Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: Analysis of pooled events from 19 clinical trials

    Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: analysis of pooled events from 19 clinical trials Michael Lehrke, Lawrence A. Leiter, Uwe Hehnke, Sandra Thiemann, Amit Bhandari, Thomas Meinicke, Odd Erik Johansen PII: DOI: Reference:

S1056-8727(16)30216-1 doi: 10.1016/j.jdiacomp.2016.06.015 JDC 6773

To appear in:

Journal of Diabetes and Its Complications

Received date: Revised date: Accepted date:

28 April 2016 13 June 2016 15 June 2016

Please cite this article as: Lehrke, M., Leiter, L.A., Hehnke, U., Thiemann, S., Bhandari, A., Meinicke, T. & Johansen, O.E., Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: analysis of pooled events from 19 clinical trials, Journal of Diabetes and Its Complications (2016), doi: 10.1016/j.jdiacomp.2016.06.015

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ACCEPTED MANUSCRIPT Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: analysis of pooled events

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from 19 clinical trials

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Thomas Meinicke e, Odd Erik Johansen f*

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Michael Lehrke a, Lawrence A. Leiter b, Uwe Hehnke c, Sandra Thiemann c, Amit Bhandari d,

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University Hospital Aachen, Aachen, Germany

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Keenan Research Centre in the Li Ka Shing Research Institute, St. Michael’s Hospital,

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University of Toronto, Toronto, Canada

Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

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Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA

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Boehringer Ingelheim Corporation, Biberach, Germany

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Boehringer Ingelheim Norway KS, Asker, Norway

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f

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c

*Corresponding Author: Odd Erik Johansen, Boehringer Ingelheim Drengsrudbekken 8, 1373 Asker, Oslo, Norway [email protected]

Keywords: Linagliptin, dipeptidyl peptidase-4 inhibitor, type 2 diabetes mellitus, coronary artery disease, drug safety, heart failure

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ACCEPTED MANUSCRIPT Abstract Aims: To examine the safety and efficacy of linagliptin in patients with type 2 diabetes

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mellitus (T2DM) and coronary artery disease (CAD) using pooled data from the global

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clinical trials program.

Methods: Patient-level data were pooled from randomized, placebo-controlled clinical trials

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of linagliptin (5 mg, monotherapy or combination therapy). Safety/efficacy analyses were

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conducted for patients with CAD and ≥12 and ≥24 weeks of treatment, respectively. Results: The safety analysis included 19 trials (linagliptin, n=451; placebo, n=272) and the efficacy analysis, 12 trials (linagliptin, n=328; placebo, n=198); mean (± standard deviation) exposure to study treatment was 212 (144) days linagliptin and 245 (171) days placebo.

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Occurrence of cardiac adverse events (AEs) was similar for linagliptin- and placebo-treated patients (9.1% and 9.2%, respectively); exposure-adjusted incidence rates (per 100 patient-

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years) were 16.6 and 14.0, respectively. Overall incidence of AEs was numerically lower with linagliptin than placebo. After 24 weeks, mean adjusted change (standard error) from

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baseline glycosylated hemoglobin was –0.64% (0.04) with linagliptin vs. –0.08% (0.05) with

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placebo (P<.001).

Conclusions: This comprehensive pooled analysis showed that addition of linagliptin to treatment regimens of patients with T2DM and CAD was not associated with an increased incidence of cardiac AEs, was well tolerated, and effective.

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ACCEPTED MANUSCRIPT 1. Introduction Coronary artery disease (CAD) is a prevalent condition in patients with type 2 diabetes

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mellitus (T2DM) (Go et al., 2014; Huxley et al., 2006); compared with individuals without

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diabetes, patients with T2DM have a two to fourfold increased risk of cardiovascular (CV) disease (Beckman et al., 2002; Haffner et al., 1998; Preis et al., 2009). For patients with

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T2DM, the presence of CAD results in poorer clinical outcomes compared with those without CAD (Beckman et al., 2002; Franco et al., 2007; Miettinen et al., 1998). The pathophysiology

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of diabetic vascular disease is complex, and patients with T2DM may also have additional risk factors which increase the risk of atherosclerosis, including hypertension, dyslipidemia, obesity, smoking and insulin resistance. The importance of controlling these risk factors through medication and lifestyle changes are well established (Beckman et al., 2002). In

