Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies

Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from... Diabetes Ther (2018) 9:1317–1334 https://doi.org/10.1007/s13300-018-0439-8 ORIGINAL RESEARCH Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies . . . Henry N. Ginsberg Michel Farnier Jennifer G. Robinson . . . Christopher P. Cannon Naveed Sattar Marie T. Baccara-Dinet . . . Alexia Letierce Maja Bujas-Bobanovic Michael J. Louie Helen M. Colhoun Received: March 28, 2018 / Published online: May 19, 2018 The Author(s) 2018 75 mg every 2 weeks (Q2W) was increased to ABSTRACT 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was C 70 mg/ Introduction: Diabetes mellitus (DM) carries an dL; two studies used alirocumab 150 mg Q2W elevated risk for cardiovascular disease. Here, we throughout. The primary endpoint was per- assessed alirocumab efficacy and safety in peo- centage change in LDL-C from baseline to week ple with/without DM from five placebo-con- trolled phase 3 studies. Results: In the alirocumab 150 mg pool Methods: Data from up to 78 weeks were ana- (n = 2416), baseline LDL-C levels were lyzed in individuals on maximally tolerated 117.4 mg/dL (DM) and 130.6 mg/dL (without background statin. In three studies, alirocumab DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C Enhanced digital features To view enhanced digital reductions from baseline were observed in per- features for this article go to https://doi.org/10.6084/ m9.figshare.6210182. sons with DM (- 59.9%; placebo, - 1.4%) and without DM (- 60.6%; placebo, ? 1.5%); 77.7% Electronic supplementary material The online (DM) and 76.8% (without DM) of subjects version of this article (https://doi.org/10.1007/s13300- achieved LDL-C \ 70 mg/dL. In the alirocumab 018-0439-8) contains supplementary material, which is available to authorized users. 75/150 mg group, 26% (DM) and 36% (without M. T. Baccara-Dinet H. N. Ginsberg (&) Sanofi, Montpellier, France Columbia University, New York, NY, USA e-mail: hng1@cumc.columbia.edu A. Letierce Sanofi, Chilly-Mazarin, France M. Farnier Point Medical and Department of Cardiology, CHU M. Bujas-Bobanovic Dijon-Bourgogne, Dijon, France Sanofi, Paris, France J. G. Robinson M. J. Louie University of Iowa, Iowa City, IA, USA Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA C. P. Cannon Harvard Clinical Research Institute, Boston, MA, H. M. Colhoun USA University of Edinburgh, Edinburgh, UK N. Sattar University of Glasgow, Glasgow, UK 1318 Diabetes Ther (2018) 9:1317–1334 DM) of subjects received dose increase. In this reactions with alirocumab treatment. Similar group, week 24 LDL-C levels changed from rates of adverse reactions were reported in the baseline by - 43.8% (DM; placebo, ? 0.3%) and corresponding placebo groups with diabetes - 49.7% (without DM; placebo, ? 5.1%); LDL- (82%) and without diabetes (81%). Regardless of C \ 70 mg/dL was achieved by 68.3% and diabetes status, the most common adverse 65.8% of individuals, respectively. At week 24, reactions among alirocumab-treated people alirocumab was also associated with improved were common cold, chest infection, and injec- levels of other lipids. Adverse event rates were tion-site reaction. generally comparable in all groups In summary, alirocumab provides an addi- (79.8–82.0%). tional treatment option for people with and Conclusions: Regardless of DM status, alir- without diabetes who do not to reach their ocumab significantly reduced LDL-C levels; cholesterol goals, even with maximally toler- safety was generally similar. ated statin dose. Funding: Sanofi and Regeneron Pharmaceuti- cals, Inc. INTRODUCTION Plain Language Summary: Plain language summary available for this article. Cardiovascular disease (CVD) is the most common cause of death in persons with dia- Keywords: Alirocumab; Cholesterol-lowering betes mellitus (DM) [1, 2]. Individuals with DM drugs; Diabetes mellitus; LDL-C; PCSK9 are, on average, at double the risk of atherosclerotic CVD (ASCVD) in comparison to those without DM, and the presence of dys- PLAIN LANGUAGE SUMMARY lipidemia in people with type 2 DM further increases the risk of adverse cardiovascular High cholesterol puts people at risk of heart outcomes [3, 4]. disease, especially those with diabetes. Physi- The elevated cardiovascular risk associated cians set individualized cholesterol treatment with DM is recognized in guidelines [1, 3, 5, 6], goals for each patient. Statins, prescribed to which recommend more intense management reduce high cholesterol levels, may not lower strategies for low-density lipoprotein choles- cholesterol enough in all people. Alirocumab is terol (LDL-C)-lowering in individuals with DM a medication for lowering cholesterol levels. than for the general population. Statins are Alirocumab is intended for use in combination recommended as first-line therapy to reduce with maximally tolerated statin. Here we LDL-C in DM [1, 5, 7, 8]. However, many people compared the effects of alirocumab to 1054 with DM have persistent lipid abnormalities people with diabetes to 2445 people without despite statin treatment [9, 10]. The 2017 diabetes. updated American College of Cardiology Expert Our study showed that most people with and Consensus Task Force and the 2018 American without diabetes reached the cholesterol goal of Diabetes Association standards of care recom- less than 70 mg per deciliter after 24 weeks of mend that a proprotein convertase subtilisin/ treatment with individualized alirocumab kexin type 9 (PCSK9) inhibitor be considered in doses. Treatment with alirocumab 150 mil- individuals with ASCVD and DM whose LDL-C ligrams every 2 weeks resulted in 78% of people levels are not optimally controlled on high-in- with diabetes and 77% of people without dia- tensity statin therapy [6, 8]. betes reaching this goal. Treatment with alir- The 2017 update of the European Society of ocumab 75 mg every 2 weeks (with some Cardiology/European Atherosclerosis Society individuals getting their dose increased to Task Force also recommends the use of a PCSK9 150 mg) also produced similar results in people inhibitor for two categories of individuals with with diabetes (68%) and without diabetes DM, depending on LDL-C levels: (1) individuals (66%). Eighty percent of people with diabetes with DM and clinical ASCVD whose LDL-C and 80% of people without diabetes had adverse Diabetes Ther (2018) 9:1317–1334 1319 levels are[ 100 mg/dL and (2) individuals with individual studies have been previously repor- DM and familial hypercholesterolemia without ted [16–19]. clinical ASCVD whose LDL-C levels are In summary, all participants, with or without [ 140 mg/dL, despite maximally tolerated sta- DM, had hypercholesterolemia at study entry tin and ezetimibe therapies [11]. and were on maximally tolerated, stable, back- The lipid profile of type 2 DM is character- ground statin therapy with or without other ized by reduced high-density lipoprotein lipid-lowering agents. The FH I and FH II studies cholesterol (HDL-C), high triglycerides, and an recruited participants with heterozygous famil- increase in the proportion of LDL-C particles ial hypercholesterolemia (HeFH) and at either that are small and dense, with or without high very high risk (LDL-C C 70 mg/dL with prior levels of LDL-C [12, 13]. In the ODYSSEY DM- CVD) or high risk (LDL-C C 100 mg/dL but no INSULIN study (NCT02585778), alirocumab prior CVD). The HIGH FH study enrolled indi- 75 mg every 2 weeks (Q2W; with possible dose viduals with HeFH and LDL-C levels C 160 mg/ increase to 150 mg Q2W) significantly reduced dL. The LONG TERM study included partici- LDL-C levels and other lipids in individuals pants who either had HeFH or established with type 1 DM (n = 76) or type 2 DM (n = 441) coronary heart disease (CHD) or CHD risk treated with insulin [14]. Furthermore, in indi- equivalents based on the European Systematic viduals with type 2 DM and mixed dyslipi- Coronary Risk Estimation (SCORE), with base- demia, the same alirocumab dosing regimen line LDL-C C 70 mg/dL. The COMBO I study also resulted in significant reductions in non- included participants with either established HDL-C, LDL-C, and other lipids in ODYSSEY CVD and LDL-C C 70 mg/dL, or CHD risk DM-DYSLIPIDEMIA (NCT02642159) [15]. How- equivalents and LDL-C C 100 mg/dL, based on ever, the efficacy and safety of alirocumab the European SCORE, which included DM with 75 mg Q2W (with possible dose adjustment to other risk factors or chronic kidney disease. 