Key Paper Evaluation
Gliptins -- do they increase cardiovascular risk or benefit? 1.
Introduction
2.
Saxagliptin in SAVOR-TIMI 53
3.
Alogliptin in EXAMINE
4.
Expert opinion
Evaluation of Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med 2013;369:1317-26 and White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
Sheila A Doggrell† & Simon B Dimmitt Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Mcgill University on 11/19/14 For personal use only.
†
Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Brisbane, Australia
Introduction: In 2008, the US FDA required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase-4 inhibitors (‘gliptins’). Areas covered: The cardiovascular safety trials of saxagliptin and alogliptin have recently been published and are the subject of this evaluation. Expert opinion: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus -- Thrombolysis in Myocardial Infarction 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care were both multicentre, randomised, double-blind, placebocontrolled, Phase IV clinical trials. These trials showed that saxagliptin and alogliptin did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, which was a component of the secondary end point. The effect of alogliptin on hospitalisations for heart failure has not been reported. Neither agent improved cardiovascular outcomes. As there is no published evidence of improved outcomes with gliptins, it is unclear to us why these agents are so widely available for use. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established. Keywords: alogliptin, cardiovascular benefit, cardiovascular risk, clinical trials, saxagliptin, type 2 diabetes Expert Opin. Drug Saf. (2014) 13(5):675-680
1.
Introduction
In the USA, the prevalence of diabetes is about 8% (24 million people), and 90% of diabetes is type 2, which has both lifestyle and genetic components [1]. Despite the treatments available for type 2 diabetes, about two-thirds of the subjects die from heart disease or stroke, and almost all experience premature cardiovascular morbidity culminating in amputations and myocardial infarction with cardiac failure [1]. In 1998, the UK prospective diabetes study (UKPDS 35) suggested a significant relationship between glycaemia and clinical complications with every 1% reduction in HbA1c being associated with a 21% reduction in the risk of any end point related to diabetes, 21% of deaths related to diabetes, 14% to myocardial infarction and 37% to microvascular complications [2]. Higher HbA1c levels were also associated with increased risk of microvascular complications such as chronic kidney disease, end-stage kidney disease and retinopathy, in the Atherosclerosis Risk in 10.1517/14740338.2014.904284 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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S. A. Doggrell & S. B. Dimmitt
Communities Study [3]. Consequently, from this time, HbA1c levels were often considered to be a surrogate marker for cardiovascular risk with high levels indicating high risk, and reductions in HbA1c indicating reduced risk. However, in 2008, this straightforward relationship between HbA1c levels and cardiovascular risk was challenged by the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial [4]. ACCORD showed that the intensive lowering of HbA1c to 6.4% was associated with an increased risk of mortality, compared to standard therapy (HbA1c of 7.5%), without affecting major cardiovascular events [4]. Thus, HbA1c levels cannot always be considered a surrogate for cardiovascular risk or safety. This led the US FDA in 2008 to require that all new glucose-lowering therapies should be required to show cardiovascular safety [5]. Subsequently, the thiazolidinedione, rosiglitazone, was shown to lower HbA1c but was shown to increase cardiovascular risk [6,7]. With the addition of these findings with rosiglitazone, the European Medicines Agency (EMA) concurred in 2010 that all new glucose-lowering therapies should be required to show cardiovascular safety [8]. The FDA Guidance for Industry suggests that the safety of new antidiabetic therapy can be evaluated either from integrated analysis of the Phase II and Phase III clinical trials or by additional Phase IV large safety trials [9]. The dipeptidyl peptidase (DPP)-4 inhibitors are relatively new group of medicines for the treatment of diabetes. These agents inhibit the degradation of the incretin hormones, leading to the increased levels of these hormones. Incretin hormones stimulate insulin secretion, with the reduction of HbA1c levels in subjects with type 2 diabetes. Sitagliptin was approved in 2006, subsequent to which vildagliptin, saxagliptin, alogliptin and linagliptin have been approved. The first two cardiovascular risk Phase IV trials, performed under the requirements of the FDA and EMA, have recently been published. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) are trials on saxagliptin and alogliptin. We have evaluated the SAVOR-TIMI 53 and EXAMINE trials and can confirm that saxagliptin and alogliptin do not increase composite cardiovascular outcomes, which did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, and alogliptin was not tested for its effects on hospitalisations for heart failure. 2.
