Diabetes and Metabolism
Effects of the dual peroxisome proliferator– activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes Erland Erdmann, MD, a Robert Califf, MD, b Hertzel C. Gerstein, MD, c Klas Malmberg, MD, d,e Luis Ruilope, MD, f Gregory G. Schwartz, MD, g Hans Wedel, MD, h Dietmar Volz, MD, e Marc Ditmarsch, MD, i Anders Svensson, MD, e and Monica Bengus, MD e Cologne, Germany; Durham, NC; Ontario, Canada; Stockholm, Frolunda, Mölndal, Sweden; Basel, Switzerland; Madrid, Spain; and Denver, CO
Background Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator–activated receptor α/γ agonist with favorable insulinsensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to b6.5%) with previous CV complications. Study design
ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar.
Results At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P b .0001), and muscular events (3 vs12; P = .012). Conclusions Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator–activated receptor α/γ activators, this class now holds little promise for CV therapeutics. (Am Heart J 2015;170:117-22.)
From the aHerzzentrum der Universität zu Köln, Cologne, Germany, bDepartment of Medicine, Duke University, Durham, NC, cDepartment of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, d Department of Medicine, Karolinska Institutet, Stockholm, Sweden, eF Hoffmann–La Roche Ltd, Basel, Switzerland, fUnidad de Hipertensión, Hospital 12 de Octubre, Madrid, Spain, gUniversity of Colorado School of Medicine, Denver, CO, hNordic School of Public Health, Frolunda, Sweden, and i Former, F Hoffmann–La Roche Ltd; Current, Astra Zeneca, Mölndal, Sweden. Guest Editor: Deepak L Bhatt, MD, MPH. Funding/support: The trial was sponsored by F Hoffmann–La Roche (Basel, Switzerland). Role of the sponsor: F Hoffmann–La Roche participated in the design of the trial and protocol in collaboration with the academic members of the executive steering committee. Furthermore, F Hoffmann–La Roche developed and maintained the trial database and was responsible for data collection. Conflict of interest: The members of the academic executive steering committee (Erland Erdmann, Robert Califf, Hertzel Gerstein, Luis Ruilope, Gregory Schwartz, and Hans Wedel) received travel grants and compensation for working in the committee from F Hoffmann–La Roche. Submitted December 12, 2014; accepted March 31, 2015. Reprint requests: Erland Erdmann, MD, Herzzentrum der Universität zu Köln, Cologne, D-50933, Germany. 0002-8703 © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2015.03.021
The treatment of metabolic disorders such as hypercholesterolemia, prediabetes, and diabetes should result in a decreased cardiovascular (CV) risk. Therefore, most guidelines advocate the liberal prescription of statins even in persons without obvious symptoms but high lowdensity lipoprotein (LDL) cholesterol and low highdensity lipoprotein cholesterol (HDL-C) levels. 1,2 With the possible exception of metformin and pioglitazone, glucose-lowering drugs have not decreased macrovascular morbidity and CV mortality. Nevertheless, elevated glycosylated hemoglobin (HbA1c), even in the prediabetic range, is associated with CV disease (CVD) and mortality. 3 Aleglitazar in a phase II, randomized dose-ranging study (SYNCHRONY) significantly reduced HbA1c in a dosedependent manner without many cases of hypoglycemia. It also decreased triglycerides and augmented HDL-C. 4 Therefore, phase III trials were initiated to investigate the effects of aleglitazar on CV events in patients with metabolic disease. The ALEPREVENT trial was initiated to evaluate the potential of aleglitazar, on top of standard of care, to reduce CV morbidity and mortality in patients
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Table I. Exclusion criteria 1. 2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12. 13. 14. 15 16. 17. 18 19. 20.
Current treatment with a thiazolidinedione or fibrate Prior intolerance to a thiazolidinedione or fibrate Previous participation in a trial with aleglitazar Other types of diabetes (eg, type 1 diabetes, diabetes resulting from pancreatic injury, or diabetes associated with acromegaly or Cushing syndrome) Triglycerides (fasting) N500 mg/dL (N5.7 mmol/L) HbA1c N10.0% Liver disease characterized by ○ALT or AST N3× ULN confirmed on 2 consecutive measurements or ○Impaired excretory function (eg, hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices or ○Acute viral or active autoimmune, alcoholic, or other types of hepatitis Anemia defined as hemoglobin b10 g/dL (b100 g/L, b6.21 mmol/L) or hematocrit b30% eGFR (MDRD) b45 mL/min per 1.73 m 2 Symptomatic congestive heart failure classified as NYHA class II-IV Hospitalization for a primary diagnosis of heart failure in the 12-month period preceding the randomization Peripheral edema, which in the judgment of the investigator, is believed to be clinically severe and of cardiac origin History of surgical coronary revascularization (CABG) b5 years before screening, except in cases of subsequent MI Currently scheduled for arterial revascularization (coronary, carotid, or peripheral) procedures Systemic corticosteroid therapy for N2 wk, within 3 m before screening Any serious medical condition with a life expectancy shorter than 5 years or which, in the judgment of the investigator would preclude participation in the trial or could interfere with the conduct of the study Diagnosed or treated malignancy (except for treated cases of basal cell skin cancer, in situ carcinoma of the cervix, or in situ prostate cancer) within the past 5 years Uninvestigated hematuria present during screening period Women with a positive pregnancy test, breast feeding, or of childbearing potential not using medically approved, highly effective methods of contraception Participation in any clinical trial with an investigational drug or device or in any clinical trial requiring interventions (eg, blood sampling) within 1 m before screening
Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal; eGFR, estimated Glomerular Filtration Rate; NYHA, New York Heart Association; CABG, coronary artery bypass graft; MI, myocardial infarction.
with documented stable CVD and T2D and/or prediabetes. The trial was stopped prematurely when the independent data safety monitoring board for another aleglitazar trial (ALECARDIO; NCT01042769) 5,6 recommended early termination of that trial for unfavorable benefit-risk balance.