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particular, the control of hyperglycemia has been shown to reduce the risk of microvascular endpoints. Data from the United Kingdom Prospective Diabetes Study (UKPDS)

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demonstrated, over a 10-year follow-up period, that intensive glycemic control was associated with a reduction of microvascular endpoints, as well as risk reduction for

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myocardial infarction (MI) and death from any cause (Holman et al., 2008). Similarly, in the

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Kumamoto study, intensive glycemic control was shown to delay the onset and progression of early diabetic microvascular complications after 8-year follow-up of Japanese patients with T2DM (Shichiri et al., 2000). In contrast, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was prematurely terminated following a recommendation by the data and safety monitoring committee due to a 22% relative increase in risk of mortality and a 38% relative increase in CV death among patients receiving an intensive strategy to reduce glycosylated hemoglobin (HbA1c) levels, compared with those with a less stringent HbA1c target, although the groups did not differ with respect to the composite outcome measure of non-fatal MI, non-fatal stroke or CV death (in fact, non-fatal MI was significantly reduced) (Gerstein et al., 2008). Subsequent reports from the ACCORD Study Group on long-term effects, following 3.7 years of intensive glucose lowering, includes reports on

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ACCEPTED MANUSCRIPT outcomes after 5 years of follow up (Gerstein et al., 2011) as well as 9-year outcomes (in the ACCORD International Ongoing [ACCORDION] Study) (The ACCORD Study Group Writing

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attenuation of the overall mortality risk, shown in ACCORDION.

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Committee, 2016), which demonstrated persistence of the original findings, in addition to an

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However, the use of intensive glucose control showed no benefit on macrovascular events for patients with T2DM in the Action in Diabetes and Vascular Disease: Preterax and

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Diamicron Modified-Release Controlled Evaluation (ADVANCE) study. Although intensive glucose control was associated with a significant 10% relative reduction in the combined outcome of major macrovascular and microvascular events during a median 5-year follow-up period, this was mainly as a result of a 21% relative reduction in the incidence of

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nephropathy (P=.006), with no risk reduction in the incidence of major macrovascular events or death from CV causes (Patel et al., 2008). In the extended follow-up of this trial (median,

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5.4 years post-trial follow-up), intensive glucose control during the trial did not lead to long-

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term benefits with respect to mortality or macrovascular events (Zoungas et al., 2014). Similarly, a study of American veterans with T2DM, the Veterans Affairs Diabetes Trial

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(VADT), showed no significant effect of intensive glycemic control on the incidence of major CV events or on the risk of death from any cause, after a median follow-up period of 5.6 years (Duckworth et al., 2009). However, after extended follow-up of the VADT population to 9.8 years after the start of the study, patients who received intensive glucose control for the first 5.6 years were found to have a significant 17% reduction of the primary endpoint of macrovascular disease but no improvement in cardiovascular- or overall survival (Hayward et al., 2015).

In addition to uncertainties about the effectiveness of tight glycemic control in reducing the risk of macrovascular events, this approach can be associated with an

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ACCEPTED MANUSCRIPT increased risk of severe hypoglycemic episodes, which can offset some of the CV benefits of therapy (Boussageon et al., 2011; Mannucci et al., 2009). Subgroup analyses of UKPDS, ACCORD, ADVANCE and VADT suggest that patients with T2DM of shorter duration and

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without established CV disease (CVD) are more likely to benefit from intensive glycemic control, compared with those having more established disease for whom the risks might

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outweigh the potential CV benefits of intensive therapy (Skyler et al., 2009).

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Developing optimal treatment strategies in patients with T2DM and CAD remains a challenge in this high-risk population, where individuals often present with multiple risk factors which substantially increase the risk for morbidity and mortality (Turner et al., 1998). In view of the need for polypharmacy, frequent hospitalization and the risk of potential side

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effects or contraindications to some drugs, selecting the appropriate glucose-lowering treatment for these patients is uniquely challenging. The latest Diabetes Management

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Guidelines from the American Association of Clinical Endocrinologists (AACE) (Garber et al.,

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2016) and the joint Position Statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (Inzucchi et al., 2015)

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recommend a patient-centered approach to management, with treatment individualized to take account of risk factors, including comorbid conditions such as CAD. Current uncertainty about the long-term CV safety of specific glucose-lowering drugs (Selvin et al., 2008), has led to the recommendation by the Food and Drug Administration (FDA) that the CV risk is evaluated for all compounds, except insulins, that are being developed as therapies for T2DM (U.S. FDA, 2008). As a result, many trials have been designed to assess the longterm CV outcomes of recently developed drugs for the management of T2DM, and there remains a clinical need for approaches to glycemic control that do not further increase CV risk (Cavender et al., 2015).