Saxagliptin in SAVOR-TIMI 53
Introduction The saxagliptin registration Phase II and III trials established that saxagliptin reduced HbA1c in type 2 diabetes and were subsequently combined in a systematic analysis of the 2.1
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cardiovascular risk of saxagliptin [10]. This analysis, of 4607 subjects with type 2 diabetes, suggested that saxagliptin did not change cardiovascular events and death [10]. However, limitations included that review of cardiovascular events was not independent, the trials were limited to drug-naı¨ve and monotherapy-treated subjects, there were low event numbers, the subjects had a relatively short duration of diabetes and participants were only monitored for a short time [10]. Methods and results The methods and results of the SAVOR-TIMI 53 trial [11] are summarised in this section. SAVOR-TIMI was a randomised, double-blind, placebo-controlled Phase IV trial performed in 26 countries. The trial was designed as a superiority trial of cardiovascular outcomes of saxagliptin versus placebo, with testing for non-inferiority, prior to testing for superiority. To be enrolled, subjects with type 2 diabetes had to have an HbA1c of 6.5 -- 12%, and either a history of established cardiovascular disease or multiple risk factors for vascular disease. Subjects were not enrolled if they had received incretin-based therapy in the previous 6 months or had kidney dysfunction (renal transplantation, end-stage renal failure or serum creatinine > 530 µmol/l). The 16,492 subjects enrolled had a mean age of ~ 65 years, a mean HbA1c of 8.0% and duration of diabetes ~ 10 years, and about two-thirds were male and 22% were Hispanic and 75% were Whites. Most of the enrolled subjects had hypertension (~ 81%), established atherosclerotic disease (~ 79%) and dyslipidemia (~ 71%), and some had prior coronary revascularisation (~ 43%), prior myocardial infarction (~ 38%) and/or prior heart failure (~ 13%). Subjects were randomised to saxagliptin 5 mg, which was lowered to 2.5 mg if renal impairment developed, or placebo, and the median follow up was 2.9 years. At baseline, diabetes medications were similar in both groups with ~ 70% of subjects taking metformin, ~ 40% taking sulphonylureas and ~ 41% taking insulin. The use of these medications did not change throughout the study in the saxagliptin group, but in the placebo group, insulin use had increased to ~ 46% by year 2. The HbA1c levels were significantly lower in the saxagliptin group than placebo group after 1 year (7.6 vs 7.9%), after 2 years (7.5 vs 7.8%) and at the end of study (7.7 vs 7.9%). The primary efficacy and safety end point was a composite of cardiovascular death, non-fatal myocardial infarction or non-fatal ischaemic stroke, and this occurred in 613 subjects (7.3%) in the saxagliptin group, compared with 609 subjects (7.2%) in the placebo group. The secondary end points included the primary end point plus hospitalisation for heart failure, coronary revascularisation or unstable angina, which occurred in 1059 subjects (12.8%) with saxagliptin and in 1034 subjects (12.4%) with placebo. Analysis of the individual cardiovascular items showed that they were similar in both groups, except for hospitalisation due to heart failure 2.2
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Gliptins -- do they increase cardiovascular risk or benefit?
which was 27% higher in the saxagliptin group (289 subjects, 3.5%) than the placebo group (228 subjects, 2.8%, p = 0.007). Kidney function was measured as a combination of doubling of creatinine level, initiation of dialysis, renal transplantation or creatinine > 6.0 mg/dl, and this was similar in both the saxagliptin group (194 subjects, 2.2%) and the placebo group (178 subjects, 2.0%). At the start of the study, the albumin-to-creatinine ratio was 1.8 in the saxagliptin and 1.9 in the placebo group, and at the end of the study, less subjects taking saxagliptin had a worsening of this ratio (833, 13.3%) than in the placebo group (969, 15.9%). Hypoglycaemia occurred more often in the saxagliptin group (1264 subjects, 15.3%) than the placebo group (1104 subjects, 13.4%, p < 0.001). Major hypoglycaemia requiring a third party active intervention was marginally more common in the saxagliptin group (177 subjects, 2.1%) than the placebo group (140 subjects, 1.7%, p = 0.047). Rates of pancreatitis and other safety end points (e.g., cancer, liver abnormalities, blood cell dysfunction, infections) were similar in both groups. Discussion The authors concluded, that with regard to the primary composite end point of cardiovascular death, myocardial infarction or ischaemic stroke, saxagliptin was not inferior to placebo, but it also did not provide any cardioprotective benefit [11]. Here, the authors have given three possible reasons for the failure of the study to show any cardiovascular benefit with saxagliptin: first, the study may have been too short to show benefit; second, the difference in HbA1c was too small between the groups because of the increased use of insulin in the placebo group and third, the number of end points was substantially reduced by the frequent use of statins, anti-platelet therapy and blood pressure-lowering agents [11]. The authors suggested that the increased risk of hospitalisation with heart failure, in the saxagliptin group, may have been a false-positive result [11]. However, they do concede that this finding requires further investigation [11]. 2.3
3.
Alogliptin in EXAMINE
Introduction The developmental Phase II and III trials of alogliptin established that alogliptin lowered HbA1c in subjects with type 2 diabetes and have been pooled to assess cardiovascular safety [12]. This pooling had 4168 subjects with type 2 diabetes who had been treated with alogliptin, and 2023 subjects who had been treated with placebo and showed that alogliptin had no effect on the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke [12]. However, this pooling had several limitations: the studies were not designed to measure cardiovascular safety, the duration of the clinical trials was short, the population had 3.1
only moderate cardiovascular risk and the number of cardiovascular end points was relatively low [12]. Subsequently, the cardiovascular risk of alogliptin has been determined in EXAMINE, which did not have these limitations. Methods and results The methods and results of the EXAMINE trial are summarised in this section [13]. EXAMINE was a non-inferiority trial of alogliptin and placebo and showed that alogliptin has no effect on a composite end point of cardiovascular safety. EXAMINE was a randomised, double-blind, placebocontrolled trial performed in 49 countries. To be enrolled, subjects with type 2 diabetes had to have an HbA1c of 6.5 -- 11% or, if taking insulin, an HbA1c level of 7 -- 11%, and have had an acute coronary syndrome (e.g., acute myocardial infarction, unstable angina requiring hospitalisation) within the last 15 -- 90 days. Subjects were not enrolled if they had unstable cardiovascular disorders such as class IV heart failure or had had undergone dialysis within 14 days before screening. The 5380 subjects who participated in EXAMINE had a mean age of 61 years, a mean HbA1c of 8.0% and a duration of diabetes of 7 years, and most were male (~ 68%) and Whites (~ 73%) or Asians (~ 20%). Most of the participants had