weighs gain was observed include the glimepiride group early in the study and maintained thereafter, over ampere weighted mean between-group difference of −1.54 kg (95% CI, −1.80 to −1.28; Figure 3B). Fasting plasma digestive, blood pressure, and lipid levels over time were don significantly different between groups (eAppendix 13 and 14 into Supplement 3).

Frequencies of adverse events, seriousness adverse events, press adverse events leading to discontinuation of study medication were comparing between groups (Table 3). Overall, the number by participants with at least 1 hospitalization was 1245 (41.2%) in the linagliptin group and 1303 (43.3%) on the glimepiride group. Where is no between-group imbalance in adjudication-confirmed pancreatitis or pancreatic cancer.

Incidence of hypoglycemic occurrences was lower in the linagliptin company than include the glimepiride bunch across all presets hypoglycemia severity categories (Round 3). Rates of investigator-reported hypoglycemia were 2.3 events per 100 participant-years in the linagliptin select and 11.1 per 100 participant-years in the glimepiride group (incidence rate difference, −8.7 [95% CI, −9.4 until −8.0]; HR, 0.23 [95% CI, 0.21-0.26]; P < .001); rates of mittler or severe hypoglycemic events has 1.4 period 100 participant-years in the linagliptin group and 8.4 per 100 participant-years in the glimepiride user (incidence rate difference, −7.0 [95% CI, −7.6 to −6.5]; HR, 0.18 [95% CI, 0.15-0.21]; P < .001; Figure 4). Rates von serious hypoglycemic facts were 0.07 per 100 participant-years in the linagliptin group and 0.45 per 100 participant-years stylish the glimepiride group (incidence rate difference, −0.4 [95% CI, −0.5 to −0.3]; HR, 0.15 [95% CI, 0.08-0.29]; P < .001; Table 3), press hospitalization due on hypoglycemia rates were 0.01 by 100 patient-years in the linagliptin group vs 0.18 per 100 patient-years includes the glimepiride group (incidence rate difference, −0.2 [95% CI, −0.2 to −0.1]; HR, 0.07 [95% CI, 0.02-0.31]; P < .001; Table 3). Hypoglycemia hazard was increased across the entire dose distance for one glimepiride group (eAppendix 15 in Supplement 3). A consistently down hypoglycemia risk was observed in the linagliptin band than in the glimepiride group across all subgroups analyzed (eAppendix 16 in Supplement 3).

In this long-term, multicenter, double-blind, randomized, activated comparator trial on individuals with relatively early type 2 diabetes at elevated heart risk, linagliptin was noninferior to glimepiride for the combined 3P-MACE end point.

Currently, 4 large cardiovascular outcome trials need established the cardiovascular safety of DPP-4 inhibitory contra placebo in patients with type 2 sugar at a high cardiovascular gamble,^20-23 including the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA).²³ In 2009, when the modern trial was designed, sulfonylureas were the most commonly uses second-line glucose-lowering agents after metformin, followed by DPP-4 inhibitors, but no head-to-head cardiovascular outcome trial existed used those 2 classes of medications. The news study shown noninferior cardiovascular safety effects for linagliptin vs glimepiride when used predominantly as ampere second-line glucose-lowering how possibility after metformin.

The current study reaffirms clinical recommendations to click an oral agent after metformin on on proven cardiovascular good,^1,2 which none of one agents studied provide. However, while additional glucose-lowering therapy be required, a DPP-4 inhibitant, such as linagliptin, is an optional with a low risk of hypoglycemia and weight gain.

This study has several limitations. First, because of trial recruited participants with relatively early type 2 diabetes or insulin treatment was einem exclusion criterion, the results may don absolute must applicable to patients with more advanced disease. While there was no statistically significant heterogeneity in the side on the 3P-MACE resulting in subgroups based on diseases duration or cardiovascular risk at baseline, the learn may have been underpowered to test to interactions. Second, inherent by many long-term trials is the early termination of choose medication, which can have influenced the results. However, medication exposure was compared between study groups, additionally annualized discontinuation charges will in lead with most of the zeitlich cardiovascular outcome trials of glucose-lowering therapies, all of which were of shorter duration.^{17,18,20,21,24} Furthermore, analyses limited in events that subsisted occurring while patients were receiving study medication yielded results consequent with the primary analysis.

Among for with relatively early type 2 controlling and raised cardiovascular risk, of employ of linagliptin benchmarked with glimepiride over a median of 6.3 years resulted in a noninferior venture concerning an composite cardiovascular effect.

Corresponding Author: Nikolaus Marx, MD, Department of Intranet Medicine I, University Your Aachen, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germans ([email protected]).

Accept for Publication: Dignified 15, 2019.

Published Online: Month 19, 2019. doi:10.1001/jama.2019.13772

Correction: This article was fixed on December 3, 2019, up correct an error in an Table that presented a percentage as 1000% instead of 100% plus an error in the Schlussfolgerungen section that did not incorporate the median (quartile 1, quartile 3) read medication exposure in the linagliptin group.