150 mg Q2W) and 150 mg Q2W (without dose All study protocols were approved by the adjustment) have not been compared in a larger appropriate institutional review boards, and all pool of individuals with and without DM trea- participants provided informed, written con- ted for longer duration. This subgroup analysis sent. All trials were performed in accordance of five placebo-controlled phase 3 studies with the ethical principles that have their origin (LONG TERM [NCT01507831] [16], HIGH FH in the Declaration of Helsinki and all applicable [NCT01617655] [17], COMBO I [NCT01644175] amendments laid down by the World Medical [18], FH I [NCT01623115] [19], and FH II Assemblies and the International Conference [NCT01709500] [19]) aimed to compare the Harmonisation Guidelines for Good Clinical efficacy and safety of alirocumab in a large Practice. group of individuals with and without DM at Participants were randomized to alirocumab baseline, with the primary efficacy endpoint or placebo groups in a 2:1 ratio. Two studies being LDL-C reduction from baseline to (LONG TERM and HIGH FH) used an alir- week 24. ocumab dose of 150 mg Q2W throughout the trial period. The other three studies (COMBO I, FH I, and FH II) used an initial alirocumab dose METHODS of 75 mg Q2W, with an increase to 150 mg Q2W at week 12 if the LDL-C level at week 8 Trial Participants and Study Designs remained C 70 mg/dL. All doses were delivered by subcutaneous injection (alirocumab 75 mg, The current analysis used patient-level data alirocumab 150 mg, or placebo) using a 1-mL from study participants according to alir- dose volume. ocumab dosing regimen who enrolled for five Participants were classified as having DM double-blind, randomized, placebo-controlled (type 1 or 2) or not, according to medical his- ODYSSEY phase 3 studies with 52–78 weeks’ tory reported by the investigator. treatment duration. Methods for each of the 1320 Diabetes Ther (2018) 9:1317–1334 Efficacy Analysis Safety Analysis Efficacy was compared in individuals with and Safety data are reported in subgroups of indi- without DM in two pools according to alir- viduals assigned to alirocumab or placebo, ocumab dose regimen (pool of 150 mg Q2W regardless of alirocumab dose, according to studies; pool of 75 mg Q2W with possible baseline DM status. All adverse events, regard- increase to 150 mg Q2W, abbreviated in the text less of seriousness and irrespective of potential relationship to alirocumab, were recorded by to 75/150 mg Q2W). The main efficacy endpoint for this pooled the investigators up to the last visit planned in analysis was the mean percentage change in the protocol. Treatment-emergent adverse calculated LDL-C from baseline to week 24 (the events (TEAEs) were defined as events that primary endpoint of the individual studies). developed, worsened, or became serious Other efficacy endpoints included percentage between the first and last dose of study treat- change in calculated LDL-C from baseline to ment plus 70 days, classified according to the week 12 (prior to potential dose increase in tri- Medical Dictionary for Regulatory Activities. als utilizing the 75/150 mg Q2W dosing regi- Adverse events of special interest included men), proportion of individuals achieving risk- injection-site reactions, general allergic events, based LDL-C goals, and the percentage change neurocognitive disorders, and adjudicated car- in other lipid parameters from baseline to diovascular events. Statistical analysis of the weeks 12 and 24. Mean percentage change in safety population included all randomized LDL-C and other lipid parameters over time is individuals who received at least one dose or also reported up to week 78. part of a dose of study drug, and safety data Changes from baseline for the main LDL-C were analyzed by descriptive statistics. efficacy endpoint and other lipid values were The effect of alirocumab treatment on gly- statistically evaluated with an intention-to-treat cated hemoglobin (HbA1c) and fasting plasma (ITT) approach, which included lipid data from glucose (FPG) was also evaluated according to all randomized persons regardless of adherence DM status throughout the studies using to treatment. The analysis utilized a mixed-ef- descriptive statistics conducted on the safety fect model with repeated measures to account population. for missing data, as previously described [20]. Data on changes over time were presented RESULTS according to ITT analysis, and on-treatment analysis using a modified ITT approach, which Study Participants included only lipid data collected while the individual was receiving study treatment. Other lipid parameters were analyzed either In total, 30.1% of alirocumab-treated individu- als (n = 699) and 30.2% of those receiving pla- in the same way as the main efficacy endpoint or, in the case of lipoprotein (a) [Lp(a)] and cebo (n = 355) were classified as having DM at baseline (n = 1625 and n = 820, respectively, triglyceride (TG) percentage changes, and LDL- were classified as not having diabetes) (Table 1; C goal achievement proportions, analysis involved a multiple imputation approach then Supplementary Fig. 1). In total, 24 persons (0.69%) had type 1 DM and the remainder had robust regression (for Lp(a) and TG percentage changes) or logistic regression (for LDL-C goal type 2 DM. Individuals with DM were generally older and had a higher BMI versus those with- achievement), in the ITT population. Consistency of treatment effect across sub- out DM. Fewer subjects with DM were male, white, or had HeFH compared with subjects groups was assessed by providing interaction p values. A further subgroup analysis was per- without DM (Table 1). Fewer participants with DM had a history of ASCVD (62.5–62.8%) formed to compare alirocumab efficacy in per- sons with and without DM according to HeFH compared with those without DM (72.4–74.6%). Regardless of DM status, all status at week 12 and week 24. Diabetes Ther (2018) 9:1317–1334 1321 Table 1 Baseline demographics, clinical characteristics, and lipid profile in individuals with and without DM (randomized population) Individuals with DM (n = 1054) Individuals without DM (n = 2445) Alirocumab Placebo Alirocumab Placebo (n = 699) (n = 355) (n = 1625) (n = 820) Age, years, mean (SD) 61.7 (9.5) 60.8 (10.2) 57.3 (12.2) 57.9 (11.7) Male, n (%) 405 (57.9) 192 (54.1) 1010 (62.2) 520 (63.4) Race, white, n (%) 581 (83.1) 290 (81.7) 1558 (95.9) 782 (95.4) BMI, kg/m , mean (SD) 32.4 (6.3) 32.9 (6.0) 29.1 (5.0) 29.2 (5.1) ASCVD , n (%) 439 (62.8) 222 (62.5) 1176 (72.4) 612 (74.6) CHD, n (%) 388 (55.5) 193 (54.4) 1066 (65.6) 573 (69.9) ACS, n (%) 247 (35.3) 134 (37.7) 733 (45.1) 394 (48.0) Coronary revascularization 271 (38.8) 133 (37.5) 735 (45.2) 389 (47.4) procedure, n (%) Other clinically significant 145 (20.7) 74 (20.8) 477 (29.4) 248 (30.2) CHD , n (%) Peripheral arterial disease, n (%) 32 (4.6) 23 (6.5) 65 (4.0) 33 (4.0) Ischemic stroke, n (%) 60 (8.6) 26 (7.3) 139 (8.6) 60 (7.3) HeFH, n (%) 85 (12.2) 55 (15.5) 753 (46.3) 364 (44.4) High-intensity statin , n (%) 311 (44.5) 153 (43.1) 1016 (62.5) 529 (64.5) With HeFH 63 (74.1) 42 (76.4) 600 (79.7) 294 (80.8) Without HeFH 248 (40.4) 111 (37.0) 416 (47.7) 235 (51.5) With ASCVD 213 (48.5) 115 (51.8) 697 (59.3) 377 (61.6) Without ASCVD 98 (37.7) 38 (28.6) 319 (71.0) 152 (73.1) Baseline lipids, mean (SD), mg/dL Calculated LDL-C 116.5 (37.6) 119.7 (41.2) 131.3 (48.9) 129.8 (45.9) Non-HDL-C 150.0 (42.6) 151.6 (46.7) 158.1 (52.1) 157.2 (49.2) Apo B 101.6 (26.4) 101.1 (28.0) 105.4 (30.0) 105.2 (28.7) Lp(a), median (Q1, Q3) 21.1 (6.0, 58.0) 19.0 (5.8, 61.6) 26.0 (10.0, 73.0) 24.9 (7.5, 71.8) Fasting TGs, median (Q1, Q3) 147.0 (108.0, 205.3) 144.0 (105.3, 205.0) 118.0 (85.0, 163.7) 120.7 (88.0, 169.0) 1322 Diabetes Ther (2018) 9:1317–1334 Table 1 continued Individuals with DM (n = 1054) Individuals without DM (n = 2445) Alirocumab Placebo Alirocumab Placebo (n = 699) (n = 355) (n = 1625) (n = 820) HDL-C 47.6 (11.6) 48.1 (12.3) 51.1 (13.8) 50.5 (13.2) ACS acute coronary syndrome, Apo apolipoprotein, ASCVD atherosclerotic cardiovascular disease, BMI body mass index, CHD coronary heart disease, DM diabetes mellitus, HDL-C high-density lipoprotein cholesterol, HeFH heterozygous familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), Q1, Q3 first and third quartiles, SD standard deviation, TG triglyceride Included CHD, peripheral arterial disease, and ischemic stroke; for study FH II, ischemic stroke, transient ischemic attack, carotid endarterectomy, or carotid artery stent procedure and renal artery stent procedure were also included Diagnosed by invasive or non-invasive testing High-intensity statins defined as atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg patients received statin therapy. Baseline high- similar in participants with and without DM intensity statin use was lower among individu- (Fig. 1). Mean week 24 LDL-C levels of 52.3 mg/ als with DM (43.1–44.5%) versus without DM dL were achieved in alirocumab-treated indi- (62.5–64.5%), but was greater in individuals viduals with DM (absolute change from base- with HeFH versus those without (74.1–80.8% vs line, - 73.6 mg/dL) and 50.2 mg/dL in those 37.0–51.5%, respectively). In total, 48.6–61.6% without DM (absolute change from baseline, of individuals with ASCVD and 28.6–73.1% of - 75.7 mg/dL). LDL-C levels \ 70 mg/dL at those without ASCVD received high-intensity week 24 were attained by 77.7% of alirocumab- statin at baseline (Table 1). treated individuals with DM and 76.8% of those Overall, individuals with DM had lower without DM (placebo, 10.3% and 6.4%, respec- baseline Lp(a) and HDL-C levels but higher TG tively) (Table 2). levels than individuals without DM (Table 1). In the same alirocumab 150 mg Q2W group, Among individuals with DM, 27.8% were least-squares mean percentage change from receiving injectable treatments which always baseline to week 12 in LDL-C levels was consisted of insulin (27.8%), sometimes com- - 62.1% in individuals with DM (placebo, bined with a glucagon-like peptide 1 antagonist ? 0.1%) and - 62.9% in individuals without (GLP 1; 3.3%). No individuals were receiving DM (placebo, ? 