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ACCEPTED MANUSCRIPT Linagliptin is a dipeptidyl-peptidase (DPP)-4 inhibitor approved for the treatment of T2DM. The overall safety and tolerability of linagliptin has been established in a large clinical trial program and further demonstrated in a pooled analysis of 22 placebo-controlled trials of

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linagliptin (Lehrke et al., 2014). The findings of this analysis supported previous findings of a low incidence of adverse events and good overall tolerability of linagliptin in a broad range of patients with T2DM. The CV safety of linagliptin has been evaluated in a comprehensive

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patient-level pooled analysis of prospectively adjudicated CV events from the clinical trial

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program (Rosenstock et al., 2015). This analysis of 19 trials of at least 12 weeks’ duration, in which linagliptin was evaluated in comparison with placebo or one or more active comparators, showed that linagliptin was not associated with increased CV risk in patients with T2DM. A post-hoc pooled analysis of linagliptin as add-on to insulin therapy in T2DM also demonstrated a neutral effect of linagliptin on the occurrence of major adverse CV

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events (Zinman et al., 2016). Two CV outcome trials are underway with the aim of further

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evaluating the CV safety of linagliptin. The CARdiovascular Outcome Study of LINAgliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA®) (NCT01243424) has

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randomized 6041 patients with early T2DM who are at high CV risk to receive therapy with linagliptin or the sulfonylurea (SU) glimepiride (Marx et al., 2015; Rosenstock et al., 2013).

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The CARdiovascular Safety & Clinical outcoME with LINAgliptin (CARMELINA®) trial will compare the CV and renal safety of linagliptin vs. placebo, added to standard care in patients with T2DM who are at high risk of vascular complications. While the outcomes of dedicated CV safety trials of linagliptin are awaited, analysis of available data from completed clinical trials can provide some insights into the role of this agent in patients with CAD or at high risk of CV events. The aim of this analysis was to examine the safety and efficacy of linagliptin in patients with CAD using pooled data from a global clinical trials program.

2. Materials and methods 7

ACCEPTED MANUSCRIPT Patient-level data were pooled for this analysis from randomized, placebo-controlled clinical trials of linagliptin 5 mg, of at least 12 weeks’ duration. The trials included linagliptin administered either as monotherapy or in combination with other glucose-lowering drugs. All

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trials were conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Eligibility criteria across the included trials were similar and included a diagnosis of T2DM, age ≥18 years, HbA1c 7–10% entrance criterion in most

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studies, and a body mass index (BMI) of 20–45 kg/m2. In all studies, rescue therapy could

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be initiated in response to a deterioration in glycemic control. In general, rescue therapy was initiated if glucose levels exceeded 240, 200 or 180 mg/dl (after an overnight fast) on two separate days during the first 12, 12–24 or >24 weeks, respectively. Data collected after

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initiation of rescue therapy were included in the analysis.

Patients with CAD were identified using relevant cardiac terms from the standardized

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Medical Dictionary for Regulatory Activities (MedDRA, v16.0) query “embolic and thrombotic

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events”. Included terms were: acute coronary syndrome; acute myocardial infarction; angina pectoris; angina unstable; arteriosclerosis coronary artery; arteriospasm coronary; coronary

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angioplasty; coronary arterial stent insertion; coronary artery bypass; coronary artery dilatation; coronary artery disease; coronary artery insufficiency; coronary artery occlusion; coronary artery stenosis; coronary revascularization; microvascular coronary artery disease; myocardial infarction; myocardial ischemia; percutaneous coronary intervention; post procedural myocardial infarction; postinfarction angina; Prinzmetal angina; silent myocardial infarction.