Methods Description and design ALEPREVENT was a randomized, double-blind, placebocontrolled, parallel group, multicenter study in patients with evidence of stable CVD and glucose abnormalities as markers of residual risk (EUDRACT no. 2012-000671-16). Qualifying patients were either age ≥40 years with evidence of a prior CV event (prior myocardial infarction or prior ischemic stroke confirmed by a brain imaging study) or age ≥55 years with stable CVD (coronary heart disease, cerebrovascular disease, or peripheral arterial disease). In addition, all patients also had to have either T2D (ie, previously known or newly diagnosed according to 2010 American Diabetes Association criteria; treatment could include diet alone or any approved glucose-lowering therapies except for Thiazolidindiones) or prediabetes (5.7% ≤ HbA1c b 6.5% in the
absence of diabetic treatment). Exclusion criteria are listed in Table I. All participants were managed according to the best judgment of their treating physicians and the best clinical evidence for patients with stable CVD, CV risk factors, and cardiometabolic abnormalities. After a screening period of up to 4 weeks to assess eligibility, patients were randomly assigned in 1:1 ratio to treatment with aleglitazar 150 μg daily or matching placebo. Follow-up visits were scheduled 1, 3, and 6 months after randomization and every 6 months thereafter until completion of the trial. Of a planned enrollment of 19,000 patients, 1,999 had been randomized when the trial was stopped prematurely. The primary efficacy objective for this study was to determine whether the addition of aleglitazar versus placebo will reduce a composite outcome of CV death, nonfatal myocardial infarction, or nonfatal stroke in patients with stable CVD and glucose abnormalities. The secondary efficacy objectives for this study were to further explore the potential of aleglitazar to reduce CV morbidity and all-cause mortality and to delay the onset of T2D. Other efficacy objectives for this study were to determine the effects of aleglitazar on other macrovascular and microvascular outcomes, glycemic control, lipid parameters, and other CV risk factors.
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Table II. Baseline demographics of prediabetic patients
A. Male (n, %) Age (y) Body weight (kg, SD) Body mass index (kg/m 2) Waist/hip ratio Systolic blood pressure (mm Hg), mean (SD) Diastolic blood pressure (mm Hg), mean (SD)
Placebo (n = 212)
Aleglitazar (0.15 mg) (n = 203)
151 (71.2) 66.6 ± 8.4 87.3 ± 18.2 30.4 ± 4.9 0.961 ± 0.076 133.4 ± 16.0
148 (72.9) 66.7 ± 7.7 85.5 ± 16.7 30.0 ± 4.9 0.961 ± 0.075 132 ± 17.9
76.9 ± 9.9
75.9 ± 10.3
B. Baseline HbA1c and eGFR MDRD category in prediabetic patients HbA1c category (n, %) b5.7 30 (14.2) 31 (15.3) 5.7 to b6.5 178 (84.0) 166 (81.8) 6.5 to b8.5 4 (1.9) 6 (3.0) eGFR MDRD category (mL/min per 1.73 m2)(n, %) N90 27 (12.7) 23 (11.3) 60 to b90 139 (65.6) 144 (70.9) 45 to b60 42 (19.8) 31 (15.3) 30 to b45 4 (1.9) 5 (2.5)
The safety objectives for this study were to further evaluate the safety and tolerability of aleglitazar with specific focus on events relevant to the PPARα and γ agonists. The following events were considered safety events of interest: • Heart failure (incidence and time to occurrence) • Abnormal kidney function AEs and kidney laboratory abnormalities • Muscular AEs and creatine phosphokinase elevations • Hepatic AEs and liver laboratory abnormalities • Bone fractures • Malignancies Statistical methods. The planned study was event- and time driven and was to continue until approximately 1,260 positively adjudicated primary CV end points occurred in the overall population and approximately 630 CV events in the subgroup of patients without evidence of T2D at baseline. Under the following assumptions: • A risk reduction of 20% (a constant hazard ratio of 0.80); • Statistical significance defined as a 2-sided α of .05 for a log-rank test. The planned study had 97% power if it continued until 1,260 primary clinical event committee adjudicated events occurred in the combined treatment groups. With the expected event count of 630 events in the subgroup of
Table III. Baseline demographics of T2D patients
A. Male (n, %) Age (y) Body weight (kg, SD) Body mass index (kg/m 2) Waist/hip ratio Systolic blood pressure (mm Hg), mean (SD) Diastolic blood pressure (mm Hg), mean (SD)
Placebo (n = 785)
Aleglitazar (0.15 mg) (n = 796)
565 (72.0) 65.8 ± 8.2 88.8 ± 18.5 31.1 ± 5.5 0.984 ± 0.111 134.7 ± 16.4
607 (76.3) 65.8 ± 8.5 88.7 ± 18.0 30.8 ± 5.2 0.983 ± 0.082 134.1 ± 16.4
76.3 ± 9.4
76.0 ± 9.7
B. Baseline HbA1c and eGFR MDRD category in T2D patients HbA1c category (%) b5.7 33 (4.7) 30 (4.2) 5.7 to b6.5 228 (32.6) 220 (30.7) 6.5 to b8.5 422 (60.4) 452 (63.0) 8.5 to b10 10 (1.4) 11 (1.5) N10 6 (0.9) 4 (0.6) eGFR MDRD category (mL/min per 1.73 m2)(%) N90 160 (20.4) 145 (18.2) 60 to b90 442 (56.3) 461 (57.9) 45 to b60 133 (16.9) 156 (19.6) 30 to b45 49 (6.2) 31 (3.9) b30 1 (0.1) 3 (0.4)
patients without evidence of T2D at baseline; it was anticipated to show a favorable effect of aleglitazar versus placebo with approximately 80% power. All patients were to be followed up for ≥3 years. The analyses of baseline data as well as laboratory data and safety signals were based on the safety population, that is, the subset of randomized patients who received ≥1 dose of study medication. Because of premature termination of the study by the sponsor, CV end points were not adjudicated by the clinical event committee, and the planned statistical analysis of efficacy end points was not performed. All analyses provided in this article are descriptive in nature. As the number of collected primary end point events is much lower than the originally anticipated 1,260 events from the protocol, also no formal hypothesis testing based on the primary end point was performed. Where not otherwise specified, proposed figures show means and SDs. The software used to do the calculations was SAS version 9.2. In collaboration with the investigators, the sponsor of the trial contributed to the design of the study, collection of data, statistical analysis, and interpretation and reporting of the results. As defined by the protocol, all CV events were assessed by an independent adjudication
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Table IV. Baseline concomitant medications Prediabetes (n = 415) Blood glucose-lowering drugs (%) Biguanides (%) Sulfonylureas (%) Dipeptidy-peptidase-4 inhibitors (%) Glucagon-like peptide-1 receptor agonists (%) Statins (%) Cholesterol absorption inhibitors (%) ARB, ACE, and other RAAS inhibitors (%) β-blockers (%) Calcium-channel blockers (%) Diuretics (%) Nitrates (%) Vitamin K antagonists (%) ASS (%) Other platelet aggregation inhibitors (%)
1 1 – – – 90 8 72 70 28 30 10 7 80 19
T2D (n = 1581) 80 72 31 13 2 86 9 83 69 35 40 8 6 74 31
Abbreviations: ARB, angiotensin-receptor-blocker; ACE, Angiotensin-converting enzyme; ASS, acetylsalicylic acid = aspinrin.
committee. This report was prepared by the authors, with contributions from the sponsor. The authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors are solely responsible for drafting and editing of the paper and its final contents.