had a myocardial infarction (~ 88%) and/or a percutaneous coronary intervention (~ 63%) and/or coronary-artery intervention (~ 13%), and most were hypertensive (~ 83%), and some had congestive heart failure (~ 28%), peripheral arterial disease (~ 10%), or a previous stroke (~ 7%). Subjects were allocated to placebo or alogliptin, and the dose of alogliptin was dependent on kidney function with a dose of 25 mg in subjects with a glomerular filtration rate (GFR) of 60 ml/min/173 m2, with a dose of 12.5 mg in subjects with GFR of 30 to < 60 ml/min/173 m2 or with a dose of 6.25 mg in subjects with GFR < 30 ml/min/173 m2, and the median follow up was ~ 18 months. At the start of the study, diabetes medications were similar in both groups, with ~ 66% of subjects taking metformin, ~ 46% taking sulphonylureas and ~ 30% taking insulin. The HbA1c levels were lowered in the alogliptin group, compared to the placebo group, and the mean change from 8.0% was in the range of 0.3 -- 0.6%. The primary end point was a composite of death from cardiovascular causes, non-fatal myocardial infarction or nonfatal stroke, and this was similar in both groups: occurring in 305 (11.3%) in the alogliptin group, compared to 316 (11.8%) in the placebo group. There was also no difference in the components of the primary end points between groups. In addition, the secondary end point included urgent revascularisation due to unstable angina, and this was not different between groups. Alogliptin did not alter the GFR. The rates of serious hypoglycaemia (placebo, 0.6%; alogliptin, 0.7%) and any hypoglycaemia (placebo, 6.5%; alogliptin, 6.7%) were similar in both groups. Rates of pancreatitis and other safety end points (e.g., cancer, angioedema, 3.2
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liver enzyme abnormalities and kidney function) were not different between groups. Discussion As EXAMINE did not show cardiovascular risk or benefit, with the median duration of only 18 months, the authors could not rule out longer-term risks or benefits with alogliptin [13]. 3.3
4.
Expert opinion
Populations The populations of both SAVOR-TIMI 53 and EXAMINE were predominantly White, and thus the findings of these studies predominantly apply to Whites taking saxagliptin or alogliptin. However, some other populations with type 2 diabetes have a higher incidence and more cardiovascularrelated disease, for example, Hispanics and Blacks. SAVORTIMI 53 has a significant population of Hispanics (22%), whereas EXAMINE does not. The findings for subpopulation of Hispanics in SAVOR-TIMI have not been reported and should be reported. Neither SAVOR-TIMI 53 nor EXAMINE has a significant sub-population of Blacks. Thus, the cardiovascular safety and benefits of gliptins need to be studied in populations, other than Whites, including Hispanics and Blacks.
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4.1
Change in diabetic medications/HbA1c during study
4.2
In SAVOR-TIMI 53, the use of anti-diabetes medicines was matched at baseline [11]. However, there was an increased use of insulin in the placebo, but not the saxagliptin group, during the study, and thus the anti-diabetes medications were no longer matched between the groups [11]. The increased use of insulin in the placebo group was likely to diminish the difference in HbA1c levels between the placebo group and the saxagliptin group, such that it was small (0.2 -- 0.3%). In EXAMINE, the use of anti-diabetes medicines was also matched at baseline [12], but it was not reported whether this changed during the study. Thus, we do not know whether the use of anti-diabetes medicines remained matched or not during the study. EXAMINE also does not report HbA1c values for the placebo and alogliptin groups, but it reports mean changes in HbA1c from 8.0%, which were in the range 0.3 -- 0.5% that equates to a reduction in HbA1c of 0.2 -- 0.4%, which is similar to the reduction with saxagliptin in SAVORTIMI 53. It would be easier to compare the studies, and to compare with other studies, if EXAMINE had given the absolute values for HbA1c. In UKPDS 35, reductions in cardiovascular outcomes of 14 -- 37% were associated with a 1% reduction in HbA1c in subjects with type 2 diabetes [2]. It is possible that there were no effects on cardiovascular outcomes (safety or beneficial) for saxagliptin in SAVOR-TIMI 53 or for alogliptin in 678
EXAMINE because the reductions in HbA1c of 0.2 -- 0.4% were too small to significantly affect clinical outcomes. Hospitalisations for heart failure and ongoing trials with gliptins
4.3
To date, there is only one meta-analysis that includes hospitalisations for heart failure in the analysis of gliptins as a group, and this was a presentation to the Australasian Society of Experimental and Clinical Pharmacologists and Toxicologists, and it reported that DPP-4 inhibitors had no effect on allcause mortality, cardiovascular mortality, myocardial infarction and stroke, but that DPP-4 inhibitors significantly increased hospitalisation for heart failure [14]. Despite only enrolling 13% of subjects with heart failure, SAVOR-TIMI 53 shows that saxagliptin increased hospitalisations for heart failure [11]. Subjects with class IV heart failure were not enrolled in EXAMINE, but the trial did enrol a higher percentage of subjects with heart failure (28%) than SAVOR-TIMI 53. However, hospitalisation for heart failure was not an end point in EXAMINE, and [13] thus we do not know whether alogliptin has an effect on hospitalisations for heart failure. Despite sitagliptin being approved in 2008, no Phase III/IV cardiovascular safety or benefit outcome trials have been reported to date. However, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is in progress and will report on cardiovascular safety [15]. Meta-analysis of the Phase III program with linagliptin, suggested that it had no effect on cardiovascular outcomes [16], and it is being compared to glimepiride in a cardiovascular outcome trial -- Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) -- which, however, will not be completed until 2018 [17]. Thus, neither TECOS nor CAROLINA has hospitalisation for heart failure as an end point. To our knowledge, there is no ongoing cardiovascular risk trial with vildagliptin. Thus, even when all the trials are completed, we may not be clear as to whether sitagliptin, linagliptin or vildagliptin increase heart failure. Given the finding that saxagliptin increased hospitalisation for heart failure in SAVOR-TIMI 53, this should be an essential study end point for cardiovascular safety trials with all gliptins. Thus, hospitalisations for heart failure should be added as an end point to all ongoing cardiovascular safety trials with gliptins, if possible. If this is not possible, new clinical trials may have to be set up to evaluate the effects of gliptins on hospitalisations for heart failure. In any new studies on the effect of gliptins on cardiovascular safety, hospitalisations for heart failure need to be an end point. Any further meta-analyses of gliptins as a group, or individually, should also consider hospitalisations for heart failure. Cardiovascular benefits Microvascular disease was not evaluated in either SAVORTIMI 53 or EXAMINE for unclear reasons, perhaps due to 4.4
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Gliptins -- do they increase cardiovascular risk or benefit?