Safety analyses were conducted on patients who had at least 12 weeks of treatment and who had received at least one dose of study drug (treated set). Data on adverse events (AEs) were collected by the study investigators using electronic case report forms. The

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ACCEPTED MANUSCRIPT incidence and intensity of AEs, including cardiac and hypoglycemic events, were coded using MedDRA v16.0 and analyzed using descriptive statistical methods. Data on investigator-reported cardiac AEs were defined by the MedDRA System Organ Class of

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“cardiac disorders” based on clinical interpretation. Exposure-adjusted incidence rates were calculated using the number of patients with the respective events per treatment divided by the time at risk, expressed as 100 patient-years. Heart failure data were calculated as a total

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of the narrow standardized MedDRA queries (SMQ), and consisted of the following terms:

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acute left ventricular failure; acute pulmonary edema; acute right ventricular failure; cardiac asthma; cardiac failure; cardiac failure, acute; cardiac failure, chronic; cardiac failure, congestive; cardiac failure, high output; cardiogenic shock; cardiopulmonary failure cardiorenal syndrome; chronic left ventricular failure; chronic right ventricular failure; cor pulmonale; cor pulmonale, acute; cor pulmonale, chronic; ejection fraction decreased;

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hepatic congestion; hepatojugular reflux; left ventricular failure; low cardiac output syndrome;

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neonatal cardiac failure; pulmonary edema; pulmonary edema, neonatal; right ventricular failure; ventricular failure. Reporting of AEs was also analyzed according to concomitant use

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of insulin and/or SU therapy.

Overall hypoglycemic events included both asymptomatic and symptomatic hypoglycemic events. In general, asymptomatic hypoglycemia was defined as an event that was not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration ≤70 mg/dl (3.9 mmol/l). Symptomatic hypoglycemia was defined as a measured plasma glucose concentration ≥54 mg/dl and ≤70 mg/dl (≥3.0 mmol/l and ≤3.9 mmol/l), accompanied by typical symptoms of hypoglycemia, or symptomatic hypoglycemia with a measured plasma glucose concentration <54 mg/dl (<3.0 mmol/l): event accompanied by typical symptoms of hypoglycemia but no need for external assistance. A severe hypoglycemic episode was defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. 9

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Efficacy analyses were conducted using data from patients who had received at least 24

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weeks of treatment and at least one dose of study drug at the 5-mg dosage, and who also

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had an HbA1c value at baseline and at least one on-treatment value (full analysis set). The change from baseline glycemic parameters for linagliptin and placebo groups were

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compared using an analysis of covariance (ANCOVA). The model included treatment, washout, study, and continuous baseline HbA1c (HbA1c analysis) and baseline HbA1c and

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baseline fasting plasma glucose (FPG) (FPG analysis). The analysis used the last observation carried forward (LOCF) method to assign values to missing data. ANCOVA and logistic regression techniques were applied to assess all continuous and categorical secondary and safety endpoints, respectively.

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3. Results

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The safety analysis included patients from 19 trials (linagliptin, n=451; placebo, n=272) (Supplementary Table 1). The mean [± standard deviation (SD)] exposure to study treatment

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was 212 (144) days in the linagliptin group and 245 (171) days for patients allocated to placebo. Baseline characteristics, including the presence of CV risk factors and use of non-

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study drugs for CV indications, were well matched between the treatment groups (Table 1). Similar proportions of patients were receiving none, one or more than two glucose-lowering drugs. However, there were modest differences in the composition of classes of drugs used, i.e., use of concomitant insulin (± other glucose-lowering drugs), SU (± other glucoselowering drugs) or insulin + SU (Table 1).

Cardiac AEs were reported by 9.1% of patients in the linagliptin group and 9.2% in the placebo group (Fig. 1A; Table 2). Exposure adjusted incidence rates (per 100 patient-years) of cardiac AEs were 16.6 for linagliptin and 14.0 for placebo. The proportion of patients reporting cardiac AEs was higher among those receiving concomitant SU and/or insulin 10

ACCEPTED MANUSCRIPT (linagliptin, 11.9%; placebo, 11.3%) compared with patients not receiving these drugs

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(linagliptin, 2.8%; placebo, 2.9%) (Fig. 1B).