Results The ALEPREVENT trial was started in January 2013 and stopped on July 10, 2013, when 1,999 patients had been randomized. At study end, data had been collected from 1,581 with T2D and 415 with pre-T2D. The mean duration of treatment with aleglitazar 150 μg or placebo was 58 ± 38 days (range 1-234 days). Tables II and III show the baseline demographics of the patients with prediabetes and T2D. Ten patients in the prediabetes group with HbA1c values above 6.5% were misclassified by investigators (4 in the placebo and 6 in the aleglitazar group). Glycosylated hemoglobin was 7.09 ± 1.07 % in the subgroup with T2D and 5.93 ± 0.27 % in the subgroup with prediabetes. Fasting insulin levels were 16.58 with T2D and 9.87 μU/mL in prediabetes. Homeostasis Model Assessment index was 6.03 in T2D and 2.63 μU/mL*mg/dL in prediabetes (Tables II, III, and V). Sixty-six percent of patients had prior myocardial infarction and/or ischemic stroke. In this respect, there were no significant differences between prediabetic and T2D patients. Table IV shows the baseline concomitant medications reflecting utilization of antihypertensive drugs, antiplatelet agents, and statins in a large majority of the patients. Blood pressure and LDL cholesterol levels were well controlled. Aleglitazar lowered HbA1c by 0.31% even during this short treatment time in T2D and raised HDL-C as expected by 12.8% in T2D and by 16% in pre-T2D (Table V).
Aleglitazar lowered triglycerides by 24.3% in T2D and by 20.5% in prediabetes. Low-density lipoprotein cholesterol and total cholesterol were more or less unchanged during this short period of treatment. Aleglitazar caused a reversible increase of serum creatinine (Table V) from 1.01 ± 0.24 (n = 999) to 1.11 ± 0.28 (end of treatment; n = 663) and back to 1.03 ± 0.25 (end of follow-up; n = 839), whereas the placebo group experienced no change of serum creatinine. Similar changes occurred with creatinine clearance (Modification of Diet in Renal Disease formula [MDRD]; mL/min per 1.73 m 2 ; ±SD): from 73.4 ± 18 at baseline (n = 999) to 66.8 ± 18 (end of treatment; n = 663) to 71.9 ± 18 (end of follow-up; n = 839) without changes in the placebo group (Table V).
Safety There were 4 deaths in the placebo and 2 deaths in the aleglitazar group. One patient on aleglitazar committed suicide on day 38 of treatment, the other one died on day 35 of treatment during elective percutaneous coronary intervention. Three patients in the placebo group died after study end; the fourth one died from sepsis on day 62 of placebo treatment. Hypoglycemia (signs or symptoms with prompt resolution with food intake, subcutaneous glucagon, or intravenous glucose, as reported by the patient and/or blood glucose levels ≤50 mg/dL [2.8 mmol/L], regardless of the presence of hypoglycemic signs or symptoms) was more often recorded in patients on aleglitazar (6.9 % vs 3.9%; P b .0001). Muscular events (myalgia, muscle tenderness or weakness, myositis, or myopathy) (1.2 % vs 0.3 %; P = .012) occurred also more frequently in the aleglitazar group. The investigators more often found peripheral edema (2.9 % vs 1.7 %; P = .087) but not a higher incidence of congestive heart failure (Table VI).
Discussion In 2 previous dose finding studies, aleglitazar treatment caused significant, dose-dependent improvements in HbA1c concentrations and fasting plasma glucose compared with placebo, along with favorable effects on blood lipids, suggesting favorable multifactorial risk factor modification. 4,7 The 150-μg dose provided glycemic effects similar to the 45-mg pioglitazone reference group but without apparent heart failure episodes. 4 The ALEPREVENT study was started as a phase III investigation to evaluate the potential of aleglitazar, on top of standard of care, to reduce CV morbidity and mortality in patients with documented stable CVD and either T2D or prediabetes. However, the study was halted with enrolment of far fewer than the intended 19,000 subjects when the data safety and monitoring board became aware of the absence of CV benefit along with serious safety concerns in another aleglitazar trial (ALECARDIO). 5,6 Most of the safety concerns in the ALECARDIO trial
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Table V. Changes during treatment from baseline T2D on aleglitazar (n = 796)
Baseline
End of treatment
Pre-T2D on aleglitazar (n = 203)
Baseline
End of treatment
Placebo (n = 997)
Baseline
End of treatment
Body weight (kg, SD) 88.65 (18.019) 89.46 (18.585) 85.46 (16.742) 86.14 (17.697) 88.49 (18.456) 88.64 (18.304) Systolic blood pressure (mm Hg), 134.1 (16.36) 131.2 (16.24) 132.5 (17.91) 131.8 (17.00) 134.4 (16.31) 132.2 (16.67) mean (SD) Diastolic blood pressure (mm Hg), 76.0 (9.73) 73.8 (9.99) 75.9 (10.32) 74.0 (9.89) 76.4 (9.54) 75.3 (10.00) mean (SD) HbA1c (%) mean (SD) 7.11 (1.064) 6.80 (0.998) 5.93 (0.278) 5.89 (0.270) 6.82 (1.006) 6.87 (1.089) Insulin fasting (μU/mL) mean (SD) 16.58 (21.297) 11.80 (14.411) 9.87 (6.733) 8.09 (6.474) 15.55 (17.671) 17.92 (19.891) HOMA IR (μU/mL*mg/dL), mean 6.03 (8.796) 3.66 (4.700) 2.63 (2.008) 2.00 (1.776) 5.38 (6.828) 6.42 (8.351) Serum creatinine (mg/dL), mean 1.01 (0.246) 1.11 (0.276) 1.00 (0.213) 1.09 (0.271) 1.00 (0.249) 0.99 (0.259) eGFR MDRD (mL/min per 1.73 m 2), 73.77 (18.811) 66.57 (17.975) 72.12 (14.745) 67.6 (16.765) 74.21 (19.343) 75.41 (20.258) mean (SD) eGFR CKD-EPI 75.23 (17.383) 65.78 (18.368) 74.38 (14.624) 69.78 (16.648) 75.46 (17.470) 76.55 (17.872) (mL/min per 1.73 m 2) mean (SD) LDL-C (mg/dL), mean (SD) 77.62 (33.808) 80.28 (32.503) 84.51 (31.901) 85.00 (31.153) 81.19 (34.178) 77.01 (33.085) HDL-C (mg/dL), mean (SD) 47.74 (13.448) 53.88 (14.380) 50.28 (12.197) 58.31 (13.947) 48.1 (12.617) 47.85 (12.477) Triglycerides (mg/dL), mean (SD) 155.52 (128.158) 117.72 (69.016) 134.35 (60.991) 106.89 (48.754) 152.69 (83.475) 163.19 (102.011) Total cholesterol (mg/dL), mean (SD) 155.47 (40.751) 157.50 (38.744) 161.42 (36.626) 164.64 (32.808) 159.4 (40.280) 156.59 (38.883) Abbreviation: LDL-C, LDL cholesterol. Visits are time windowed. Includes all available central and local laboratory data with preference given to central laboratory data within a time window. Baseline is the last available assessment up to and including the first day of study drug intake. End of treatment is the last available assessment up until day 1 after the day of last dose of study drug intake.