lack of power, despite the obvious clinical importance of retinopathy, neuropathy and nephropathy. In SAVORTIMI 53, subjects with kidney dysfunction were excluded, and kidney function was measured as a surrogate of the combination of doubling of creatinine level, initiation of dialysis, renal transplantation or creatinine > 6.0 mg/dl, which was not altered by saxagliptin. These kidney function parameters are not given for alogliptin in EXAMINE. However, it should be noted that in both SAVOR-TIMI 53 and EXAMINE, about 80% of all subjects were taking a blocker of the renin--angiotensin system throughout, and these would have offered nephroprotection. Nevertheless, in our opinion, improvements in microvascular disease probably should be demonstrated unequivocally with each class of diabetic pharmacotherapy. Thus, one of the major limitations to the studies to date with the saxagliptin and alogliptin (and the other gliptins) is that no clinically beneficial outcomes (e.g., on cardiovascular mortality and morbidity) have emerged in published individual studies or meta-analysis of individual studies [18]. Thus, meta-analysis of 12 trials with events for saxagliptin and 4 trials with alogliptin did not show a significant effect on cardiovascular mortality and morbidity [18]. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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6.
Stratton IM, Adler AI, Matthews DR, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12
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Selvin E, Ning Y, Steffes MW, et al. Glycated hemoglobin and the risk of kidney disease and retinopathy in adults with and without diabetes. Diabetes 2011;60:298-305
8.
Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose
Declaration of interest The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010;122:16-27
lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59
Ligaray KPL, Isley WL. Diabetes mellitus, type 2. Available from: http:// emedicine.medscape.com/article/117853overview [Accessed 24 September 2013]
FDA announces new recommendations on evaluating cardiovascular risk in drugs intended to treat type 2 diabetes. Available from: http://www.fda.gov/ Newsevents/Newsroom/ PressAnnouncements/2008/ucm116994. htm [Accessed 27 November 2013] This is the ruling by the FDA that the new drugs that lower HbA1c, for use in the treatment of type 2 diabetes, should be the subject of major cardiovascular safety trials.
Conclusion The cardiovascular safety of gliptins in type 2 diabetes mellitus is unclear in the light of a significant increase in hospitalisations for heart failure, with saxagliptin increasing the rate [11]. The gliptins also have not been demonstrated to lower the cardiovascular events or microvascular disease. Whilst there is no published evidence of improved outcomes with gliptins, it is unclear why these agents are so widely available and utilised. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established. 4.5
9.
10.
Nissen SE, Wolski K. Rosiglitazone revisited: and updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010;170:1191-201 Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411-18 European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. Available from: http://www. ema.europa.eu/ema/index.jsp?curl=pages/ news_and_events/news/2010/09/ news_detail_001119.jsp&murl=menus/ news_and_events/news_and_events. jsp&mid=WC0b01ac058004d5c1 [Accessed 27 November 2013] FDA Guidance for Industry. Diabetes Mellitus -- Evaluating Cardiovascular Risk in New Antidiabetes therapies to treat type 2 diabetes. Available from: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/ucm071627.pdf [Accessed 11 December 2013] Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of
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11.
..
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med 2013;369:1317-26 The cardiovascular outcome trial for saxagliptin showed that it did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. Saxagliptin increased hospitalisations for heart failure.
12.
White WB, Pratley R, Fleck P, et al. Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:688-73
13.
White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35 The cardiovascular outcomes trial for alogliptin showed that it did not increase the primary end point. The effect of alogliptin on hospitalisations for heart failure was not reported.
..
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Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl peptidase-inhibitors and cardiovascular outcomes: a meta-analysis of randomized clinical trials. Available from: http://www.asceptasm.com/wpcontent/uploads/2013/06/ASCEPTabstracts-202-315.pdf [Accessed 26 February 2014] Green JB, Bethel MA, Paul SK, et al. Rational, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013;166:983-9.e7 Johansen OE, Neubacher D, Von Eynatten M, et al. Cardiovascular
safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated metaanalysis or a phase 3 programme. Cardiovasc Diabetol 2012,doi:10.1186/1475-2840-11-3 17.
CAROLINA: cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. Available from: http://clinicaltrials.gov/ct2/show/ NCT01243424? term=linagliptin&rank=23 [Accessed 28 November 2013]
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Monami M, Ahre´n B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical
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trials. Diabetes Obes Metab 2013;15:112-20
Affiliation
Sheila A Doggrell†1 PhD DSc & Simon B Dimmitt2 MBBS FRACP FCSANZ † Author for correspondence 1 Senior Lecturer in Pharmacology, Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, GPO 2434, QLD 4002, Brisbane, Australia Tel: + 61 7 3138 2015; Fax: +61 7 3138 1534; E-mail: [email protected] 2 Clinical Professor of Medicine, University of Western Australia, School of Medicine and Pharmacology, Perth, Australia
Gliptins -- do they increase cardiovascular risk or benefit? 1.