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The overall incidence of AEs was numerically lower with linagliptin than placebo (Supplementary Table 2). In the linagliptin group, the proportion of patients with any AE was

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higher among patients receiving concomitant SU and/or insulin compared with patients who were not receiving these drugs (73.2% vs. 47.5%); corresponding values in the placebo

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group were 77.0% vs. 70.6% (Table 3). The overall occurrence of investigator-reported events that were suggestive of congestive heart failure (CHF) was low for linagliptin- and placebo-treated patients, but higher among patients on SU and/or insulin background therapy (Table 3). Similarly, among linagliptin-treated patients, the proportion of patients with

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investigator-reported hypoglycemia was greater among those receiving concomitant SU and/or insulin compared with patients who were not taking these treatments (29.4% vs.

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2.1%); corresponding values were 32.8% and 0% in the placebo group (Supplementary

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Table 3). Overall, the rates of exposure-adjusted investigator-reported hypoglycemia were

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slightly lower with linagliptin than with placebo (Fig. 2).

The efficacy analysis included patients from 12 trials (linagliptin, n=328; placebo, n=198). The analysis demonstrated a significantly greater reduction in HbA1c among patients receiving linagliptin vs. placebo: after 24 weeks of treatment the mean adjusted change (± standard error) from baseline HbA1c was –0.65% (± 0.04) for linagliptin-treated patients compared with –0.08% (± 0.05) for the placebo group (P<.001) (Supplementary Table 4). Patients were more likely to achieve HbA1c lowering to <7% with linagliptin vs. placebo (odds ratio 3.70; P<.0001).

4. Discussion 11

ACCEPTED MANUSCRIPT The results from this comprehensive pooled analysis show that the addition of linagliptin to the treatment regimens of patients with a previous history of CAD was well tolerated, with no changes to the known safety profile listed in the current prescribing information

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(Boehringer Ingelheim Pharmaceuticals, 2015). Thus, the findings, in patients with a preexisting diagnosis of CAD and at high risk for further CV events, are consistent with those of previous pooled analyses of double-blind, randomized, controlled trials of lower risk

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populations that have evaluated safety data from the linagliptin global clinical trials program

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(Lehrke et al., 2014; Rosenstock et al., 2015; Schernthaner et al., 2014).

A key finding relative to the high-risk CAD patients that were the focus of this analysis was that the overall incidence of cardiac AEs was similar for patients receiving linagliptin and

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placebo (9.1% vs. 9.2%, respectively). The exposure-adjusted incidence rate (per 100 patient-years), which allows for possible differences in follow-up duration between treatment

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groups, also indicated that the incidence of cardiac AEs was similar among linagliptin- vs.

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placebo-treated patients (16.6% vs. 14.0%, respectively).

Given the potential influence of background medication on AE rates, the occurrence of AEs was specifically investigated with regard to patients receiving SU and insulin. We found that the proportion of patients who reported cardiac AEs with linagliptin was numerically greater among patients treated with concomitant SU and/or insulin compared with patients who were not receiving these drugs. As with cardiac AEs, the overall rate of AEs with linagliptin was higher with concomitant SU and/or insulin therapy than without. One obvious explanation for this difference might be the presence of more advanced T2DM among patients who required additional SU and/or insulin to achieve glycemic control, and hence the presence of a greater number of comorbidities in these patients than in those who do not require SU and/or insulin. Previous studies have shown linagliptin to be generally well

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ACCEPTED MANUSCRIPT tolerated when used as add-on therapy to SU and/or insulin (Barnett et al., 2013; McGill et

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al., 2014; McGill et al., 2012; Yki-Järvinen et al., 2013).

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Randomized trials have demonstrated a low incidence of hypoglycemia with linagliptin therapy, both alone and when used in combination with other glucose-lowering agents (Del

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Prato et al., 2011; Inagaki et al., 2013; Owens et al., 2011; Taskinen et al., 2011). In this study, rates of hypoglycemia with linagliptin were low and comparable with prior pooled

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analyses, with slightly fewer hypoglycemic episodes reported in the linagliptin group vs. placebo. Of course, this finding could be a consequence of differences in background therapies – there was more insulin use in the placebo group, although conversely there was

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also greater SU use in the linagliptin group.