1.7%) (Supplementary Table 1). GLP 1 antagonist only. At week 12, alirocumab-associated LDL-C changes were similar for patients with or with- out DM in the HeFH subgroup (DM, - 56.2%; Efficacy non-DM, - 57.2%) and the non-HeFH subgroup (DM, - 62.5%; non-DM, - 65.4%) (Supple- LDL-C Outcomes: Pool of Alirocumab 150 mg mentary Tables 2 and 3). LDL-C levels were Q2W Studies (LONG TERM and HIGH FH) maintained through 78 weeks in individuals At week 24 in the full alirocumab 150 mg Q2W with and without DM in the on-treatment cohort, the least-squares mean LDL-C levels population (Fig. 2a). The reductions up to were changed from baseline by - 59.9% (with 78 weeks for the ITT population are presented in DM; placebo, - 1.4%) and - 60.6% (without Supplementary Fig. 2A. DM; placebo, ? 1.5%) (Table 2). Regardless of In the HeFH subjects from the LONG TERM high-intensity statin status, the LDL-C per- and HIGH FH studies, least-squares mean LDL-C centage change from baseline to week 24 was levels changed from baseline to week 24 by Diabetes Ther (2018) 9:1317–1334 1323 Table 2 Change from baseline of lipids and achievement of LDL-C \ 70 mg/dL at week 24 (intention-to-treat population) Alirocumab 150 mg Q2W pool (n = 2416) Alirocumab 75/150 mg Q2W pool (n = 1043) Individuals with DM Individuals without DM Individuals with DM Individuals without DM (n = 836) (n = 1580) (n = 202) (n = 841) Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo (n = 556) (n = 280) (n = 1045) (n = 535) (n = 132) (n = 70) (n = 561) (n = 280) Calculated LDL-C, mg/dL Baseline, mean (SE) 117.4 (1.6) 119.1 (2.4) 130.6 (1.5) 128.7 (2.0) 112.8 (3.6) 119.8 (5.5) 133.0 (2.0) 132.5 (2.7) Calculated LDL-C at week 24, mean 52.3 (1.5) 116.8 (2.1) 50.2 (1.1) 124.4 (1.5) 71.1 (3.5) 122.5 (4.7) 63.1 (1.6) 136.4 (2.2) (SE) a a Percentage change from baseline to - 59.9 (1.2) - 1.4 (1.7) - 60.6 (0.9) 1.5 (1.3) - 43.8 (2.5) 0.3 (3.4) - 49.7 (1.6) 5.1 (1.6) week 24, LS mean (SE) Percentage difference vs placebo - 58.5 (2.1) - 62.1 (1.5) - 44.0 (4.1) - 54.8 (2.0) Interaction p value 0.1600 0.0201 Percentage of persons achieving LDL- 77.7 10.3 76.8 6.4 68.3 5.9 65.8 2.8 C \ 70 mg/dL at week 24 Interaction p value 0.0188 0.2525 Other lipids, mg/dL Apo B, baseline, mean (SE) 101.7 (1.1) 100.6 (1.7) 104.2 (1.0) 104.4 (1.3) 99.5 (2.5) 100.4 (3.4) 107.6 (1.3) 107.3 (1.6) Percentage change from baseline to - 49.6 (1.1) 1.1 (1.6) - 53.5 (0.8) 0.6 (1.2) - 34.4 (2.0) - 0.3 (2.6) - 41.6 (0.9) 1.3 (1.2) week 24, LS mean (SE) Percentage difference vs placebo - 50.7 (2.0) - 54.1 (1.4) - 34.0 (3.2) - 42.9 (1.5) Interaction p value 0.1608 0.0121 Lp(a), baseline, mean (SE) 34.9 (1.8) 34.9 (2.3) 48.4 (1.6) 46.1 (2.2) 61.2 (6.3) 54.7 (6.9) 48.4 (2.2) 47.5 (3.2) Percentage change from baseline to - 28.5 (1.2) - 2.0 (1.8) - 29.3 (0.9) - 5.1 (1.2) - 18.1 (2.4) - 7.6 (3.2) - 26.5 (1.1) - 7.7 (1.5) week 24, adjusted mean (SE) Percentage difference vs placebo - 26.5 (2.1) - 24.2 (1.5) - 10.5 (4.0) - 18.8 (1.9) Interaction p value 0.3861 0.0581 1324 Diabetes Ther (2018) 9:1317–1334 Table 2 continued Alirocumab 150 mg Q2W pool (n = 2416) Alirocumab 75/150 mg Q2W pool (n = 1043) Individuals with DM Individuals without DM Individuals with DM Individuals without DM (n = 836) (n = 1580) (n = 202) (n = 841) Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo (n = 556) (n = 280) (n = 1045) (n = 535) (n = 132) (n = 70) (n = 561) (n = 280) Non-HDL-C, baseline, mean (SE) 151.4 (1.8) 151.3 (2.7) 158.1 (1.6) 157.5 (2.2) 143.2 (3.8) 149.5 (5.9) 158.6 (2.2) 156.9 (2.8) Percentage change from baseline to - 49.1 (1.1) - 0.3 (1.5) - 52.2 (0.8) 0.8 (1.1) - 36.0 (2.3) 2.6 (3.1) - 43.0 (1.1) 5.2 (1.5) week 24, LS mean (SE) Percentage difference vs placebo - 48.8 (1.8) - 53.0 (1.3) - 38.7 (3.7) - 48.2 (1.8) Interaction p value 0.0603 0.0218 TGs, baseline, mean (SE) 172.1 (4.3) 163.5 (4.9) 137.8 (2.2) 144.7 (3.3) 155.5 (8.6) 148.7 (8.0) 129.0 (3.0) 122.9 (3.6) Percentage change from baseline to - 12.2 (1.4) 6.3 (2.0) - 16.8 (1.0) - 0.6 (1.4) - 7.7 (2.7) 2.4 (3.6) - 9.1 (1.2) 1.2 (1.7) week 24, adjusted mean (SE) Percentage difference vs placebo - 18.5 (2.4) - 16.2 (1.7) - 10.1 (4.3) - 10.3 (2.1) Interaction p value 0.4319 0.9659 HDL-C, baseline, mean (SE) 48.3 (0.5) 48.6 (0.7) 50.7 (0.4) 50.4 (0.5) 44.5 (1.1) 45.9 (1.4) 51.9 (0.7) 50.7 (0.9) Percentage change from baseline to 2.3 (0.6) - 1.0 (0.9) 5.1 (0.5) - 0.1 (0.6) 5.3 (1.4) - 2.4 (1.9) 6.9 (0.7) - 0.7 (0.9) week 24, LS mean (SE) Percentage difference vs placebo 3.3 (1.1) 5.1 (0.8) 7.6 (2.3) 7.5 (1.1) Interaction p value 0.1680 0.9692 Apo apolipoprotein, DM diabetes mellitus, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), LS least- squares, Q2W every 2 weeks, SE standard error, TG triglyceride At week 12, 26.2% of subjects with DM and 36.4% of those without DM received dose increase of 75 mg Q2W to 150 mg Q2W Diabetes Ther (2018) 9:1317–1334 1325 Fig. 1 Percentage change from baseline in calculated CI confidence interval, DM diabetes mellitus, LDL-C low- LDL-C at week 24—subgroup analysis by DM status density lipoprotein cholesterol, LS least-squares, SE stan- and statin intensity at baseline (intention-to-treat popu- dard error lation). High-intensity statin defined as atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg. - 53.1% (with DM; placebo, ? 0.1%) and (placebo, ? 7.0%) and - 46.0% in those with- - 55.3% (without DM; placebo, ? 1.5%) (Sup- out DM (placebo, ? 3.4%) in the alirocumab plementary Table 4). In subjects without HeFH, 75/150 mg Q2W treatment pool (Supplemen- the least-squares mean LDL-C changes from tary Table 1). When the HeFH and non-HeFH baseline to week 24 were - 60.3% in subjects subjects in this cohort were examined sepa- with DM (placebo, - 1.4%) and - 62.9% in rately, similar percentage reductions from those without DM (placebo, ? 1.6%) (Supple- baseline to week 12 were observed in alir- mentary Table 5). ocumab-treated groups, except for a less pro- nounced change in LDL-C levels in individuals with DM in the HeFH subgroup (- 34.9%; pla- LDL-C Outcomes: Pool of Alirocumab cebo, ? 3.6%) (Supplementary Tables 2 and 3). 75/150 mg Q2W Studies (FH I, FH II, The protocol for the three studies starting and COMBO I) with the alirocumab 75 mg Q2W dose specified At week 24 in the full 75/150 mg Q2W cohort, a blinded dose increase from 75 mg to 150 mg least-squares mean percentage change from Q2W at week 12 (if week 8 LDL-C levels were baseline in LDL-C level was - 43.8% (with DM; C 70 mg/dL); 26.2% of individuals with DM placebo, ? 0.3%) and - 49.7% (without DM; received a dose increase to 150 mg Q2W, as did placebo, ? 5.1%) (Table 2). Mean week 24 LDL- 36.4% of those without DM. In subjects C levels of 71.1 mg/dL were achieved in alir- remaining on 75 mg Q2W, the baseline LDL-C ocumab-treated individuals with DM (absolute levels were lower in those with DM (99.5 mg/ change from baseline, - 58.3 mg/dL) and dL) versus subjects without DM (117.9 mg/dL; 63.1 mg/dL in those without DM (absolute interaction p value \ 0.0001). In subjects change from baseline, - 66.3 mg/dL). Subgroup receiving alirocumab dose increase to 150 mg analysis with and without high-intensity statin Q2W, the baseline LDL-C levels were 149.7 mg/ demonstrated similar LDL-C reductions at dL (DM) and 159.4 mg/dL (without DM). week 24, regardless of DM status (Fig. 1). LDL-C reductions were maintained with At week 12 in this cohort (i.e., before possi- alirocumab 75/150 mg Q2W until end of study ble dose increase), least-squares mean percent- treatment, regardless of DM status, in the on- age change from baseline to week 12 in LDL-C treatment population (Fig. 2a). Similar LDL-C levels was - 38.0% in persons with DM 1326 Diabetes Ther (2018) 9:1317–1334 Diabetes Ther (2018) 9:1317–1334 1327 bFig. 2 Percentage change from baseline over time for (placebo, ? 2.7%) and - 48.4% in those with- a LDL-C, b Apo B, c Lp(a), d non-HDL-C, e TGs, and out DM (placebo, ? 7.6%) (Supplementary f HDL-C according to DM status for the alirocumab Table 4). In the non-HeFH subgroup, 16.5% of 150 mg Q2W and 75/150 mg Q2W treatment pools persons with DM and 17.0% of those without (modified intention-to-treat population). Apo apolipopro- DM received dose adjustment at week 12. In tein, DM diabetes mellitus, HDL-C high-density lipopro- this same group, the week 24 least-squares mean tein cholesterol, LDL-C low-density lipoprotein LDL-C levels changed from baseline by - 42.2% cholesterol, Lp(a) lipoprotein (a), LS least-squares, Q2W in persons with DM (placebo, - 2.6%) and every 2 weeks, SE standard error, TG triglyceride - 53.2% in those without DM in the subgroup (placebo, - 2.0%) (Supplementary Table 5). reductions were observed in the ITT population Other Lipid Parameters (Supplementary Fig. 2a). From baseline to week 24, alirocumab treatment At week 24, LDL-C \ 70 mg/dL was attained was associated with reduced levels of by 68.3% of individuals in the alirocumab apolipoprotein (Apo) B, Lp(a), non-HDL-C, and group with DM and 65.8% without DM (pla- TGs, and increased levels of HDL-C (Table 2). In cebo, 5.9% and 2.8%, respectively) (Table 2). the alirocumab 150 mg Q2W pool, no differ- In the HeFH subgroup, the proportion of ences between subjects with and without DM individuals requiring dose increase from alir- were observed (Table 2). In the alirocumab ocumab 75 mg to 150 mg Q2W was 48.7% (DM) 75/150 mg Q2W pool, lower percentage chan- and 41.2% (without DM). At week 24, least- ges in Apo B and non-HDL-C