(edema/heart failure and fractures) could have been expected for a PPARγ agonist, as they had been recorded in other trials with thiazolidinedione drugs. 8-10 However, several smaller trials with aleglitazar with short duration had not revealed these complications. 4,7 Although the ALEPREVENT trial was stopped after an exposure to study medication of just 58 ± 38 days, there were nonetheless indicators of metabolic actions and safety concerns. There was an excess of hypoglycemia and muscular events and numerically more reports of edema and gastrointestinal (GI) hemorrhage. These findings mirrored those in the larger ALECARDIO trial and thus increase the likelihood that they are caused by aleglitazar. The negative results of this well-planned trial with a promising drug, aleglitazar, raise important issues for future development of metabolic agents intended to influence CV outcomes. In light of previous studies that suggested pioglitazone may reduce macrovascular complications, 9,10 the effect of aleglitazar on lipid profiles observed in SYNCHRONY 4 had raised hope that an agent with balanced PPARα and PPARγ agonism might favorably and safely influence CV end points. As with other trials in the past, we had to learn, however, that surrogate parameters in CV medicine, that is, a better metabolic profile, may not automatically result in a better clinical outcome— particularly if previously underrated side effects of the investigational drug become apparent. The serious side
effects of aleglitazar seen in our trial were not recorded in preceding phase II trials with 71 or 332 patients, respectively. 4,7 In fact, the most frequently reported adverse events in the SYNCHRONY trial 7 were peripheral edema, nasopharyngitis, slightly increased blood creatine phosphokinase, and upper respiratory tract infection, all of which were rated as mild and not significantly different between groups treated with aleglitazar 150 μg daily or placebo. The results of the present investigation sound a familiar cautionary note that favorable effects on laboratory measurements of metabolic status in phase II studies with small sample size and short duration may not translate into clinical efficacy and safety in phase III evaluation. This lesson has to be kept in mind for future drug trials. In the end, large-scale phase III studies often remain necessary to provide definitive evidence of safety as well as CV efficacy of investigational drugs. In conclusion, aleglitazar was started as a promising drug in patients with CVD and metabolic abnormalities including hyperglycemia and dyslipidemia. However, adverse effects in 2 trials and absence of CV benefit in one have extinguished hope that aleglitazar will be a useful treatment in patients with either diabetes or prediabetes. Coupled with the earlier failure of several other dual PPARα/γ activators including tesaglitazar and muraglitazar, this class of drug now holds very little promise of clinical utility.
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Table VI. Safety reporting and selected events of interest safety analysis population⁎ Placebo (n = 997) Total no. of deaths AE leading to permanent study drug discontinuation Selected events of interest † Peripheral edema Congestive HF Abnormal kidney function‡ Muscular events§ Hepatobiliary events║ Fractures¶ Malignancy# Hypoglycemia⁎⁎ GI hemorrhage
Aleglitazar (n = 999)
4 (0.4%) 25 (2.5%)
2 (0.2%) 39 (3.9%)
17 (1.7%) 4 (0.4%) 5 (0.5%) 3 (0.3%) 5 (0.5%) 5 (0.5%) 0 39 (3.9%) 1 (0.1%)
29 (2.9%) 4 (0.4%) 8 (0.8) 12 (1.2%) 0 2 (0.2%) 2 (0.2%) 69 (6.9%) 5 (0.5%)
A. Selected events of interest† safety analysis population⁎ T2D on aleglitazar (n = 796) Peripheral edema Congestive HF Abnormal kidney function‡ Muscular events§ Hepatobiliary events║ Fractures¶ Malignancy# Hypoglycemia⁎⁎ GI hemorrhage
23 4 8 9 0 1 2 67 5
Pre-T2D on aleglitazar (n = 203) 6 0 0 3 0 1 0 2 0
Placebo (n = 997) 17 4 5 3 5 5 0 39 1
Abbreviation: HF, heart failure. • signs or symptoms of hypoglycemia with prompt resolution with food intake, subcutaneous glucagon, or intravenous glucose as reported by the patient and/or • blood glucose levels ≤50 mg/dL (2.8 mmol/L), regardless of the presence of hypoglycemic signs or symptoms. ⁎ Selected events of interest were collected on dedicated CRFs except for peripheral edema and GI bleeding. Selected events of interest were assessed using predefined baskets of terms. † Number of patients with ≥1 AE. ‡ AEs of abnormal kidney function such as renal impairment or failure were reported on dedicated renal eCRF. § Myalgia, muscle tenderness or weakness, myositis, myopathy, or rhabdomyolysis was reported on the dedicated muscular eCRF. ║ Any adverse event of hepatocellular or cholestatic damage, including cholecystitis and cholelithiasis, had to be reported on the dedicated hepatic eCRF. ¶ Fractures were reported on the dedicated fracture eCRF. # Any adverse event of malignancy had to be reported on a dedicated malignancy eCRF. ⁎⁎ Hypoglycemic episodes were defined by the following:
References 1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1-S45. 2. Abramson JD, Rosenberg HG, Jewell N, et al. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123-8. 3. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800-11. 4. Henry RR, Lincoff AM, Mudaliar S, et al. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009;374:126-35. 5. Lincoff AM, Tardif JC, Neal B, et al. Evaluation of the dual peroxisome proliferator–activated receptor α/γ agonist aleglitazar to reduce cardiovascular events in patients with acute coronary syndrome and type 2 diabetes mellitus: rationale and design of the AleCardio trial. Am Heart J 2013;166:429-34.
6. Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus the AleCardio randomized clinical trial. JAMA 2014;311(15):1515-25. 7. Sanwald-Ducray P, Liogier D'ardhuy X, Jamois C, et al. Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from a randomized, placebo-controlled clinical study. Clin Pharmacol Ther 2010;88:197-203. 8. Nissen SE, Kathy Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71. 9. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89. 10. Erdmann E, Charbonnel B, Wilcox RG, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease. Diabetes Care 2007;30:2773-8.
Effects of the dual peroxisome proliferator– activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes Erland Erdmann, MD, a Robert Califf, MD, b Hertzel C. Gerstein, MD, c Klas Malmberg, MD, d,e Luis Ruilope, MD, f Gregory G. Schwartz, MD, g Hans Wedel, MD, h Dietmar Volz, MD, e Marc Ditmarsch, MD, i Anders Svensson, MD, e and Monica Bengus, MD e Cologne, Germany; Durham, NC; Ontario, Canada; Stockholm, Frolunda, Mölndal, Sweden; Basel, Switzerland; Madrid, Spain; and Denver, CO
Background Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator–activated receptor α/γ agonist with favorable insulinsensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to b6.5%) with previous CV complications. Study design
ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar.
Results At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P b .0001), and muscular events (3 vs12; P = .012). Conclusions Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator–activated receptor α/γ activators, this class now holds little promise for CV therapeutics. (Am Heart J 2015;170:117-22.)
From the aHerzzentrum der Universität zu Köln, Cologne, Germany, bDepartment of Medicine, Duke University, Durham, NC, cDepartment of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, d Department of Medicine, Karolinska Institutet, Stockholm, Sweden, eF Hoffmann–La Roche Ltd, Basel, Switzerland, fUnidad de Hipertensión, Hospital 12 de Octubre, Madrid, Spain, gUniversity of Colorado School of Medicine, Denver, CO, hNordic School of Public Health, Frolunda, Sweden, and i Former, F Hoffmann–La Roche Ltd; Current, Astra Zeneca, Mölndal, Sweden. Guest Editor: Deepak L Bhatt, MD, MPH. Funding/support: The trial was sponsored by F Hoffmann–La Roche (Basel, Switzerland). Role of the sponsor: F Hoffmann–La Roche participated in the design of the trial and protocol in collaboration with the academic members of the executive steering committee. Furthermore, F Hoffmann–La Roche developed and maintained the trial database and was responsible for data collection. Conflict of interest: The members of the academic executive steering committee (Erland Erdmann, Robert Califf, Hertzel Gerstein, Luis Ruilope, Gregory Schwartz, and Hans Wedel) received travel grants and compensation for working in the committee from F Hoffmann–La Roche. Submitted December 12, 2014; accepted March 31, 2015. Reprint requests: Erland Erdmann, MD, Herzzentrum der Universität zu Köln, Cologne, D-50933, Germany. 0002-8703 © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2015.03.021
The treatment of metabolic disorders such as hypercholesterolemia, prediabetes, and diabetes should result in a decreased cardiovascular (CV) risk. Therefore, most guidelines advocate the liberal prescription of statins even in persons without obvious symptoms but high lowdensity lipoprotein (LDL) cholesterol and low highdensity lipoprotein cholesterol (HDL-C) levels. 1,2 With the possible exception of metformin and pioglitazone, glucose-lowering drugs have not decreased macrovascular morbidity and CV mortality. Nevertheless, elevated glycosylated hemoglobin (HbA1c), even in the prediabetic range, is associated with CV disease (CVD) and mortality. 3 Aleglitazar in a phase II, randomized dose-ranging study (SYNCHRONY) significantly reduced HbA1c in a dosedependent manner without many cases of hypoglycemia. It also decreased triglycerides and augmented HDL-C. 4 Therefore, phase III trials were initiated to investigate the effects of aleglitazar on CV events in patients with metabolic disease. The ALEPREVENT trial was initiated to evaluate the potential of aleglitazar, on top of standard of care, to reduce CV morbidity and mortality in patients
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Table I. Exclusion criteria 1. 2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12. 13. 14. 15 16. 17. 18 19. 20.
Current treatment with a thiazolidinedione or fibrate Prior intolerance to a thiazolidinedione or fibrate Previous participation in a trial with aleglitazar Other types of diabetes (eg, type 1 diabetes, diabetes resulting from pancreatic injury, or diabetes associated with acromegaly or Cushing syndrome) Triglycerides (fasting) N500 mg/dL (N5.7 mmol/L) HbA1c N10.0% Liver disease characterized by ○ALT or AST N3× ULN confirmed on 2 consecutive measurements or ○Impaired excretory function (eg, hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices or ○Acute viral or active autoimmune, alcoholic, or other types of hepatitis Anemia defined as hemoglobin b10 g/dL (b100 g/L, b6.21 mmol/L) or hematocrit b30% eGFR (MDRD) b45 mL/min per 1.73 m 2 Symptomatic congestive heart failure classified as NYHA class II-IV Hospitalization for a primary diagnosis of heart failure in the 12-month period preceding the randomization Peripheral edema, which in the judgment of the investigator, is believed to be clinically severe and of cardiac origin History of surgical coronary revascularization (CABG) b5 years before screening, except in cases of subsequent MI Currently scheduled for arterial revascularization (coronary, carotid, or peripheral) procedures Systemic corticosteroid therapy for N2 wk, within 3 m before screening Any serious medical condition with a life expectancy shorter than 5 years or which, in the judgment of the investigator would preclude participation in the trial or could interfere with the conduct of the study Diagnosed or treated malignancy (except for treated cases of basal cell skin cancer, in situ carcinoma of the cervix, or in situ prostate cancer) within the past 5 years Uninvestigated hematuria present during screening period Women with a positive pregnancy test, breast feeding, or of childbearing potential not using medically approved, highly effective methods of contraception Participation in any clinical trial with an investigational drug or device or in any clinical trial requiring interventions (eg, blood sampling) within 1 m before screening
Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal; eGFR, estimated Glomerular Filtration Rate; NYHA, New York Heart Association; CABG, coronary artery bypass graft; MI, myocardial infarction.
with documented stable CVD and T2D and/or prediabetes. The trial was stopped prematurely when the independent data safety monitoring board for another aleglitazar trial (ALECARDIO; NCT01042769) 5,6 recommended early termination of that trial for unfavorable benefit-risk balance.