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The improvements in glucose control in this vulnerable population were consistent with previously reported data for the general T2DM population (Del Prato et al., 2011; Owens et

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al., 2011; Taskinen et al., 2011).

Several longer term studies designed to evaluate the CV safety of other DPP-4 inhibitors have reported results: SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53 trial) (Scirica et al., 2013), EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) (White et al., 2013) and TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) (Green et al., 2015). All of these placebo-controlled trials have demonstrated a neutral effect of these agents (saxagliptin, alogliptin and sitagliptin, respectively) on composite CV outcomes [CV death, stroke and myocardial infarction (MI) in SAVOR and EXAMINE, and CV death, stroke, MI and hospitalization for unstable angina in TECOS] in patients with high risk for CV events (Scirica et al., 2013; White et al., 2013). 13

ACCEPTED MANUSCRIPT However, in SAVOR-TIMI 53, a statistically significant increased risk of hospitalization for CHF was associated with saxagliptin therapy compared with the placebo group [3.5% vs. 2.8%, respectively; HR, 1.27 (95% CI, 1.07 to 1.51; P=.007)] (Scirica et al., 2013). Further

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evaluation of the EXAMINE data has shown no increase in the risk of heart failure outcomes associated with alogliptin therapy (Zannad et al., 2015). More recently, results have been published from the TECOS study, which evaluated sitagliptin in patients with T2DM and

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established CVD (Green et al., 2015). In this large study, sitagliptin was found to be

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associated with no increase in the risk of major adverse CV events [sitagliptin was noninferior to placebo for the composite outcome of CV death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina; HR, 0.98 (95% CI, 0.88 to 1.09; P<.001)] or hospitalization for heart failure [HR, 1.00 (95% CI, 0.83 to 1.20; P=.98)] (Green et al., 2015). A recent retrospective, observational study, using information from a US insurance claims

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database, found no association between hospitalization for heart failure and treatment with a

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DPP-4 inhibitor relative to SU therapy, or treatment with saxagliptin relative to sitagliptin (Fu et al., 2016). At present, therefore, it remains unclear whether the observation of an increase

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in hospitalization for CHF with saxagliptin (Scirica et al., 2013) was an adverse effect of this

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specific therapy or a chance finding.

For linagliptin, where there are currently no published CV outcomes data, the aforementioned pooled analyses of linagliptin trial data provide the best indication of CV safety. This pooled analysis also showed that the occurrence of investigator-reported events that were suggestive of CHF was low for linagliptin- and placebo-treated patients [0.5% (26 events), 0.2% (8 events)] (Rosenstock et al., 2015). In the current analysis, which evaluated linagliptin in patients with a pre-existing diagnosis of CAD and, therefore, at high risk for further CV events, the incidence of reported cardiac AEs (per 100 patient-years) was comparable (16.6 for linagliptin and 14.0 for placebo) with those of the previous pooled analyses of linagliptin (Lehrke et al., 2014; Rosenstock et al., 2015). Further understanding 14

ACCEPTED MANUSCRIPT of the CV safety of linagliptin will be provided by the results of the ongoing CAROLINA® and

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CARMELINA® trials.

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The present analysis has several limitations because of its pooled design and the small number of patients with T2DM and CAD available for inclusion in the analysis. Further

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limitations are the relatively short and differing durations of the included studies, the fact that none of the individual studies included in this analysis was powered or designed to assess

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CV risk or events, and that there was no randomization procedure in this analysis for the patients that were identified with CAD. In addition, the mean individual patient exposure to linagliptin and placebo was less than 1 year (212 days and 245 days, respectively) and,

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therefore, no conclusions on the long-term CV safety of linagliptin can be drawn.

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In summary, and despite the limitations of this pooled analysis, the finding that linagliptin is not associated with an increase in CV risk in patients with T2DM and CAD will be

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reassuring to clinicians. The results of CAROLINA® and CARMELINA® and other ongoing

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trials of the CV safety of glucose-lowering therapies will further assist clinicians in their efforts to optimize treatment strategies for patients with or at risk of CVD and T2DM.

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ACCEPTED MANUSCRIPT Acknowledgments This study was supported by Boehringer Ingelheim, and Eli Lilly and Company. The authors

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were fully responsible for all content and editorial decisions, were involved at all stages of

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manuscript development, and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Paul MacCallum, PhD and

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Jennifer Edwards, MB BS of Envision Scientific Solutions, during the preparation of this

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manuscript.