were observed in squares mean percentage changes in LDL-C participants with DM versus those without (in- level were - 52.3% in persons with DM teraction P values \ 0.05) (Table 2). The Fig. 2 continued 1328 Diabetes Ther (2018) 9:1317–1334 percentage changes in TG and HDL-C levels with DM and 13.0% (n = 211) of those without were similar regardless of DM status. DM, and upper respiratory tract infection, From baseline to week 12, alirocumab dosing reported in 7.9% (n = 55) and 6.6% (n = 107), regimens of 150 mg Q2W and 75/150 mg Q2W respectively. Among alirocumab-treated indi- were associated with improved levels of Apo B, viduals, 3.7% (n = 26) of those with DM and Lp(a), non-HDL-C, TGs, and HDL-C in subjects 8.7% (n = 141) of individuals without DM with or without DM (Supplementary Table 1). reported injection-site reactions (Table 3). In persons with and without HeFH, similar Overall, 20.3% (alirocumab) and 23.9% (pla- alirocumab efficacy was observed at week 12, cebo) of subjects in the DM group and 15.0% regardless of DM status and alirocumab dosing (alirocumab) and 14.3% (placebo) of those regimen, except for lower Apo B and non-HDL- without DM experienced treatment-emergent C levels in individuals with HeFH in the alir- serious adverse events. Discontinuation rates ocumab 75/150 mg group with DM (interaction were 5.6% (alirocumab) and 8.0% (placebo) in p value \ 0.05 between persons with DM and individuals with DM, and 5.4% (alirocumab) those without) (Supplementary Tables 2 and 3). and 5.7% (placebo) in those without DM Reduced levels of other lipids were observed (Table 3). Occurrence of adverse events of spe- from week 4 and maintained for up to 78 weeks cial interest in alirocumab-treated individuals in individuals with and without DM in the on- was generally similar regardless of DM status treatment population (Fig. 2b–f). The lipid (Table 3). Overall, the median exposure to ran- levels for the ITT population were similar domized treatment was 78 weeks in both the (Supplementary Fig. 2B–F). In the HeFH group, alirocumab and control groups, regardless of improvements in other lipids from baseline to DM status. Mean HbA1c and FPG levels week 24 were seen in individuals with DM and remained unchanged in both groups through- without, regardless of alirocumab dosing (Sup- out the treatment period regardless of DM status plementary Table 4). No differences between (Supplementary Table 6). subjects with and without DM were observed in the non-HeFH group either, except for lower DISCUSSION mean percentage reductions in Apo B levels in subjects with DM in both alirocumab groups Across all studies in the ODYSSEY program, and lower mean percentage reductions in non- individuals with hypercholesterolemia experi- HDL-C levels in subjects with DM in the alir- enced significant LDL-C reductions from base- ocumab 150 mg Q2W pool (interaction line compared with either placebo or ezetimibe p value \ 0.05 between persons with DM and following alirocumab treatment with back- those without; Supplementary Table 5). ground statin therapy (± other lipid-lowering No correlation was found between baseline therapies) [16–19]. Similar reductions were seen HbA1c levels and LDL-C reductions in alir- with alirocumab treatment in individuals with ocumab-treated individuals with DM at week 24 or without DM, and were maintained for up to (Supplementary Fig. 3). 78 weeks. In the present analysis, alirocumab 150 mg Safety Analysis Q2W resulted in 58.5% and 62.1% reductions in LDL-C levels versus placebo at week 24 with no Overall, the incidence of TEAEs was similar significant difference being observed between between groups, occurring in 79.9% with DM those with and those without DM, respectively. and 79.8% without DM in alirocumab-treated Furthermore, LDL-C levels of \ 70 mg/dL were individuals versus 82.0% and 81.0% in the pla- achieved by the majority of persons receiving cebo groups, respectively (Table 3). The most this dose regardless of DM status (76.9–77.7%), common TEAEs occurring in C 5% of individ- with mean achieved LDL-C levels of uals treated with alirocumab were nasopharyn- 50.2–52.3 mg/dL, regardless of DM status. gitis, reported in 11.5% (n = 80) of individuals Diabetes Ther (2018) 9:1317–1334 1329 Table 3 Adverse events in persons with and without DM (safety population) n (%) DM (n = 1051) No DM (n = 2441) Alirocumab Placebo Alirocumab Placebo (n = 696) (n = 355) (n = 1622) (n = 819) TEAEs 556 (79.9) 291 (82.0) 1295 (79.8) 663 (81.0) Treatment-emergent SAEs 141 (20.3) 85 (23.9) 244 (15.0) 117 (14.3) TEAEs leading to 56 (8.0) 20 (5.6) 88 (5.4) 47 (5.7) discontinuation TEAEs leading to death 7 (1.0) 5 (1.4) 9 (0.6) 8 (1.0) Adverse events of special interest HLT: injection site reactions 26 (3.7) 10 (2.8) 141 (8.7) 52 (6.3) General allergic TEAE 63 (9.1) 28 (7.9) 163 (10.0) 77 (9.4) (CMQ) Neurocognitive disorders 9 (1.3) 6 (1.7) 12 (0.7) 3 (0.4) Adjudicated cardiovascular 37 (5.3) 27 (7.6) 57 (3.5) 19 (2.3) events ALT [ 3 9 ULN, n/N (%) 11/689 (1.6) 14/349 (4.0) 34/1610 (2.1) 7/815 (0.9) TEAEs occurring in C 5% of persons Nasopharyngitis 80 (11.5) 35 (9.9) 211 (13.0) 107 (13.1) Upper respiratory infection 55 (7.9) 36 (10.1) 107 (6.6) 58 (7.1) Injection-site reaction 26 (3.7) 10 (2.8) 141 (8.7) 52 (6.3) Bronchitis 33 (4.7) 27 (7.6) 79 (4.9) 31 (3.8) Urinary tract infection 49 (7.0) 26 (7.3) 79 (4.9) 39 (4.8) Arthralgia 27 (3.9) 26 (7.3) 91 (5.6) 50 (6.1) Influenza 39 (5.6) 19 (5.4) 108 (6.7) 44 (5.4) Back pain 33 (4.7) 17 (4.8) 90 (5.5) 53 (6.5) Headache 29 (4.2) 16 (4.5) 90 (5.5) 48 (5.9) Diarrhea 33 (4.7) 17 (4.8) 90 (5.5) 40 (4.9) Myalgia 21 (3.0) 11 (3.1) 90 (5.5) 35 (4.3) ALT alanine aminotransferase, CMQ custom MedDRA query, DM diabetes mellitus, HLT high-level term, MedDRA Medical Dictionary of Regulatory Activities, SAE serious adverse event, TEAE treatment-emergent adverse event, ULN upper limit of normal In the pool of studies where per-protocol were changed by - 43.8% (individuals with dose increase from 75 mg to 150 mg Q2W DM) and - 49.7% (individuals without DM) in occurred if LDL-C goals were not reached at the alirocumab groups (placebo, ? 0.3% and week 8, the week 24 LDL-C levels from baseline ? 5.1%, respectively), with these changes being 1330 Diabetes Ther (2018) 9:1317–1334 consistent regardless of DM status. Possibly as a Fewer injection-site reactions were reported result of the higher LDL-C levels at baseline, in individuals with DM, a difference that may in alirocumab dose was increased at week 12 in a part be due to a greater familiarity and tolerance higher proportion of subjects without DM, associated with glucometer and/or which was associated with a greater magnitude injectable medication use in the DM population of LDL-C reduction at week 24 in that group (27.8% and 72.2% of persons with DM were (absolute LDL-C change, - 66.3 mg/dL) versus receiving antihyperglycemic injectable and the DM group (absolute LDL-C change, non-injectable medication at baseline, respec- - 58.3 mg/dL); however, similar LDL-C levels tively). However, as previously reported, (63.1–71.1 mg/dL) were achieved in both administration by injection does not deter per- groups. In the subgroup without HeFH, the sons from self-administration of alirocumab percentage of individuals requiring dose [23]. The ODYSSEY OUTCOMES study increase was similar regardless of DM status. (NCT01663402) will help to further establish if Therefore, this analysis indicates that the higher DM status has an influence on the frequency of proportion of individuals in the subgroup injection-site reactions [24]. without DM who received alirocumab dose Mean HbA1c and FPG measurements in increase versus the subgroup with DM could be individuals with DM were comparable between explained by more individuals with HeFH with alirocumab and placebo for up to 78 weeks of higher baseline LDL-C being included in the treatment. These variables were comparable subgroup without DM. between alirocumab and placebo in individuals At baseline, the differences in prevalence of without DM, as previously reported [25]. On the HeFH, ASCVD, and high-intensity statin use, basis of these results, alirocumab treatment does and baseline LDL-C levels between individuals not appear to affect blood glucose, which is very with and without DM may reflect discrepancies reassuring given that statins modestly raise the in selection criteria between the studies inclu- risk of DM [26], and recent genetic publications ded in the analysis. Furthermore, consistent have suggested that the PCSK9 pathway might with previous studies [21, 22], fewer individuals be relevant to glycemia levels [27, 28]. In a with HeFH had DM (12.2–15.5%) compared subgroup analysis of 11,031 individuals with with those without HeFH (44.4–46.3%). Possi- DM in FOURIER (median follow-up, 2.2 years), bly as a result of this imbalance, fewer individ- neither HbA1c nor incidence of DM was uals in the cohort with DM had a history of increased in the evolocumab groups versus the ASCVD and received high-intensity statin placebo groups [29]. In contrast, a recent meta- compared with the cohort without DM. The analysis of phase 2/3 randomized PCSK9 inhi- lower rate of high-intensity statin use in indi- bitor clinical studies (excluding FOURIER) sug- viduals with DM indicates that this high-risk gested that PCSK9-mediated lowering of LDL-C population