Introduction
2.
Saxagliptin in SAVOR-TIMI 53
3.
Alogliptin in EXAMINE
4.
Expert opinion
Evaluation of Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med 2013;369:1317-26 and White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
Sheila A Doggrell† & Simon B Dimmitt Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Mcgill University on 11/19/14 For personal use only.
†
Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Brisbane, Australia
Introduction: In 2008, the US FDA required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase-4 inhibitors (‘gliptins’). Areas covered: The cardiovascular safety trials of saxagliptin and alogliptin have recently been published and are the subject of this evaluation. Expert opinion: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus -- Thrombolysis in Myocardial Infarction 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care were both multicentre, randomised, double-blind, placebocontrolled, Phase IV clinical trials. These trials showed that saxagliptin and alogliptin did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, which was a component of the secondary end point. The effect of alogliptin on hospitalisations for heart failure has not been reported. Neither agent improved cardiovascular outcomes. As there is no published evidence of improved outcomes with gliptins, it is unclear to us why these agents are so widely available for use. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established. Keywords: alogliptin, cardiovascular benefit, cardiovascular risk, clinical trials, saxagliptin, type 2 diabetes Expert Opin. Drug Saf. (2014) 13(5):675-680
1.
Introduction
In the USA, the prevalence of diabetes is about 8% (24 million people), and 90% of diabetes is type 2, which has both lifestyle and genetic components [1]. Despite the treatments available for type 2 diabetes, about two-thirds of the subjects die from heart disease or stroke, and almost all experience premature cardiovascular morbidity culminating in amputations and myocardial infarction with cardiac failure [1]. In 1998, the UK prospective diabetes study (UKPDS 35) suggested a significant relationship between glycaemia and clinical complications with every 1% reduction in HbA1c being associated with a 21% reduction in the risk of any end point related to diabetes, 21% of deaths related to diabetes, 14% to myocardial infarction and 37% to microvascular complications [2]. Higher HbA1c levels were also associated with increased risk of microvascular complications such as chronic kidney disease, end-stage kidney disease and retinopathy, in the Atherosclerosis Risk in 10.1517/14740338.2014.904284 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
675
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S. A. Doggrell & S. B. Dimmitt
Communities Study [3]. Consequently, from this time, HbA1c levels were often considered to be a surrogate marker for cardiovascular risk with high levels indicating high risk, and reductions in HbA1c indicating reduced risk. However, in 2008, this straightforward relationship between HbA1c levels and cardiovascular risk was challenged by the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial [4]. ACCORD showed that the intensive lowering of HbA1c to 6.4% was associated with an increased risk of mortality, compared to standard therapy (HbA1c of 7.5%), without affecting major cardiovascular events [4]. Thus, HbA1c levels cannot always be considered a surrogate for cardiovascular risk or safety. This led the US FDA in 2008 to require that all new glucose-lowering therapies should be required to show cardiovascular safety [5]. Subsequently, the thiazolidinedione, rosiglitazone, was shown to lower HbA1c but was shown to increase cardiovascular risk [6,7]. With the addition of these findings with rosiglitazone, the European Medicines Agency (EMA) concurred in 2010 that all new glucose-lowering therapies should be required to show cardiovascular safety [8]. The FDA Guidance for Industry suggests that the safety of new antidiabetic therapy can be evaluated either from integrated analysis of the Phase II and Phase III clinical trials or by additional Phase IV large safety trials [9]. The dipeptidyl peptidase (DPP)-4 inhibitors are relatively new group of medicines for the treatment of diabetes. These agents inhibit the degradation of the incretin hormones, leading to the increased levels of these hormones. Incretin hormones stimulate insulin secretion, with the reduction of HbA1c levels in subjects with type 2 diabetes. Sitagliptin was approved in 2006, subsequent to which vildagliptin, saxagliptin, alogliptin and linagliptin have been approved. The first two cardiovascular risk Phase IV trials, performed under the requirements of the FDA and EMA, have recently been published. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) are trials on saxagliptin and alogliptin. We have evaluated the SAVOR-TIMI 53 and EXAMINE trials and can confirm that saxagliptin and alogliptin do not increase composite cardiovascular outcomes, which did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, and alogliptin was not tested for its effects on hospitalisations for heart failure. 2.