Methods Description and design ALEPREVENT was a randomized, double-blind, placebocontrolled, parallel group, multicenter study in patients with evidence of stable CVD and glucose abnormalities as markers of residual risk (EUDRACT no. 2012-000671-16). Qualifying patients were either age ≥40 years with evidence of a prior CV event (prior myocardial infarction or prior ischemic stroke confirmed by a brain imaging study) or age ≥55 years with stable CVD (coronary heart disease, cerebrovascular disease, or peripheral arterial disease). In addition, all patients also had to have either T2D (ie, previously known or newly diagnosed according to 2010 American Diabetes Association criteria; treatment could include diet alone or any approved glucose-lowering therapies except for Thiazolidindiones) or prediabetes (5.7% ≤ HbA1c b 6.5% in the
absence of diabetic treatment). Exclusion criteria are listed in Table I. All participants were managed according to the best judgment of their treating physicians and the best clinical evidence for patients with stable CVD, CV risk factors, and cardiometabolic abnormalities. After a screening period of up to 4 weeks to assess eligibility, patients were randomly assigned in 1:1 ratio to treatment with aleglitazar 150 μg daily or matching placebo. Follow-up visits were scheduled 1, 3, and 6 months after randomization and every 6 months thereafter until completion of the trial. Of a planned enrollment of 19,000 patients, 1,999 had been randomized when the trial was stopped prematurely. The primary efficacy objective for this study was to determine whether the addition of aleglitazar versus placebo will reduce a composite outcome of CV death, nonfatal myocardial infarction, or nonfatal stroke in patients with stable CVD and glucose abnormalities. The secondary efficacy objectives for this study were to further explore the potential of aleglitazar to reduce CV morbidity and all-cause mortality and to delay the onset of T2D. Other efficacy objectives for this study were to determine the effects of aleglitazar on other macrovascular and microvascular outcomes, glycemic control, lipid parameters, and other CV risk factors.
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Table II. Baseline demographics of prediabetic patients
A. Male (n, %) Age (y) Body weight (kg, SD) Body mass index (kg/m 2) Waist/hip ratio Systolic blood pressure (mm Hg), mean (SD) Diastolic blood pressure (mm Hg), mean (SD)
Placebo (n = 212)
Aleglitazar (0.15 mg) (n = 203)
151 (71.2) 66.6 ± 8.4 87.3 ± 18.2 30.4 ± 4.9 0.961 ± 0.076 133.4 ± 16.0
148 (72.9) 66.7 ± 7.7 85.5 ± 16.7 30.0 ± 4.9 0.961 ± 0.075 132 ± 17.9
76.9 ± 9.9
75.9 ± 10.3
B. Baseline HbA1c and eGFR MDRD category in prediabetic patients HbA1c category (n, %) b5.7 30 (14.2) 31 (15.3) 5.7 to b6.5 178 (84.0) 166 (81.8) 6.5 to b8.5 4 (1.9) 6 (3.0) eGFR MDRD category (mL/min per 1.73 m2)(n, %) N90 27 (12.7) 23 (11.3) 60 to b90 139 (65.6) 144 (70.9) 45 to b60 42 (19.8) 31 (15.3) 30 to b45 4 (1.9) 5 (2.5)
The safety objectives for this study were to further evaluate the safety and tolerability of aleglitazar with specific focus on events relevant to the PPARα and γ agonists. The following events were considered safety events of interest: • Heart failure (incidence and time to occurrence) • Abnormal kidney function AEs and kidney laboratory abnormalities • Muscular AEs and creatine phosphokinase elevations • Hepatic AEs and liver laboratory abnormalities • Bone fractures • Malignancies Statistical methods. The planned study was event- and time driven and was to continue until approximately 1,260 positively adjudicated primary CV end points occurred in the overall population and approximately 630 CV events in the subgroup of patients without evidence of T2D at baseline. Under the following assumptions: • A risk reduction of 20% (a constant hazard ratio of 0.80); • Statistical significance defined as a 2-sided α of .05 for a log-rank test. The planned study had 97% power if it continued until 1,260 primary clinical event committee adjudicated events occurred in the combined treatment groups. With the expected event count of 630 events in the subgroup of
Table III. Baseline demographics of T2D patients
A. Male (n, %) Age (y) Body weight (kg, SD) Body mass index (kg/m 2) Waist/hip ratio Systolic blood pressure (mm Hg), mean (SD) Diastolic blood pressure (mm Hg), mean (SD)
Placebo (n = 785)
Aleglitazar (0.15 mg) (n = 796)
565 (72.0) 65.8 ± 8.2 88.8 ± 18.5 31.1 ± 5.5 0.984 ± 0.111 134.7 ± 16.4
607 (76.3) 65.8 ± 8.5 88.7 ± 18.0 30.8 ± 5.2 0.983 ± 0.082 134.1 ± 16.4
76.3 ± 9.4
76.0 ± 9.7
B. Baseline HbA1c and eGFR MDRD category in T2D patients HbA1c category (%) b5.7 33 (4.7) 30 (4.2) 5.7 to b6.5 228 (32.6) 220 (30.7) 6.5 to b8.5 422 (60.4) 452 (63.0) 8.5 to b10 10 (1.4) 11 (1.5) N10 6 (0.9) 4 (0.6) eGFR MDRD category (mL/min per 1.73 m2)(%) N90 160 (20.4) 145 (18.2) 60 to b90 442 (56.3) 461 (57.9) 45 to b60 133 (16.9) 156 (19.6) 30 to b45 49 (6.2) 31 (3.9) b30 1 (0.1) 3 (0.4)
patients without evidence of T2D at baseline; it was anticipated to show a favorable effect of aleglitazar versus placebo with approximately 80% power. All patients were to be followed up for ≥3 years. The analyses of baseline data as well as laboratory data and safety signals were based on the safety population, that is, the subset of randomized patients who received ≥1 dose of study medication. Because of premature termination of the study by the sponsor, CV end points were not adjudicated by the clinical event committee, and the planned statistical analysis of efficacy end points was not performed. All analyses provided in this article are descriptive in nature. As the number of collected primary end point events is much lower than the originally anticipated 1,260 events from the protocol, also no formal hypothesis testing based on the primary end point was performed. Where not otherwise specified, proposed figures show means and SDs. The software used to do the calculations was SAS version 9.2. In collaboration with the investigators, the sponsor of the trial contributed to the design of the study, collection of data, statistical analysis, and interpretation and reporting of the results. As defined by the protocol, all CV events were assessed by an independent adjudication
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Table IV. Baseline concomitant medications Prediabetes (n = 415) Blood glucose-lowering drugs (%) Biguanides (%) Sulfonylureas (%) Dipeptidy-peptidase-4 inhibitors (%) Glucagon-like peptide-1 receptor agonists (%) Statins (%) Cholesterol absorption inhibitors (%) ARB, ACE, and other RAAS inhibitors (%) β-blockers (%) Calcium-channel blockers (%) Diuretics (%) Nitrates (%) Vitamin K antagonists (%) ASS (%) Other platelet aggregation inhibitors (%)
1 1 – – – 90 8 72 70 28 30 10 7 80 19
T2D (n = 1581) 80 72 31 13 2 86 9 83 69 35 40 8 6 74 31
Abbreviations: ARB, angiotensin-receptor-blocker; ACE, Angiotensin-converting enzyme; ASS, acetylsalicylic acid = aspinrin.
committee. This report was prepared by the authors, with contributions from the sponsor. The authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors are solely responsible for drafting and editing of the paper and its final contents.