is undertreated. does increase risk for DM [30]. Taking all of Overall, alirocumab treatment was generally these publications into consideration, it is not well tolerated with no particular differences yet clear whether LDL-C reduction per se or the observed in incidence of TEAEs, serious adverse means of attaining lower LDL-C levels influence effects, or deaths compared with placebo in DM risk. In the ODYSSEY and FOURIER studies, individuals with or without DM. Overall, mean most individuals received statin therapy, which exposure to randomized treatment was similar may mask the glycemic effect of PCSK9 inhibi- (78 weeks) in individuals with or without DM tors [29, 31]. The results of ODYSSEY OUT- regardless of treatment status. This analysis does COMES will provide key additional data not allow for conclusive safety observations to relevant to this important issue. be made, in particular for rare adverse events Overall efficacy and safety findings from such as adjudicated cardiovascular events. As a these placebo-controlled studies were consistent consequence, safety results should be consid- with findings from studies comparing alir- ered in the context of the overall ODYSSEY ocumab with ezetimibe and employing back- program. ground statin therapy [32, 33]. A recently Diabetes Ther (2018) 9:1317–1334 1331 and Desmond Thompson; Sanofi: Corinne published study of the efficacy and safety of Hanotin, Michael Howard, L. Veronica Lee, alirocumab in individuals with type 2 DM and Guillaume Lecorps, Laurence Merlet, Christelle mixed dyslipidemia (defined as non-HDL- Lorenzato, and Jonas Mandel. C C 100 mg/dL; TGs C 150 mg/dL and \ 500 mg/dL) showed similar responses for non-HDL-C (37.7% reduction) and TGs (13.0% Funding. This analysis as well as journal reduction) at week 24 compared to the larger article processing charges were funded by Sanofi group of individuals with type 1 and 2 DM in and Regeneron Pharmaceuticals, Inc. The the present analysis [15]. In the DM-INSULIN sponsor was involved in the study design, col- phase 3b study, alirocumab demonstrated simi- lection, analysis, and interpretation of data, as lar results in reducing LDL-C and other lipids in well as data checking of information provided insulin-treated type 1 DM and type 2 DM indi- in the manuscript. The authors had unrestricted viduals [14]; all individuals were at high car- access to data, were responsible for all content diovascular risk and received maximally and editorial decisions, and received no hono- tolerated statin therapy. raria related to the development of this This analysis was limited by the non-ran- publication. domized nature of DM status in subgroups, which could introduce bias to the analyses. Medical Writing and Editorial Assis- Nevertheless, this placebo-controlled analysis of tance. Medical writing support was provided by up to 78 weeks adds to the body of evidence on Susanne Ulm, PhD, and Rachel Wright, PhD, of PCSK9 inhibitor use in people with DM [34]. Prime (Knutsford, UK), funded by Sanofi and Regeneron Pharmaceuticals Inc. according to Good Publication Practice guidelines. CONCLUSION Authorship. All named authors meet the On the basis of these data from placebo-con- International Committee of Medical Journal trolled phase 3 studies, DM status does not Editors (ICMJE) criteria for authorship for this appear to meaningfully affect lipid-modifying article, take responsibility for the integrity of efficacy or safety of alirocumab treatment, nor the work as a whole, and have given their does alirocumab appear to significantly affect approval for this version to be published. blood glucose control in individuals with or without DM. The results presented here provide Author Contributions. Henry N. Ginsberg, support for the recent recommendation by the Michel Farnier, and Jennifer G. Robinson con- American Diabetes Association that PCSK9 tributed to study design or concept, data inhibitor therapy may be considered for indi- acquisition, analysis and interpretation of the viduals with DM and ASCVD [8]. The ODYSSEY data, and critically reviewed and edited the OUTCOMES study is expected to provide an manuscript. Christopher P. Cannon, Marie T. opportunity to evaluate the effect of alirocumab Baccara-Dinet, Maja Bujas-Bobanovic, Michael in a larger sample of individuals with DM [24]. J. Louie, and Helen M. Colhoun contributed to study design or concept, analysis and interpre- tation of the data, and critically reviewed and edited the manuscript. Naveed Sattar and Alexia ACKNOWLEDGEMENTS Letierce contributed to analysis and interpreta- tion of data, and critically reviewed and edited The authors would like to thank study individ- the manuscript. uals and investigators, and the following per- sons from sponsors for their contributions to Disclosures. Henry N. Ginsberg has received data collection and analysis, assistance with other research support from Genzyme (Sanofi), statistical analysis, or critical review of the Merck, Sanofi, Regeneron Pharmaceuticals Inc., manuscript: Regeneron Pharmaceuticals Inc.: and Amgen; and is a consultant and on the Eva-Lynne Greene, Carol Hudson, Rita Samuel, 1332 Diabetes Ther (2018) 9:1317–1334 advisory board for Amarin, Amgen, AstraZe- Boehringer Ingelheim, and AstraZeneca LP, and neca, Bristol Myers Squibb, GlaxoSmithKline, shareholding in Bayer and Roche. IONIS, Janssen, Kowa, Merck, Novartis, Sanofi, Compliance with Ethics Guidelines. All Regeneron Pharmaceuticals, Inc., and Pfizer. study protocols were approved by the appro- Michel Farnier has received research support priate institutional review boards, and all par- from and participated in a speakers’ bureau for ticipants provided informed, written consent. Amgen, Merck, and Sanofi; received honoraria All trials were performed in accordance with the from Abbott/Mylan, Akcea/Ionis, Eli Lilly, and ethical principles that have their origin in the Pfizer; and acted as a consultant/advisory panel Declaration of Helsinki and all applicable member for Amgen, AstraZeneca, Roche, Kowa, amendments laid down by the World Medical Merck, Pfizer, Sanofi, and Servier. Jennifer G. Assemblies and the International Conference Robinson has received research grants from Harmonisation guidelines for Good Clinical Amarin, Amgen, AstraZeneca, Daiichi-Sankyo, Practice. Eli Lilly, Esai, Genentech/F. Hoffman La Roche, GlaxoSmith Kline, Merck, Pfizer, Regeneron Open Access. This article is distributed Pharmaceuticals, Inc./Sanofi, and Zinfandel/ under the terms of the Creative Commons Takeda; and is a consultant and on the advisory Attribution-NonCommercial 4.0 International board for Akcea/Ionis, Amgen, Eli Lilly, F. License (http://creativecommons.org/licenses/ Hoffman LaRoche, Merck, Pfizer, and Sanofi/ by-nc/4.0/), which permits any noncommercial Regeneron Pharmaceuticals, Inc. Christopher P. use, distribution, and reproduction in any Cannon has received research grants from Acc- medium, provided you give appropriate credit umetrics, Arisaph, AstraZeneca, Boehringer to the original author(s) and the source, provide Ingelheim, GlaxoSmithKline, Janssen, Merck, a link to the Creative Commons license, and Takeda, Amgen, BMS, American College of indicate if changes were made. Cardiology, and Sanofi/Regeneron Pharmaceu- ticals, Inc; and is a consultant and on the advisory board for Boehringer Ingelheim CSL Behring, Essentialis, GlaxoSmithKline, Merck, REFERENCES Kowa, Takeda, BMS, Pfizer, Sanofi, Regeneron Pharmaceuticals, Inc., and Lipimedix. Alexia 1. Catapano AL, Graham I, De Backer G, et al. 2016 Letierce is an employee and a stockholder of ESC/EAS guidelines for the management of dyslip- Sanofi. 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Efficacy and diabetes, and bodyweight: evidence from genetic safety of alirocumab in high cardiovascular risk analysis and randomised trials. Lancet. patients with inadequately controlled hyperc- 2015;385(9965):351–61. holesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized con- 27. Ference BA, Robinson JG, Brook RD, et al. Variation trolled trial. Eur Heart J. 2015;36(19):1186–94. in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 33. Bays H, Gaudet D, Weiss R, et al. Alirocumab as add- 2016;375(22):2144–53. on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. 28. Lotta LA, Sharp SJ, Burgess S, et al. Association J Clin Endocrinol Metab. 2015;100(8):3140–8. between low-density lipoprotein cholesterol-lower- ing genetic variants and risk of type 2 diabetes: a 34. Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering meta-analysis. JAMA. 2016;316(13):1383–91. efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-anal- 29. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardio- ysis of individual patient data. Lancet Diabetes vascular safety and efficacy of the PCSK9 inhibitor Endocrinol. 2016;4(5):403–10. evolocumab in patients with and without diabetes http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetes Therapy Springer Journals

Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies

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Copyright © 2018 by The Author(s)
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Medicine & Public Health; Internal Medicine; Diabetes; Cardiology; Endocrinology
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Abstract