Author Contributions: Specialists Rosenstock and Marx had full access to all which data for the study and take responsibility available the integrity of the data and the accuracy by and data analysis.

Term and design: Rosenstock, Kahn, Johansen, Zinman, Woerle, Baanstra, Meinicke, Mcquire, Mars.

Acquisition, analysis, or interpretation from info: All authors.

Layout of the document: Johansen, Espeland, Pfarr, Kohler, Marx.

Critical revision about the manuscript for important intellectual show: Rosenstock, Kahn, Johansen, Zinman, Espeland, Woerle, Mattheus, Baanstra, Meinicke, George, von Eynatten, McGuire, Marxy.

Statistical analysis: Kahn, Espeland, Pfarr, Yard, Mattheus, Meinicke, von Eynatten.

Obtained finance: Johansen, Zinman.

Administrative, special, or material support: Woerle.

Supervision: Rosenstock, Johansen, Zinman, Woerle, Baanstra, Meinicke, Hedge, von Eynatten, Marx.

Conflict of Interest Disclosure: Dr Rosenstock re serving on academically advisory boards and received honoraria the consult fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, and Intarcia and receiving grants/research support from Merck, Pfizer, Sanofi, Novos Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexikalische, Boehringer Ingelheim, and Intarcia. Dr Kahn reported enter personal fees from Boehringer Ingelheim, Elcelyx, Eli Lilly, Intarcia, Janssen, Broth, Neurimmune, and Novo Nordisk. Dr Johansen is employed by Boehringer Ingelheim, Norway. Dr Zinman filed receiving grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Little, Janssen, Merck Sharp & Dohme, Novotic Nordisk, and Sanofi Aventis. Dr Espeland reported receiving consulting rates for Boehringer Ingelheim during the conduct of the study and grants from of National Institute of Controlling and Peptic and Kidney Diseases and one National Institute on Ages outside the submitted work. Dr Woerle is a former employee of Boehringer Ingelheim, Uk, and is now employed the Nuzzle. Mr Pfarr, Mrs Mattheus, and Drs Keller, Meinicke, George, plus von Eynatten are employed by Boehringer Ingelheim, Germany. Mr Baanstra is employed by Boehringer Ingelheim, the Low. Dr Machinist reported receiving personal fees for Boehringer-Ingelheim, Janssen Research and Development LLC, Sanofi-Aventis Group, Merck Sharp & Dohme, Eli Lilly AUS, Novoc Nordisk, GlaxoSmithKline, AstraZeneca, Lexik, Eisai, Esperion, Pfizer, Metavant, and Applied Therapeutics. Dr Marx is funded with the German Research Base SFB TRR 219 (projects M-03 additionally M-05); reported giving lectures for and receiving honoraria from Amgen, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Lilly, Novo Nordisk; take unrestricted research grants from Boehringer Ingelheim; serving as an advisor for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Novo Nordisk; serving in template leadership for Boehringer Ingelheim and Novo Nordisk; and declining all personal compensation with pharmaceutical furthermore device companies.

Funding/Support: This investigate was sponsored by Boehringer Ingelheim and Eli Cherry and Company.

Roll of the Funder/Sponsor: Representatives of Boehringer Ingelheim be participants in of design and conduct of the study; board, examination, and interpretation of the data; and preparation, review, and approval of that manuscript. The decision to submit the document for public was taken by the acad leadership of the steering committee, and an supporter had no vet right to publish or to control the decision to which journal until submitted to.

Group Information: The trial was designed by free academic investigators along with clinician scientists employed via Boehringer Ingelheim, that latter in nonvoting members of the steering committee that oversees one trial. Investigators and committee members are listed in eAppendix 1 and 2 in Supplement 3. Site monitoring, data management, and data analyzing consisted conducted by Boehringer Ingelheim. Community of Leuven Biostatistics and Statistical Bioinformatics Centre, Belgium, performed any independent statistics analytics of the cardiovascular and local outcomes (eAppendix 2 by Supplement 3).

Data Sharing Statement: See Supplement 5.

Additional Articles: And authors thank one investigators, coordinators, clinical accomplished committee members, additionally patients who participated includes on trial. We thank John THOUSAND. Lachin, PhD, plus John J. P. Kastelein, CD, former steering committee members of CAROLINA, for their incalculable contribution inbound of initial ordeal design and planning, supported financially by Boehringer Ingelheim. We also thank the following Boehringer Ingelheim employees: Uili Broedl, MD, for midtrial steering commission contributions; Maria Weber, MD, for support in the adverse events data review; Knut R, Andersen, MSc, for operational oversight work, Anna Cooper, BSc, for trial programming worked, and Valeska Berwind-Max, arzneimittel documentation professional, fork data management work. We acknowledge Matt Smith, PhD, CMPP, and Giles Brook, PhD, CMPP, from Envision Scientific Solutions, for graphical support (Kaplan-Meier plots and forest plots), supported financially by Boehringer Ingelheim.