Results The ALEPREVENT trial was started in January 2013 and stopped on July 10, 2013, when 1,999 patients had been randomized. At study end, data had been collected from 1,581 with T2D and 415 with pre-T2D. The mean duration of treatment with aleglitazar 150 μg or placebo was 58 ± 38 days (range 1-234 days). Tables II and III show the baseline demographics of the patients with prediabetes and T2D. Ten patients in the prediabetes group with HbA1c values above 6.5% were misclassified by investigators (4 in the placebo and 6 in the aleglitazar group). Glycosylated hemoglobin was 7.09 ± 1.07 % in the subgroup with T2D and 5.93 ± 0.27 % in the subgroup with prediabetes. Fasting insulin levels were 16.58 with T2D and 9.87 μU/mL in prediabetes. Homeostasis Model Assessment index was 6.03 in T2D and 2.63 μU/mL*mg/dL in prediabetes (Tables II, III, and V). Sixty-six percent of patients had prior myocardial infarction and/or ischemic stroke. In this respect, there were no significant differences between prediabetic and T2D patients. Table IV shows the baseline concomitant medications reflecting utilization of antihypertensive drugs, antiplatelet agents, and statins in a large majority of the patients. Blood pressure and LDL cholesterol levels were well controlled. Aleglitazar lowered HbA1c by 0.31% even during this short treatment time in T2D and raised HDL-C as expected by 12.8% in T2D and by 16% in pre-T2D (Table V).
Aleglitazar lowered triglycerides by 24.3% in T2D and by 20.5% in prediabetes. Low-density lipoprotein cholesterol and total cholesterol were more or less unchanged during this short period of treatment. Aleglitazar caused a reversible increase of serum creatinine (Table V) from 1.01 ± 0.24 (n = 999) to 1.11 ± 0.28 (end of treatment; n = 663) and back to 1.03 ± 0.25 (end of follow-up; n = 839), whereas the placebo group experienced no change of serum creatinine. Similar changes occurred with creatinine clearance (Modification of Diet in Renal Disease formula [MDRD]; mL/min per 1.73 m 2 ; ±SD): from 73.4 ± 18 at baseline (n = 999) to 66.8 ± 18 (end of treatment; n = 663) to 71.9 ± 18 (end of follow-up; n = 839) without changes in the placebo group (Table V).
Safety There were 4 deaths in the placebo and 2 deaths in the aleglitazar group. One patient on aleglitazar committed suicide on day 38 of treatment, the other one died on day 35 of treatment during elective percutaneous coronary intervention. Three patients in the placebo group died after study end; the fourth one died from sepsis on day 62 of placebo treatment. Hypoglycemia (signs or symptoms with prompt resolution with food intake, subcutaneous glucagon, or intravenous glucose, as reported by the patient and/or blood glucose levels ≤50 mg/dL [2.8 mmol/L], regardless of the presence of hypoglycemic signs or symptoms) was more often recorded in patients on aleglitazar (6.9 % vs 3.9%; P b .0001). Muscular events (myalgia, muscle tenderness or weakness, myositis, or myopathy) (1.2 % vs 0.3 %; P = .012) occurred also more frequently in the aleglitazar group. The investigators more often found peripheral edema (2.9 % vs 1.7 %; P = .087) but not a higher incidence of congestive heart failure (Table VI).
Discussion In 2 previous dose finding studies, aleglitazar treatment caused significant, dose-dependent improvements in HbA1c concentrations and fasting plasma glucose compared with placebo, along with favorable effects on blood lipids, suggesting favorable multifactorial risk factor modification. 4,7 The 150-μg dose provided glycemic effects similar to the 45-mg pioglitazone reference group but without apparent heart failure episodes. 4 The ALEPREVENT study was started as a phase III investigation to evaluate the potential of aleglitazar, on top of standard of care, to reduce CV morbidity and mortality in patients with documented stable CVD and either T2D or prediabetes. However, the study was halted with enrolment of far fewer than the intended 19,000 subjects when the data safety and monitoring board became aware of the absence of CV benefit along with serious safety concerns in another aleglitazar trial (ALECARDIO). 5,6 Most of the safety concerns in the ALECARDIO trial
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Table V. Changes during treatment from baseline T2D on aleglitazar (n = 796)
Baseline
End of treatment
Pre-T2D on aleglitazar (n = 203)
Baseline
End of treatment
Placebo (n = 997)
Baseline
End of treatment
Body weight (kg, SD) 88.65 (18.019) 89.46 (18.585) 85.46 (16.742) 86.14 (17.697) 88.49 (18.456) 88.64 (18.304) Systolic blood pressure (mm Hg), 134.1 (16.36) 131.2 (16.24) 132.5 (17.91) 131.8 (17.00) 134.4 (16.31) 132.2 (16.67) mean (SD) Diastolic blood pressure (mm Hg), 76.0 (9.73) 73.8 (9.99) 75.9 (10.32) 74.0 (9.89) 76.4 (9.54) 75.3 (10.00) mean (SD) HbA1c (%) mean (SD) 7.11 (1.064) 6.80 (0.998) 5.93 (0.278) 5.89 (0.270) 6.82 (1.006) 6.87 (1.089) Insulin fasting (μU/mL) mean (SD) 16.58 (21.297) 11.80 (14.411) 9.87 (6.733) 8.09 (6.474) 15.55 (17.671) 17.92 (19.891) HOMA IR (μU/mL*mg/dL), mean 6.03 (8.796) 3.66 (4.700) 2.63 (2.008) 2.00 (1.776) 5.38 (6.828) 6.42 (8.351) Serum creatinine (mg/dL), mean 1.01 (0.246) 1.11 (0.276) 1.00 (0.213) 1.09 (0.271) 1.00 (0.249) 0.99 (0.259) eGFR MDRD (mL/min per 1.73 m 2), 73.77 (18.811) 66.57 (17.975) 72.12 (14.745) 67.6 (16.765) 74.21 (19.343) 75.41 (20.258) mean (SD) eGFR CKD-EPI 75.23 (17.383) 65.78 (18.368) 74.38 (14.624) 69.78 (16.648) 75.46 (17.470) 76.55 (17.872) (mL/min per 1.73 m 2) mean (SD) LDL-C (mg/dL), mean (SD) 77.62 (33.808) 80.28 (32.503) 84.51 (31.901) 85.00 (31.153) 81.19 (34.178) 77.01 (33.085) HDL-C (mg/dL), mean (SD) 47.74 (13.448) 53.88 (14.380) 50.28 (12.197) 58.31 (13.947) 48.1 (12.617) 47.85 (12.477) Triglycerides (mg/dL), mean (SD) 155.52 (128.158) 117.72 (69.016) 134.35 (60.991) 106.89 (48.754) 152.69 (83.475) 163.19 (102.011) Total cholesterol (mg/dL), mean (SD) 155.47 (40.751) 157.50 (38.744) 161.42 (36.626) 164.64 (32.808) 159.4 (40.280) 156.59 (38.883) Abbreviation: LDL-C, LDL cholesterol. Visits are time windowed. Includes all available central and local laboratory data with preference given to central laboratory data within a time window. Baseline is the last available assessment up to and including the first day of study drug intake. End of treatment is the last available assessment up until day 1 after the day of last dose of study drug intake.