Diabetes Ther (2018) 9:1317–1334 https://doi.org/10.1007/s13300-018-0439-8 ORIGINAL RESEARCH Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies . . . Henry N. Ginsberg Michel Farnier Jennifer G. Robinson . . . Christopher P. Cannon Naveed Sattar Marie T. Baccara-Dinet . . . Alexia Letierce Maja Bujas-Bobanovic Michael J. Louie Helen M. Colhoun Received: March 28, 2018 / Published online: May 19, 2018 The Author(s) 2018 75 mg every 2 weeks (Q2W) was increased to ABSTRACT 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was C 70 mg/ Introduction: Diabetes mellitus (DM) carries an dL; two studies used alirocumab 150 mg Q2W elevated risk for cardiovascular disease. Here, we throughout. The primary endpoint was per- assessed alirocumab efficacy and safety in peo- centage change in LDL-C from baseline to week ple with/without DM from five placebo-con- trolled phase 3 studies. Results: In the alirocumab 150 mg pool Methods: Data from up to 78 weeks were ana- (n = 2416), baseline LDL-C levels were lyzed in individuals on maximally tolerated 117.4 mg/dL (DM) and 130.6 mg/dL (without background statin. In three studies, alirocumab DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C Enhanced digital features To view enhanced digital reductions from baseline were observed in per- features for this article go to https://doi.org/10.6084/ m9.figshare.6210182. sons with DM (- 59.9%; placebo, - 1.4%) and without DM (- 60.6%; placebo, ? 1.5%); 77.7% Electronic supplementary material The online (DM) and 76.8% (without DM) of subjects version of this article (https://doi.org/10.1007/s13300- achieved LDL-C \ 70 mg/dL. In the alirocumab 018-0439-8) contains supplementary material, which is available to authorized users. 75/150 mg group, 26% (DM) and 36% (without M. T. Baccara-Dinet H. N. Ginsberg (&) Sanofi, Montpellier, France Columbia University, New York, NY, USA e-mail: hng1@cumc.columbia.edu A. Letierce Sanofi, Chilly-Mazarin, France M. Farnier Point Medical and Department of Cardiology, CHU M. Bujas-Bobanovic Dijon-Bourgogne, Dijon, France Sanofi, Paris, France J. G. Robinson M. J. Louie University of Iowa, Iowa City, IA, USA Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA C. P. Cannon Harvard Clinical Research Institute, Boston, MA, H. M. Colhoun USA University of Edinburgh, Edinburgh, UK N. Sattar University of Glasgow, Glasgow, UK 1318 Diabetes Ther (2018) 9:1317–1334 DM) of subjects received dose increase. In this reactions with alirocumab treatment. Similar group, week 24 LDL-C levels changed from rates of adverse reactions were reported in the baseline by - 43.8% (DM; placebo, ? 0.3%) and corresponding placebo groups with diabetes - 49.7% (without DM; placebo, ? 5.1%); LDL- (82%) and without diabetes (81%). Regardless of C \ 70 mg/dL was achieved by 68.3% and diabetes status, the most common adverse 65.8% of individuals, respectively. At week 24, reactions among alirocumab-treated people alirocumab was also associated with improved were common cold, chest infection, and injec- levels of other lipids. Adverse event rates were tion-site reaction. generally comparable in all groups In summary, alirocumab provides an addi- (79.8–82.0%). tional treatment option for people with and Conclusions: Regardless of DM status, alir- without diabetes who do not to reach their ocumab significantly reduced LDL-C levels; cholesterol goals, even with maximally toler- safety was generally similar. ated statin dose. Funding: Sanofi and Regeneron Pharmaceuti- cals, Inc. INTRODUCTION Plain Language Summary: Plain language summary available for this article. Cardiovascular disease (CVD) is the most common cause of death in persons with dia- Keywords: Alirocumab; Cholesterol-lowering betes mellitus (DM) [1, 2]. Individuals with DM drugs; Diabetes mellitus; LDL-C; PCSK9 are, on average, at double the risk of atherosclerotic CVD (ASCVD) in comparison to those without DM, and the presence of dys- PLAIN LANGUAGE SUMMARY lipidemia in people with type 2 DM further increases the risk of adverse cardiovascular High cholesterol puts people at risk of heart outcomes [3, 4]. disease, especially those with diabetes. Physi- The elevated cardiovascular risk associated cians set individualized cholesterol treatment with DM is recognized in guidelines [1, 3, 5, 6], goals for each patient. Statins, prescribed to which recommend more intense management reduce high cholesterol levels, may not lower strategies for low-density lipoprotein choles- cholesterol enough in all people. Alirocumab is terol (LDL-C)-lowering in individuals with DM a medication for lowering cholesterol levels. than for the general population. Statins are Alirocumab is intended for use in combination recommended as first-line therapy to reduce with maximally tolerated statin. Here we LDL-C in DM [1, 5, 7, 8]. However, many people compared the effects of alirocumab to 1054 with DM have persistent lipid abnormalities people with diabetes to 2445 people without despite statin treatment [9, 10]. The 2017 diabetes. updated American College of Cardiology Expert Our study showed that most people with and Consensus Task Force and the 2018 American without diabetes reached the cholesterol goal of Diabetes Association standards of care recom- less than 70 mg per deciliter after 24 weeks of mend that a proprotein convertase subtilisin/ treatment with individualized alirocumab kexin type 9 (PCSK9) inhibitor be considered in doses. Treatment with alirocumab 150 mil- individuals with ASCVD and DM whose LDL-C ligrams every 2 weeks resulted in 78% of people levels are not optimally controlled on high-in- with diabetes and 77% of people without dia- tensity statin therapy [6, 8]. betes reaching this goal. Treatment with alir- The 2017 update of the European Society of ocumab 75 mg every 2 weeks (with some Cardiology/European Atherosclerosis Society individuals getting their dose increased to Task Force also recommends the use of a PCSK9 150 mg) also produced similar results in people inhibitor for two categories of individuals with with diabetes (68%) and without diabetes DM, depending on LDL-C levels: (1) individuals (66%). Eighty percent of people with diabetes with DM and clinical ASCVD whose LDL-C and 80% of people without diabetes had adverse Diabetes Ther (2018) 9:1317–1334 1319 levels are[ 100 mg/dL and (2) individuals with individual studies have been previously repor- DM and familial hypercholesterolemia without ted [16–19]. clinical ASCVD whose LDL-C levels are In summary, all participants, with or without [ 140 mg/dL, despite maximally tolerated sta- DM, had hypercholesterolemia at study entry tin and ezetimibe therapies [11]. and were on maximally tolerated, stable, back- The lipid profile of type 2 DM is character- ground statin therapy with or without other ized by reduced high-density lipoprotein lipid-lowering agents. The FH I and FH II studies cholesterol (HDL-C), high triglycerides, and an recruited participants with heterozygous famil- increase in the proportion of LDL-C particles ial hypercholesterolemia (HeFH) and at either that are small and dense, with or without high very high risk (LDL-C C 70 mg/dL with prior levels of LDL-C [12, 13]. In the ODYSSEY DM- CVD) or high risk (LDL-C C 100 mg/dL but no INSULIN study (NCT02585778), alirocumab prior CVD). The HIGH FH study enrolled indi- 75 mg every 2 weeks (Q2W; with possible dose viduals with HeFH and LDL-C levels C 160 mg/ increase to 150 mg Q2W) significantly reduced dL. The LONG TERM study included partici- LDL-C levels and other lipids in individuals pants who either had HeFH or established with type 1 DM (n = 76) or type 2 DM (n = 441) coronary heart disease (CHD) or CHD risk treated with insulin [14]. Furthermore, in indi- equivalents based on the European Systematic viduals with type 2 DM and mixed dyslipi- Coronary Risk Estimation (SCORE), with base- demia, the same alirocumab dosing regimen line LDL-C C 70 mg/dL. The COMBO I study also resulted in significant reductions in non- included participants with either established HDL-C, LDL-C, and other lipids in ODYSSEY CVD and LDL-C C 70 mg/dL, or CHD risk DM-DYSLIPIDEMIA (NCT02642159) [15]. How- equivalents and LDL-C C 100 mg/dL, based on ever, the efficacy and safety of alirocumab the European SCORE, which included DM with 75 mg Q2W (with possible dose adjustment to other risk factors or chronic kidney disease. 