Saxagliptin in SAVOR-TIMI 53
Introduction The saxagliptin registration Phase II and III trials established that saxagliptin reduced HbA1c in type 2 diabetes and were subsequently combined in a systematic analysis of the 2.1
676
cardiovascular risk of saxagliptin [10]. This analysis, of 4607 subjects with type 2 diabetes, suggested that saxagliptin did not change cardiovascular events and death [10]. However, limitations included that review of cardiovascular events was not independent, the trials were limited to drug-naı¨ve and monotherapy-treated subjects, there were low event numbers, the subjects had a relatively short duration of diabetes and participants were only monitored for a short time [10]. Methods and results The methods and results of the SAVOR-TIMI 53 trial [11] are summarised in this section. SAVOR-TIMI was a randomised, double-blind, placebo-controlled Phase IV trial performed in 26 countries. The trial was designed as a superiority trial of cardiovascular outcomes of saxagliptin versus placebo, with testing for non-inferiority, prior to testing for superiority. To be enrolled, subjects with type 2 diabetes had to have an HbA1c of 6.5 -- 12%, and either a history of established cardiovascular disease or multiple risk factors for vascular disease. Subjects were not enrolled if they had received incretin-based therapy in the previous 6 months or had kidney dysfunction (renal transplantation, end-stage renal failure or serum creatinine > 530 µmol/l). The 16,492 subjects enrolled had a mean age of ~ 65 years, a mean HbA1c of 8.0% and duration of diabetes ~ 10 years, and about two-thirds were male and 22% were Hispanic and 75% were Whites. Most of the enrolled subjects had hypertension (~ 81%), established atherosclerotic disease (~ 79%) and dyslipidemia (~ 71%), and some had prior coronary revascularisation (~ 43%), prior myocardial infarction (~ 38%) and/or prior heart failure (~ 13%). Subjects were randomised to saxagliptin 5 mg, which was lowered to 2.5 mg if renal impairment developed, or placebo, and the median follow up was 2.9 years. At baseline, diabetes medications were similar in both groups with ~ 70% of subjects taking metformin, ~ 40% taking sulphonylureas and ~ 41% taking insulin. The use of these medications did not change throughout the study in the saxagliptin group, but in the placebo group, insulin use had increased to ~ 46% by year 2. The HbA1c levels were significantly lower in the saxagliptin group than placebo group after 1 year (7.6 vs 7.9%), after 2 years (7.5 vs 7.8%) and at the end of study (7.7 vs 7.9%). The primary efficacy and safety end point was a composite of cardiovascular death, non-fatal myocardial infarction or non-fatal ischaemic stroke, and this occurred in 613 subjects (7.3%) in the saxagliptin group, compared with 609 subjects (7.2%) in the placebo group. The secondary end points included the primary end point plus hospitalisation for heart failure, coronary revascularisation or unstable angina, which occurred in 1059 subjects (12.8%) with saxagliptin and in 1034 subjects (12.4%) with placebo. Analysis of the individual cardiovascular items showed that they were similar in both groups, except for hospitalisation due to heart failure 2.2
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Gliptins -- do they increase cardiovascular risk or benefit?
which was 27% higher in the saxagliptin group (289 subjects, 3.5%) than the placebo group (228 subjects, 2.8%, p = 0.007). Kidney function was measured as a combination of doubling of creatinine level, initiation of dialysis, renal transplantation or creatinine > 6.0 mg/dl, and this was similar in both the saxagliptin group (194 subjects, 2.2%) and the placebo group (178 subjects, 2.0%). At the start of the study, the albumin-to-creatinine ratio was 1.8 in the saxagliptin and 1.9 in the placebo group, and at the end of the study, less subjects taking saxagliptin had a worsening of this ratio (833, 13.3%) than in the placebo group (969, 15.9%). Hypoglycaemia occurred more often in the saxagliptin group (1264 subjects, 15.3%) than the placebo group (1104 subjects, 13.4%, p < 0.001). Major hypoglycaemia requiring a third party active intervention was marginally more common in the saxagliptin group (177 subjects, 2.1%) than the placebo group (140 subjects, 1.7%, p = 0.047). Rates of pancreatitis and other safety end points (e.g., cancer, liver abnormalities, blood cell dysfunction, infections) were similar in both groups. Discussion The authors concluded, that with regard to the primary composite end point of cardiovascular death, myocardial infarction or ischaemic stroke, saxagliptin was not inferior to placebo, but it also did not provide any cardioprotective benefit [11]. Here, the authors have given three possible reasons for the failure of the study to show any cardiovascular benefit with saxagliptin: first, the study may have been too short to show benefit; second, the difference in HbA1c was too small between the groups because of the increased use of insulin in the placebo group and third, the number of end points was substantially reduced by the frequent use of statins, anti-platelet therapy and blood pressure-lowering agents [11]. The authors suggested that the increased risk of hospitalisation with heart failure, in the saxagliptin group, may have been a false-positive result [11]. However, they do concede that this finding requires further investigation [11]. 2.3
3.
Alogliptin in EXAMINE
Introduction The developmental Phase II and III trials of alogliptin established that alogliptin lowered HbA1c in subjects with type 2 diabetes and have been pooled to assess cardiovascular safety [12]. This pooling had 4168 subjects with type 2 diabetes who had been treated with alogliptin, and 2023 subjects who had been treated with placebo and showed that alogliptin had no effect on the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke [12]. However, this pooling had several limitations: the studies were not designed to measure cardiovascular safety, the duration of the clinical trials was short, the population had 3.1
only moderate cardiovascular risk and the number of cardiovascular end points was relatively low [12]. Subsequently, the cardiovascular risk of alogliptin has been determined in EXAMINE, which did not have these limitations. Methods and results The methods and results of the EXAMINE trial are summarised in this section [13]. EXAMINE was a non-inferiority trial of alogliptin and placebo and showed that alogliptin has no effect on a composite end point of cardiovascular safety. EXAMINE was a randomised, double-blind, placebocontrolled trial performed in 49 countries. To be enrolled, subjects with type 2 diabetes had to have an HbA1c of 6.5 -- 11% or, if taking insulin, an HbA1c level of 7 -- 11%, and have had an acute coronary syndrome (e.g., acute myocardial infarction, unstable angina requiring hospitalisation) within the last 15 -- 90 days. Subjects were not enrolled if they had unstable cardiovascular disorders such as class IV heart failure or had had undergone dialysis within 14 days before screening. The 5380 subjects who participated in EXAMINE had a mean age of 61 years, a mean HbA1c of 8.0% and a duration of diabetes of 7 years, and most were male (~ 68%) and Whites (~ 73%) or Asians (~ 20%). Most of the participants had had a myocardial infarction (~ 88%) and/or a percutaneous coronary intervention (~ 63%) and/or coronary-artery intervention (~ 13%), and most were hypertensive (~ 83%), and some had congestive heart failure (~ 28%), peripheral arterial disease (~ 10%), or a previous stroke (~ 7%). Subjects were allocated to placebo or alogliptin, and the dose of alogliptin was dependent on kidney function with a dose of 25 mg in subjects with a glomerular filtration rate (GFR) of 60 ml/min/173 m2, with a dose of 12.5 mg in subjects with GFR of 30 to < 60 ml/min/173 m2 or with a dose of 6.25 mg in subjects with GFR < 30 ml/min/173 m2, and the median follow up was ~ 18 months. At the start of the study, diabetes medications were similar in both groups, with ~ 66% of subjects taking metformin, ~ 46% taking sulphonylureas and ~ 30% taking insulin. The HbA1c levels were lowered in the alogliptin group, compared to the placebo group, and the mean change from 8.0% was in the range of 0.3 -- 0.6%. The primary end point was a composite of death from cardiovascular causes, non-fatal myocardial infarction or nonfatal stroke, and this was similar in both groups: occurring in 305 (11.3%) in the alogliptin group, compared to 316 (11.8%) in the placebo group. There was also no difference in the components of the primary end points between groups. In addition, the secondary end point included urgent revascularisation due to unstable angina, and this was not different between groups. Alogliptin did not alter the GFR. The rates of serious hypoglycaemia (placebo, 0.6%; alogliptin, 0.7%) and any hypoglycaemia (placebo, 6.5%; alogliptin, 6.7%) were similar in both groups. Rates of pancreatitis and other safety end points (e.g., cancer, angioedema, 3.2
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liver enzyme abnormalities and kidney function) were not different between groups. Discussion As EXAMINE did not show cardiovascular risk or benefit, with the median duration of only 18 months, the authors could not rule out longer-term risks or benefits with alogliptin [13]. 3.3
4.
Expert opinion
Populations The populations of both SAVOR-TIMI 53 and EXAMINE were predominantly White, and thus the findings of these studies predominantly apply to Whites taking saxagliptin or alogliptin. However, some other populations with type 2 diabetes have a higher incidence and more cardiovascularrelated disease, for example, Hispanics and Blacks. SAVORTIMI 53 has a significant population of Hispanics (22%), whereas EXAMINE does not. The findings for subpopulation of Hispanics in SAVOR-TIMI have not been reported and should be reported. Neither SAVOR-TIMI 53 nor EXAMINE has a significant sub-population of Blacks. Thus, the cardiovascular safety and benefits of gliptins need to be studied in populations, other than Whites, including Hispanics and Blacks.
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4.1
Change in diabetic medications/HbA1c during study
4.2
In SAVOR-TIMI 53, the use of anti-diabetes medicines was matched at baseline [11]. However, there was an increased use of insulin in the placebo, but not the saxagliptin group, during the study, and thus the anti-diabetes medications were no longer matched between the groups [11]. The increased use of insulin in the placebo group was likely to diminish the difference in HbA1c levels between the placebo group and the saxagliptin group, such that it was small (0.2 -- 0.3%). In EXAMINE, the use of anti-diabetes medicines was also matched at baseline [12], but it was not reported whether this changed during the study. Thus, we do not know whether the use of anti-diabetes medicines remained matched or not during the study. EXAMINE also does not report HbA1c values for the placebo and alogliptin groups, but it reports mean changes in HbA1c from 8.0%, which were in the range 0.3 -- 0.5% that equates to a reduction in HbA1c of 0.2 -- 0.4%, which is similar to the reduction with saxagliptin in SAVORTIMI 53. It would be easier to compare the studies, and to compare with other studies, if EXAMINE had given the absolute values for HbA1c. In UKPDS 35, reductions in cardiovascular outcomes of 14 -- 37% were associated with a 1% reduction in HbA1c in subjects with type 2 diabetes [2]. It is possible that there were no effects on cardiovascular outcomes (safety or beneficial) for saxagliptin in SAVOR-TIMI 53 or for alogliptin in 678
EXAMINE because the reductions in HbA1c of 0.2 -- 0.4% were too small to significantly affect clinical outcomes. Hospitalisations for heart failure and ongoing trials with gliptins
4.3
To date, there is only one meta-analysis that includes hospitalisations for heart failure in the analysis of gliptins as a group, and this was a presentation to the Australasian Society of Experimental and Clinical Pharmacologists and Toxicologists, and it reported that DPP-4 inhibitors had no effect on allcause mortality, cardiovascular mortality, myocardial infarction and stroke, but that DPP-4 inhibitors significantly increased hospitalisation for heart failure [14]. Despite only enrolling 13% of subjects with heart failure, SAVOR-TIMI 53 shows that saxagliptin increased hospitalisations for heart failure [11]. Subjects with class IV heart failure were not enrolled in EXAMINE, but the trial did enrol a higher percentage of subjects with heart failure (28%) than SAVOR-TIMI 53. However, hospitalisation for heart failure was not an end point in EXAMINE, and [13] thus we do not know whether alogliptin has an effect on hospitalisations for heart failure. Despite sitagliptin being approved in 2008, no Phase III/IV cardiovascular safety or benefit outcome trials have been reported to date. However, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is in progress and will report on cardiovascular safety [15]. Meta-analysis of the Phase III program with linagliptin, suggested that it had no effect on cardiovascular outcomes [16], and it is being compared to glimepiride in a cardiovascular outcome trial -- Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) -- which, however, will not be completed until 2018 [17]. Thus, neither TECOS nor CAROLINA has hospitalisation for heart failure as an end point. To our knowledge, there is no ongoing cardiovascular risk trial with vildagliptin. Thus, even when all the trials are completed, we may not be clear as to whether sitagliptin, linagliptin or vildagliptin increase heart failure. Given the finding that saxagliptin increased hospitalisation for heart failure in SAVOR-TIMI 53, this should be an essential study end point for cardiovascular safety trials with all gliptins. Thus, hospitalisations for heart failure should be added as an end point to all ongoing cardiovascular safety trials with gliptins, if possible. If this is not possible, new clinical trials may have to be set up to evaluate the effects of gliptins on hospitalisations for heart failure. In any new studies on the effect of gliptins on cardiovascular safety, hospitalisations for heart failure need to be an end point. Any further meta-analyses of gliptins as a group, or individually, should also consider hospitalisations for heart failure. Cardiovascular benefits Microvascular disease was not evaluated in either SAVORTIMI 53 or EXAMINE for unclear reasons, perhaps due to 4.4
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Gliptins -- do they increase cardiovascular risk or benefit?