(edema/heart failure and fractures) could have been expected for a PPARγ agonist, as they had been recorded in other trials with thiazolidinedione drugs. 8-10 However, several smaller trials with aleglitazar with short duration had not revealed these complications. 4,7 Although the ALEPREVENT trial was stopped after an exposure to study medication of just 58 ± 38 days, there were nonetheless indicators of metabolic actions and safety concerns. There was an excess of hypoglycemia and muscular events and numerically more reports of edema and gastrointestinal (GI) hemorrhage. These findings mirrored those in the larger ALECARDIO trial and thus increase the likelihood that they are caused by aleglitazar. The negative results of this well-planned trial with a promising drug, aleglitazar, raise important issues for future development of metabolic agents intended to influence CV outcomes. In light of previous studies that suggested pioglitazone may reduce macrovascular complications, 9,10 the effect of aleglitazar on lipid profiles observed in SYNCHRONY 4 had raised hope that an agent with balanced PPARα and PPARγ agonism might favorably and safely influence CV end points. As with other trials in the past, we had to learn, however, that surrogate parameters in CV medicine, that is, a better metabolic profile, may not automatically result in a better clinical outcome— particularly if previously underrated side effects of the investigational drug become apparent. The serious side
effects of aleglitazar seen in our trial were not recorded in preceding phase II trials with 71 or 332 patients, respectively. 4,7 In fact, the most frequently reported adverse events in the SYNCHRONY trial 7 were peripheral edema, nasopharyngitis, slightly increased blood creatine phosphokinase, and upper respiratory tract infection, all of which were rated as mild and not significantly different between groups treated with aleglitazar 150 μg daily or placebo. The results of the present investigation sound a familiar cautionary note that favorable effects on laboratory measurements of metabolic status in phase II studies with small sample size and short duration may not translate into clinical efficacy and safety in phase III evaluation. This lesson has to be kept in mind for future drug trials. In the end, large-scale phase III studies often remain necessary to provide definitive evidence of safety as well as CV efficacy of investigational drugs. In conclusion, aleglitazar was started as a promising drug in patients with CVD and metabolic abnormalities including hyperglycemia and dyslipidemia. However, adverse effects in 2 trials and absence of CV benefit in one have extinguished hope that aleglitazar will be a useful treatment in patients with either diabetes or prediabetes. Coupled with the earlier failure of several other dual PPARα/γ activators including tesaglitazar and muraglitazar, this class of drug now holds very little promise of clinical utility.
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Table VI. Safety reporting and selected events of interest safety analysis population⁎ Placebo (n = 997) Total no. of deaths AE leading to permanent study drug discontinuation Selected events of interest † Peripheral edema Congestive HF Abnormal kidney function‡ Muscular events§ Hepatobiliary events║ Fractures¶ Malignancy# Hypoglycemia⁎⁎ GI hemorrhage
Aleglitazar (n = 999)
4 (0.4%) 25 (2.5%)
2 (0.2%) 39 (3.9%)
17 (1.7%) 4 (0.4%) 5 (0.5%) 3 (0.3%) 5 (0.5%) 5 (0.5%) 0 39 (3.9%) 1 (0.1%)
29 (2.9%) 4 (0.4%) 8 (0.8) 12 (1.2%) 0 2 (0.2%) 2 (0.2%) 69 (6.9%) 5 (0.5%)
A. Selected events of interest† safety analysis population⁎ T2D on aleglitazar (n = 796) Peripheral edema Congestive HF Abnormal kidney function‡ Muscular events§ Hepatobiliary events║ Fractures¶ Malignancy# Hypoglycemia⁎⁎ GI hemorrhage
23 4 8 9 0 1 2 67 5
Pre-T2D on aleglitazar (n = 203) 6 0 0 3 0 1 0 2 0
Placebo (n = 997) 17 4 5 3 5 5 0 39 1
Abbreviation: HF, heart failure. • signs or symptoms of hypoglycemia with prompt resolution with food intake, subcutaneous glucagon, or intravenous glucose as reported by the patient and/or • blood glucose levels ≤50 mg/dL (2.8 mmol/L), regardless of the presence of hypoglycemic signs or symptoms. ⁎ Selected events of interest were collected on dedicated CRFs except for peripheral edema and GI bleeding. Selected events of interest were assessed using predefined baskets of terms. † Number of patients with ≥1 AE. ‡ AEs of abnormal kidney function such as renal impairment or failure were reported on dedicated renal eCRF. § Myalgia, muscle tenderness or weakness, myositis, myopathy, or rhabdomyolysis was reported on the dedicated muscular eCRF. ║ Any adverse event of hepatocellular or cholestatic damage, including cholecystitis and cholelithiasis, had to be reported on the dedicated hepatic eCRF. ¶ Fractures were reported on the dedicated fracture eCRF. # Any adverse event of malignancy had to be reported on a dedicated malignancy eCRF. ⁎⁎ Hypoglycemic episodes were defined by the following:
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6. Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus the AleCardio randomized clinical trial. JAMA 2014;311(15):1515-25. 7. Sanwald-Ducray P, Liogier D'ardhuy X, Jamois C, et al. Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from a randomized, placebo-controlled clinical study. Clin Pharmacol Ther 2010;88:197-203. 8. Nissen SE, Kathy Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71. 9. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89. 10. Erdmann E, Charbonnel B, Wilcox RG, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease. Diabetes Care 2007;30:2773-8.