150 mg Q2W) and 150 mg Q2W (without dose All study protocols were approved by the adjustment) have not been compared in a larger appropriate institutional review boards, and all pool of individuals with and without DM trea- participants provided informed, written con- ted for longer duration. This subgroup analysis sent. All trials were performed in accordance of five placebo-controlled phase 3 studies with the ethical principles that have their origin (LONG TERM [NCT01507831] [16], HIGH FH in the Declaration of Helsinki and all applicable [NCT01617655] [17], COMBO I [NCT01644175] amendments laid down by the World Medical [18], FH I [NCT01623115] [19], and FH II Assemblies and the International Conference [NCT01709500] [19]) aimed to compare the Harmonisation Guidelines for Good Clinical efficacy and safety of alirocumab in a large Practice. group of individuals with and without DM at Participants were randomized to alirocumab baseline, with the primary efficacy endpoint or placebo groups in a 2:1 ratio. Two studies being LDL-C reduction from baseline to (LONG TERM and HIGH FH) used an alir- week 24. ocumab dose of 150 mg Q2W throughout the trial period. The other three studies (COMBO I, FH I, and FH II) used an initial alirocumab dose METHODS of 75 mg Q2W, with an increase to 150 mg Q2W at week 12 if the LDL-C level at week 8 Trial Participants and Study Designs remained C 70 mg/dL. All doses were delivered by subcutaneous injection (alirocumab 75 mg, The current analysis used patient-level data alirocumab 150 mg, or placebo) using a 1-mL from study participants according to alir- dose volume. ocumab dosing regimen who enrolled for five Participants were classified as having DM double-blind, randomized, placebo-controlled (type 1 or 2) or not, according to medical his- ODYSSEY phase 3 studies with 52–78 weeks’ tory reported by the investigator. treatment duration. Methods for each of the 1320 Diabetes Ther (2018) 9:1317–1334 Efficacy Analysis Safety Analysis Efficacy was compared in individuals with and Safety data are reported in subgroups of indi- without DM in two pools according to alir- viduals assigned to alirocumab or placebo, ocumab dose regimen (pool of 150 mg Q2W regardless of alirocumab dose, according to studies; pool of 75 mg Q2W with possible baseline DM status. All adverse events, regard- increase to 150 mg Q2W, abbreviated in the text less of seriousness and irrespective of potential relationship to alirocumab, were recorded by to 75/150 mg Q2W). The main efficacy endpoint for this pooled the investigators up to the last visit planned in analysis was the mean percentage change in the protocol. Treatment-emergent adverse calculated LDL-C from baseline to week 24 (the events (TEAEs) were defined as events that primary endpoint of the individual studies). developed, worsened, or became serious Other efficacy endpoints included percentage between the first and last dose of study treat- change in calculated LDL-C from baseline to ment plus 70 days, classified according to the week 12 (prior to potential dose increase in tri- Medical Dictionary for Regulatory Activities. als utilizing the 75/150 mg Q2W dosing regi- Adverse events of special interest included men), proportion of individuals achieving risk- injection-site reactions, general allergic events, based LDL-C goals, and the percentage change neurocognitive disorders, and adjudicated car- in other lipid parameters from baseline to diovascular events. Statistical analysis of the weeks 12 and 24. Mean percentage change in safety population included all randomized LDL-C and other lipid parameters over time is individuals who received at least one dose or also reported up to week 78. part of a dose of study drug, and safety data Changes from baseline for the main LDL-C were analyzed by descriptive statistics. efficacy endpoint and other lipid values were The effect of alirocumab treatment on gly- statistically evaluated with an intention-to-treat cated hemoglobin (HbA1c) and fasting plasma (ITT) approach, which included lipid data from glucose (FPG) was also evaluated according to all randomized persons regardless of adherence DM status throughout the studies using to treatment. The analysis utilized a mixed-ef- descriptive statistics conducted on the safety fect model with repeated measures to account population. for missing data, as previously described [20]. Data on changes over time were presented RESULTS according to ITT analysis, and on-treatment analysis using a modified ITT approach, which Study Participants included only lipid data collected while the individual was receiving study treatment. Other lipid parameters were analyzed either In total, 30.1% of alirocumab-treated individu- als (n = 699) and 30.2% of those receiving pla- in the same way as the main efficacy endpoint or, in the case of lipoprotein (a) [Lp(a)] and cebo (n = 355) were classified as having DM at baseline (n = 1625 and n = 820, respectively, triglyceride (TG) percentage changes, and LDL- were classified as not having diabetes) (Table 1; C goal achievement proportions, analysis involved a multiple imputation approach then Supplementary Fig. 1). In total, 24 persons (0.69%) had type 1 DM and the remainder had robust regression (for Lp(a) and TG percentage changes) or logistic regression (for LDL-C goal type 2 DM. Individuals with DM were generally older and had a higher BMI versus those with- achievement), in the ITT population. Consistency of treatment effect across sub- out DM. Fewer subjects with DM were male, white, or had HeFH compared with subjects groups was assessed by providing interaction p values. A further subgroup analysis was per- without DM (Table 1). Fewer participants with DM had a history of ASCVD (62.5–62.8%) formed to compare alirocumab efficacy in per- sons with and without DM according to HeFH compared with those without DM (72.4–74.6%). Regardless of DM status, all status at week 12 and week 24. Diabetes Ther (2018) 9:1317–1334 1321 Table 1 Baseline demographics, clinical characteristics, and lipid profile in individuals with and without DM (randomized population) Individuals with DM (n = 1054) Individuals without DM (n = 2445) Alirocumab Placebo Alirocumab Placebo (n = 699) (n = 355) (n = 1625) (n = 820) Age, years, mean (SD) 61.7 (9.5) 60.8 (10.2) 57.3 (12.2) 57.9 (11.7) Male, n (%) 405 (57.9) 192 (54.1) 1010 (62.2) 520 (63.4) Race, white, n (%) 581 (83.1) 290 (81.7) 1558 (95.9) 782 (95.4) BMI, kg/m , mean (SD) 32.4 (6.3) 32.9 (6.0) 29.1 (5.0) 29.2 (5.1) ASCVD , n (%) 439 (62.8) 222 (62.5) 1176 (72.4) 612 (74.6) CHD, n (%) 388 (55.5) 193 (54.4) 1066 (65.6) 573 (69.9) ACS, n (%) 247 (35.3) 134 (37.7) 733 (45.1) 394 (48.0) Coronary revascularization 271 (38.8) 133 (37.5) 735 (45.2) 389 (47.4) procedure, n (%) Other clinically significant 145 (20.7) 74 (20.8) 477 (29.4) 248 (30.2) CHD , n (%) Peripheral arterial disease, n (%) 32 (4.6) 23 (6.5) 65 (4.0) 33 (4.0) Ischemic stroke, n (%) 60 (8.6) 26 (7.3) 139 (8.6) 60 (7.3) HeFH, n (%) 85 (12.2) 55 (15.5) 753 (46.3) 364 (44.4) High-intensity statin , n (%) 311 (44.5) 153 (43.1) 1016 (62.5) 529 (64.5) With HeFH 63 (74.1) 42 (76.4) 600 (79.7) 294 (80.8) Without HeFH 248 (40.4) 111 (37.0) 416 (47.7) 235 (51.5) With ASCVD 213 (48.5) 115 (51.8) 697 (59.3) 377 (61.6) Without ASCVD 98 (37.7) 38 (28.6) 319 (71.0) 152 (73.1) Baseline lipids, mean (SD), mg/dL Calculated LDL-C 116.5 (37.6) 119.7 (41.2) 131.3 (48.9) 129.8 (45.9) Non-HDL-C 150.0 (42.6) 151.6 (46.7) 158.1 (52.1) 157.2 (49.2) Apo B 101.6 (26.4) 101.1 (28.0) 105.4 (30.0) 105.2 (28.7) Lp(a), median (Q1, Q3) 21.1 (6.0, 58.0) 19.0 (5.8, 61.6) 26.0 (10.0, 73.0) 24.9 (7.5, 71.8) Fasting TGs, median (Q1, Q3) 147.0 (108.0, 205.3) 144.0 (105.3, 205.0) 118.0 (85.0, 163.7) 120.7 (88.0, 169.0) 1322 Diabetes Ther (2018) 9:1317–1334 Table 1 continued Individuals with DM (n = 1054) Individuals without DM (n = 2445) Alirocumab Placebo Alirocumab Placebo (n = 699) (n = 355) (n = 1625) (n = 820) HDL-C 47.6 (11.6) 48.1 (12.3) 51.1 (13.8) 50.5 (13.2) ACS acute coronary syndrome, Apo apolipoprotein, ASCVD atherosclerotic cardiovascular disease, BMI body mass index, CHD coronary heart disease, DM diabetes mellitus, HDL-C high-density lipoprotein cholesterol, HeFH heterozygous familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), Q1, Q3 first and third quartiles, SD standard deviation, TG triglyceride Included CHD, peripheral arterial disease, and ischemic stroke; for study FH II, ischemic stroke, transient ischemic attack, carotid endarterectomy, or carotid artery stent procedure and renal artery stent procedure were also included Diagnosed by invasive or non-invasive testing High-intensity statins defined as atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg patients received statin therapy. Baseline high- similar in participants with and without DM intensity statin use was lower among individu- (Fig. 1). Mean week 24 LDL-C levels of 52.3 mg/ als with DM (43.1–44.5%) versus without DM dL were achieved in alirocumab-treated indi- (62.5–64.5%), but was greater in individuals viduals with DM (absolute change from base- with HeFH versus those without (74.1–80.8% vs line, - 73.6 mg/dL) and 50.2 mg/dL in those 37.0–51.5%, respectively). In total, 48.6–61.6% without DM (absolute change from baseline, of individuals with ASCVD and 28.6–73.1% of - 75.7 mg/dL). LDL-C levels \ 70 mg/dL at those without ASCVD received high-intensity week 24 were attained by 77.7% of alirocumab- statin at baseline (Table 1). treated individuals with DM and 76.8% of those Overall, individuals with DM had lower without DM (placebo, 10.3% and 6.4%, respec- baseline Lp(a) and HDL-C levels but higher TG tively) (Table 2). levels than individuals without DM (Table 1). In the same alirocumab 150 mg Q2W group, Among individuals with DM, 27.8% were least-squares mean percentage change from receiving injectable treatments which always baseline to week 12 in LDL-C levels was consisted of insulin (27.8%), sometimes com- - 62.1% in individuals with DM (placebo, bined with a glucagon-like peptide 1 antagonist ? 0.1%) and - 62.9% in individuals without (GLP 1; 3.3%). No individuals were receiving DM (placebo, ? 