Conflict of Interest

ML has acted as an advisor to BMS, Astra-Zeneca, Roche, GSK, MSD, Amgen, Sanofi, and

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a speaker for BMS, Astra-Zeneca, Roche, GSK, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Amgen.

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LAL has received research funding from, has provided CME on behalf of, and/or has acted

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as an advisor to: AstraZeneca, Boehringer Ingelhiem, Eli Lilly, GSK, Janssen, Merck, Pfizer, Sanofi, and Sevier.

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UH, ST, OEJ, AB and TM are all employees of Boehringer Ingelheim.

Prior Publication The data in this manuscript have been previously presented in posters at the American Diabetes Association 75th Scientific Sessions, Boston, MA, USA, June 5–9, 2015 (Poster 1246-P), and at the 51st Annual Meeting of the European Association for the Study of Diabetes, Stockholm, Sweden, 14–18 September, 2015 (Poster 814).

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the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA(R)). Diabetes and Vascular Disease Research, 12(3), 164– 174.

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1406.

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ACCEPTED MANUSCRIPT Figure captions Fig. 1. Investigator-reported cardiac adverse events a for the treated set (A), and by use of

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concomitant SU/insulin (B). Data are unadjudicated; defined by the MedDRA System Organ Class “cardiac disorders”.

b

Exposure-adjusted incidence rates are calculated using the number of patients with the

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MedDRA version 16.0 used for reporting.

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respective events per treatment divided by the time at risk expressed as 100 patient-years.

Fig. 2. Rate of exposure-adjusted investigator-reported hypoglycemia (treated set). Asymptomatic or symptomatic hypoglycemia reported as adverse event.

b

Severe hypoglycemia is a hypoglycemic event requiring the assistance of another person

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a

c

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to actively administer carbohydrate, glucagon or other resuscitative actions. Symptomatic hypoglycemia is an adverse event reported as a hypoglycemic event with

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typical symptoms of hypoglycemia.

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PG, plasma glucose.

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ACCEPTED MANUSCRIPT Tables Table 1

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Patient demographics and clinical characteristics at baseline (treated set) Placebo

(n=451)

(n=272)

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Linagliptin 5 mg

Age (years)

64.8 (9.1)

64.6 (9.3)

62.7

65.8

84.4 (17.4)

87.4 (16.2)

30.4 (4.9)

31.0 (4.8)

77.8

78.3

16.0

10.7

Black African/American

2.7

4.4

Other

0.4

1.1

3.1

5.5

Never smoked

51.7

47.8

Ex-smoker

35.0

38.2

Current smoker

13.3

14.0

37.9

36.8

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Sex (% male) Body weight (kg) Body mass index (kg/m2)

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Race (%)

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White

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Missing

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Asian

Smoking status (%)

Alcohol status (%) Drinker

26

ACCEPTED MANUSCRIPT 8.1 (0.9)

8.1 (0.9)

<7.0%

6.2

6.3

7.0% to <8.0%

39.0

44.5

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HbA1c a (%)

8.0% to <9.0%

30.5

19.3

18.8

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≥9.0%

35.3

Fasting plasma glucose a, mg/dl

159.6 (46.7)

71.2

66.5

28.8

33.5

Systolic blood pressure (mmHg)

135.2 (15.8)

135.9 (16.8)

Pulse rate (bpm)

70.2 (10.5)

69.9 (10.5)

Total cholesterol

178.9 (49.6)

173.1 (41.2)

Triglyceride

178.5 (108.7)

173.4 (120.5)

High-density lipoprotein

44.0 (11.7)

43.1 (11.0)

Low-density lipoprotein

100.2 (41.6)

97.2 (34.2)

≤1 year

5.8

4.8

>1 to 5 years

23.3

17.6

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162.7 (46.7)

Renal function (eGFR) according to MDRD (%)

Normal or mild impairment (60 to ≥90 ml/min/1.73 m2)

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Moderate or severe impairment, or ESRD (<30 to

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Lipids a (mg/dl)

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<60 ml/min/1.73 m2)

Time since diagnosis of T2DM (%)