lack of power, despite the obvious clinical importance of retinopathy, neuropathy and nephropathy. In SAVORTIMI 53, subjects with kidney dysfunction were excluded, and kidney function was measured as a surrogate of the combination of doubling of creatinine level, initiation of dialysis, renal transplantation or creatinine > 6.0 mg/dl, which was not altered by saxagliptin. These kidney function parameters are not given for alogliptin in EXAMINE. However, it should be noted that in both SAVOR-TIMI 53 and EXAMINE, about 80% of all subjects were taking a blocker of the renin--angiotensin system throughout, and these would have offered nephroprotection. Nevertheless, in our opinion, improvements in microvascular disease probably should be demonstrated unequivocally with each class of diabetic pharmacotherapy. Thus, one of the major limitations to the studies to date with the saxagliptin and alogliptin (and the other gliptins) is that no clinically beneficial outcomes (e.g., on cardiovascular mortality and morbidity) have emerged in published individual studies or meta-analysis of individual studies [18]. Thus, meta-analysis of 12 trials with events for saxagliptin and 4 trials with alogliptin did not show a significant effect on cardiovascular mortality and morbidity [18]. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Stratton IM, Adler AI, Matthews DR, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12
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Selvin E, Ning Y, Steffes MW, et al. Glycated hemoglobin and the risk of kidney disease and retinopathy in adults with and without diabetes. Diabetes 2011;60:298-305
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Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose
Declaration of interest The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010;122:16-27
lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59
Ligaray KPL, Isley WL. Diabetes mellitus, type 2. Available from: http:// emedicine.medscape.com/article/117853overview [Accessed 24 September 2013]
FDA announces new recommendations on evaluating cardiovascular risk in drugs intended to treat type 2 diabetes. Available from: http://www.fda.gov/ Newsevents/Newsroom/ PressAnnouncements/2008/ucm116994. htm [Accessed 27 November 2013] This is the ruling by the FDA that the new drugs that lower HbA1c, for use in the treatment of type 2 diabetes, should be the subject of major cardiovascular safety trials.
Conclusion The cardiovascular safety of gliptins in type 2 diabetes mellitus is unclear in the light of a significant increase in hospitalisations for heart failure, with saxagliptin increasing the rate [11]. The gliptins also have not been demonstrated to lower the cardiovascular events or microvascular disease. Whilst there is no published evidence of improved outcomes with gliptins, it is unclear why these agents are so widely available and utilised. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established. 4.5
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Nissen SE, Wolski K. Rosiglitazone revisited: and updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010;170:1191-201 Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411-18 European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. Available from: http://www. ema.europa.eu/ema/index.jsp?curl=pages/ news_and_events/news/2010/09/ news_detail_001119.jsp&murl=menus/ news_and_events/news_and_events. jsp&mid=WC0b01ac058004d5c1 [Accessed 27 November 2013] FDA Guidance for Industry. Diabetes Mellitus -- Evaluating Cardiovascular Risk in New Antidiabetes therapies to treat type 2 diabetes. Available from: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/ucm071627.pdf [Accessed 11 December 2013] Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of
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Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med 2013;369:1317-26 The cardiovascular outcome trial for saxagliptin showed that it did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. Saxagliptin increased hospitalisations for heart failure.
12.
White WB, Pratley R, Fleck P, et al. Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:688-73
13.
White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35 The cardiovascular outcomes trial for alogliptin showed that it did not increase the primary end point. The effect of alogliptin on hospitalisations for heart failure was not reported.
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Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl peptidase-inhibitors and cardiovascular outcomes: a meta-analysis of randomized clinical trials. Available from: http://www.asceptasm.com/wpcontent/uploads/2013/06/ASCEPTabstracts-202-315.pdf [Accessed 26 February 2014] Green JB, Bethel MA, Paul SK, et al. Rational, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013;166:983-9.e7 Johansen OE, Neubacher D, Von Eynatten M, et al. Cardiovascular
safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated metaanalysis or a phase 3 programme. Cardiovasc Diabetol 2012,doi:10.1186/1475-2840-11-3 17.
CAROLINA: cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. Available from: http://clinicaltrials.gov/ct2/show/ NCT01243424? term=linagliptin&rank=23 [Accessed 28 November 2013]
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Monami M, Ahre´n B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical
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trials. Diabetes Obes Metab 2013;15:112-20
Affiliation
Sheila A Doggrell†1 PhD DSc & Simon B Dimmitt2 MBBS FRACP FCSANZ † Author for correspondence 1 Senior Lecturer in Pharmacology, Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, GPO 2434, QLD 4002, Brisbane, Australia Tel: + 61 7 3138 2015; Fax: +61 7 3138 1534; E-mail: [email protected] 2 Clinical Professor of Medicine, University of Western Australia, School of Medicine and Pharmacology, Perth, Australia