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ACCEPTED MANUSCRIPT >5 years

71.0

77.6

0

10.2

6.6

1

38.4 51.4

49.6

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Glucose-lowering drugs (%)

43.8

31.0

52.6

36.8

21.7

1.1

0.7

74.9

77.6

92.9

87.1

62.3

67.6

Peripheral artery disease (%)

11.3

13.6

Cerebrovascular disease (%)

11.1

12.5

Myocardial infarction (%)

30.4

32.4

Insulin ± other glucose-lowering drugs, excluding

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SU

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≥2

SU ± other glucose-lowering drugs, excluding insulin

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Insulin + SU ± other glucose-lowering drugs

Aspirin

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Statins

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Antihypertensives

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Cardiovascular drugs (non-study) (%)

Data are mean (SD) unless stated otherwise. a

The number of patients with data available for these parameters is as follows. HbA1c:

linagliptin n=450, placebo n=272; fasting plasma glucose: linagliptin n=445, placebo n=269; total cholesterol: linagliptin n=372, placebo n=242; triglyceride: linagliptin n=371, placebo n=242; high-density lipoprotein: linagliptin n=370, placebo n=242; low-density lipoprotein: linagliptin n=371, placebo n=239.

28

ACCEPTED MANUSCRIPT eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; ESRD,

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end-stage renal disease.

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ACCEPTED MANUSCRIPT Table 2 Investigator-reported cardiac adverse events by preferred term a (treated set)

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Incidence

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(n=451)

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Linagliptin 5 mg

rate/100 patient-

(n=272) Incidence rate/100 patient-

%

years b

16.6

9.2

14.0

Acute myocardial infarction

0.7

1.1

0.4

0.5

Angina pectoris

2.0

3.4

2.6

3.8

Atrial fibrillation

1.3

2.3

0

0

0.4

0.8

0.7

1.1

Congestive cardiac failure c

0.7

1.1

0

0

Coronary artery disease

0.9

1.5

0.7

1.1

Left ventricular failure

0.7

1.1

0

0

Myocardial ischemia

0.9

1.5

0.7

1.1

Palpitations

0.4

0.8

0.7

1.1

Tachycardia

0.7

1.1

0

0

Narrow SMQ cardiac failure§

2.0

3.4

1.1

1.6

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9.1

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Cardiac AEs

AC

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Cardiac failure c

a

years b

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%

Placebo

Data are unadjudicated; defined by the MedDRA System Organ Class “cardiac disorders”;

preferred term frequency ≥0.5%. b

Exposure-adjusted incidence rates are calculated using the number of patients with the

respective events per treatment divided by the time at risk expressed as 100 patient-years. MedDRA version 16.0 used for reporting. 30

ACCEPTED MANUSCRIPT c

Cardiac failure and congestive cardiac failure AEs are separate terms derived from the

specific investigator reporting of these events. § Based on reported preferred terms.

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MedDRA version 16.0 used for reporting.

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SMQ, standardized MedDRA query.

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ACCEPTED MANUSCRIPT Table 3 Any adverse events and heart failure adverse events by concomitant use of SU and/or

Linagliptin 5 mg

Placebo

(n=451)

(n=272)

310

204

73.2

77.0

141

68

47.5

70.6

310

204

SU/insulin: yes (%)

2.6

1.5

Patients analyzed, n

141

68

SU/insulin: no (%)

0.7

0

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insulin during screening

Any adverse event

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Concomitant SU/insulin Patients analysed, n SU/insulin: yes (%)

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Patients analysed, n

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SU/insulin: no (%) Narrow SMQ heart failure

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Concomitant SU/insulin

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Patients analyzed, n

32

ACCEPTED MANUSCRIPT Figures

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Fig. 1.

33

ACCEPTED MANUSCRIPT

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Fig. 2.

34

ACCEPTED MANUSCRIPT Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: analysis of pooled events

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from 19 clinical trials

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Highlights

This analysis evaluated the cardiovascular (CV) safety of linagliptin



Linagliptin clinical trial data were pooled for patients at high CV risk



In patients at high CV risk, linagliptin demonstrated safety and tolerability



Efficacy/safety profile was consistent with that in populations of lower CV risk



The results of long-term dedicated linagliptin CV outcome trials are awaited

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

35