1.7%) (Supplementary Table 1). GLP 1 antagonist only. At week 12, alirocumab-associated LDL-C changes were similar for patients with or with- out DM in the HeFH subgroup (DM, - 56.2%; Efficacy non-DM, - 57.2%) and the non-HeFH subgroup (DM, - 62.5%; non-DM, - 65.4%) (Supple- LDL-C Outcomes: Pool of Alirocumab 150 mg mentary Tables 2 and 3). LDL-C levels were Q2W Studies (LONG TERM and HIGH FH) maintained through 78 weeks in individuals At week 24 in the full alirocumab 150 mg Q2W with and without DM in the on-treatment cohort, the least-squares mean LDL-C levels population (Fig. 2a). The reductions up to were changed from baseline by - 59.9% (with 78 weeks for the ITT population are presented in DM; placebo, - 1.4%) and - 60.6% (without Supplementary Fig. 2A. DM; placebo, ? 1.5%) (Table 2). Regardless of In the HeFH subjects from the LONG TERM high-intensity statin status, the LDL-C per- and HIGH FH studies, least-squares mean LDL-C centage change from baseline to week 24 was levels changed from baseline to week 24 by Diabetes Ther (2018) 9:1317–1334 1323 Table 2 Change from baseline of lipids and achievement of LDL-C \ 70 mg/dL at week 24 (intention-to-treat population) Alirocumab 150 mg Q2W pool (n = 2416) Alirocumab 75/150 mg Q2W pool (n = 1043) Individuals with DM Individuals without DM Individuals with DM Individuals without DM (n = 836) (n = 1580) (n = 202) (n = 841) Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo (n = 556) (n = 280) (n = 1045) (n = 535) (n = 132) (n = 70) (n = 561) (n = 280) Calculated LDL-C, mg/dL Baseline, mean (SE) 117.4 (1.6) 119.1 (2.4) 130.6 (1.5) 128.7 (2.0) 112.8 (3.6) 119.8 (5.5) 133.0 (2.0) 132.5 (2.7) Calculated LDL-C at week 24, mean 52.3 (1.5) 116.8 (2.1) 50.2 (1.1) 124.4 (1.5) 71.1 (3.5) 122.5 (4.7) 63.1 (1.6) 136.4 (2.2) (SE) a a Percentage change from baseline to - 59.9 (1.2) - 1.4 (1.7) - 60.6 (0.9) 1.5 (1.3) - 43.8 (2.5) 0.3 (3.4) - 49.7 (1.6) 5.1 (1.6) week 24, LS mean (SE) Percentage difference vs placebo - 58.5 (2.1) - 62.1 (1.5) - 44.0 (4.1) - 54.8 (2.0) Interaction p value 0.1600 0.0201 Percentage of persons achieving LDL- 77.7 10.3 76.8 6.4 68.3 5.9 65.8 2.8 C \ 70 mg/dL at week 24 Interaction p value 0.0188 0.2525 Other lipids, mg/dL Apo B, baseline, mean (SE) 101.7 (1.1) 100.6 (1.7) 104.2 (1.0) 104.4 (1.3) 99.5 (2.5) 100.4 (3.4) 107.6 (1.3) 107.3 (1.6) Percentage change from baseline to - 49.6 (1.1) 1.1 (1.6) - 53.5 (0.8) 0.6 (1.2) - 34.4 (2.0) - 0.3 (2.6) - 41.6 (0.9) 1.3 (1.2) week 24, LS mean (SE) Percentage difference vs placebo - 50.7 (2.0) - 54.1 (1.4) - 34.0 (3.2) - 42.9 (1.5) Interaction p value 0.1608 0.0121 Lp(a), baseline, mean (SE) 34.9 (1.8) 34.9 (2.3) 48.4 (1.6) 46.1 (2.2) 61.2 (6.3) 54.7 (6.9) 48.4 (2.2) 47.5 (3.2) Percentage change from baseline to - 28.5 (1.2) - 2.0 (1.8) - 29.3 (0.9) - 5.1 (1.2) - 18.1 (2.4) - 7.6 (3.2) - 26.5 (1.1) - 7.7 (1.5) week 24, adjusted mean (SE) Percentage difference vs placebo - 26.5 (2.1) - 24.2 (1.5) - 10.5 (4.0) - 18.8 (1.9) Interaction p value 0.3861 0.0581 1324 Diabetes Ther (2018) 9:1317–1334 Table 2 continued Alirocumab 150 mg Q2W pool (n = 2416) Alirocumab 75/150 mg Q2W pool (n = 1043) Individuals with DM Individuals without DM Individuals with DM Individuals without DM (n = 836) (n = 1580) (n = 202) (n = 841) Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo (n = 556) (n = 280) (n = 1045) (n = 535) (n = 132) (n = 70) (n = 561) (n = 280) Non-HDL-C, baseline, mean (SE) 151.4 (1.8) 151.3 (2.7) 158.1 (1.6) 157.5 (2.2) 143.2 (3.8) 149.5 (5.9) 158.6 (2.2) 156.9 (2.8) Percentage change from baseline to - 49.1 (1.1) - 0.3 (1.5) - 52.2 (0.8) 0.8 (1.1) - 36.0 (2.3) 2.6 (3.1) - 43.0 (1.1) 5.2 (1.5) week 24, LS mean (SE) Percentage difference vs placebo - 48.8 (1.8) - 53.0 (1.3) - 38.7 (3.7) - 48.2 (1.8) Interaction p value 0.0603 0.0218 TGs, baseline, mean (SE) 172.1 (4.3) 163.5 (4.9) 137.8 (2.2) 144.7 (3.3) 155.5 (8.6) 148.7 (8.0) 129.0 (3.0) 122.9 (3.6) Percentage change from baseline to - 12.2 (1.4) 6.3 (2.0) - 16.8 (1.0) - 0.6 (1.4) - 7.7 (2.7) 2.4 (3.6) - 9.1 (1.2) 1.2 (1.7) week 24, adjusted mean (SE) Percentage difference vs placebo - 18.5 (2.4) - 16.2 (1.7) - 10.1 (4.3) - 10.3 (2.1) Interaction p value 0.4319 0.9659 HDL-C, baseline, mean (SE) 48.3 (0.5) 48.6 (0.7) 50.7 (0.4) 50.4 (0.5) 44.5 (1.1) 45.9 (1.4) 51.9 (0.7) 50.7 (0.9) Percentage change from baseline to 2.3 (0.6) - 1.0 (0.9) 5.1 (0.5) - 0.1 (0.6) 5.3 (1.4) - 2.4 (1.9) 6.9 (0.7) - 0.7 (0.9) week 24, LS mean (SE) Percentage difference vs placebo 3.3 (1.1) 5.1 (0.8) 7.6 (2.3) 7.5 (1.1) Interaction p value 0.1680 0.9692 Apo apolipoprotein, DM diabetes mellitus, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), LS least- squares, Q2W every 2 weeks, SE standard error, TG triglyceride At week 12, 26.2% of subjects with DM and 36.4% of those without DM received dose increase of 75 mg Q2W to 150 mg Q2W Diabetes Ther (2018) 9:1317–1334 1325 Fig. 1 Percentage change from baseline in calculated CI confidence interval, DM diabetes mellitus, LDL-C low- LDL-C at week 24—subgroup analysis by DM status density lipoprotein cholesterol, LS least-squares, SE stan- and statin intensity at baseline (intention-to-treat popu- dard error lation). High-intensity statin defined as atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg. - 53.1% (with DM; placebo, ? 0.1%) and (placebo, ? 7.0%) and - 46.0% in those with- - 55.3% (without DM; placebo, ? 1.5%) (Sup- out DM (placebo, ? 3.4%) in the alirocumab plementary Table 4). In subjects without HeFH, 75/150 mg Q2W treatment pool (Supplemen- the least-squares mean LDL-C changes from tary Table 1). When the HeFH and non-HeFH baseline to week 24 were - 60.3% in subjects subjects in this cohort were examined sepa- with DM (placebo, - 1.4%) and - 62.9% in rately, similar percentage reductions from those without DM (placebo, ? 1.6%) (Supple- baseline to week 12 were observed in alir- mentary Table 5). ocumab-treated groups, except for a less pro- nounced change in LDL-C levels in individuals with DM in the HeFH subgroup (- 34.9%; pla- LDL-C Outcomes: Pool of Alirocumab cebo, ? 3.6%) (Supplementary Tables 2 and 3). 75/150 mg Q2W Studies (FH I, FH II, The protocol for the three studies starting and COMBO I) with the alirocumab 75 mg Q2W dose specified At week 24 in the full 75/150 mg Q2W cohort, a blinded dose increase from 75 mg to 150 mg least-squares mean percentage change from Q2W at week 12 (if week 8 LDL-C levels were baseline in LDL-C level was - 43.8% (with DM; C 70 mg/dL); 26.2% of individuals with DM placebo, ? 0.3%) and - 49.7% (without DM; received a dose increase to 150 mg Q2W, as did placebo, ? 5.1%) (Table 2). Mean week 24 LDL- 36.4% of those without DM. In subjects C levels of 71.1 mg/dL were achieved in alir- remaining on 75 mg Q2W, the baseline LDL-C ocumab-treated individuals with DM (absolute levels were lower in those with DM (99.5 mg/ change from baseline, - 58.3 mg/dL) and dL) versus subjects without DM (117.9 mg/dL; 63.1 mg/dL in those without DM (absolute interaction p value \ 0.0001). In subjects change from baseline, - 66.3 mg/dL). Subgroup receiving alirocumab dose increase to 150 mg analysis with and without high-intensity statin Q2W, the baseline LDL-C levels were 149.7 mg/ demonstrated similar LDL-C reductions at dL (DM) and 159.4 mg/dL (without DM). week 24, regardless of DM status (Fig. 1). LDL-C reductions were maintained with At week 12 in this cohort (i.e., before possi- alirocumab 75/150 mg Q2W until end of study ble dose increase), least-squares mean percent- treatment, regardless of DM status, in the on- age change from baseline to week 12 in LDL-C treatment population (Fig. 2a). Similar LDL-C levels was - 38.0% in persons with DM 1326 Diabetes Ther (2018) 9:1317–1334 Diabetes Ther (2018) 9:1317–1334 1327 bFig. 2 Percentage change from baseline over time for (placebo, ? 2.7%) and - 48.4% in those with- a LDL-C, b Apo B, c Lp(a), d non-HDL-C, e TGs, and out DM (placebo, ? 7.6%) (Supplementary f HDL-C according to DM status for the alirocumab Table 4). In the non-HeFH subgroup, 16.5% of 150 mg Q2W and 75/150 mg Q2W treatment pools persons with DM and 17.0% of those without (modified intention-to-treat population). Apo apolipopro- DM received dose adjustment at week 12. In tein, DM diabetes mellitus, HDL-C high-density lipopro- this same group, the week 24 least-squares mean tein cholesterol, LDL-C low-density lipoprotein LDL-C levels changed from baseline by - 42.2% cholesterol, Lp(a) lipoprotein (a), LS least-squares, Q2W in persons with DM (placebo, - 2.6%) and every 2 weeks, SE standard error, TG triglyceride - 53.2% in those without DM in the subgroup (placebo, - 2.0%) (Supplementary Table 5). reductions were observed in the ITT population Other Lipid Parameters (Supplementary Fig. 2a). From baseline to week 24, alirocumab treatment At week 24, LDL-C \ 70 mg/dL was attained was associated with reduced levels of by 68.3% of individuals in the alirocumab apolipoprotein (Apo) B, Lp(a), non-HDL-C, and group with DM and 65.8% without DM (pla- TGs, and increased levels of HDL-C (Table 2). In cebo, 5.9% and 2.8%, respectively) (Table 2). the alirocumab 150 mg Q2W pool, no differ- In the HeFH subgroup, the proportion of ences between subjects with and without DM individuals requiring dose increase from alir- were observed (Table 2). In the alirocumab ocumab 75 mg to 150 mg Q2W was 48.7% (DM) 75/150 mg Q2W pool, lower percentage chan- and 41.2% (without DM). At week 24, least- ges in Apo B and non-HDL-C were observed in squares mean percentage changes in LDL-C participants with DM versus those without (in- level were - 52.3% in persons with DM teraction P values \ 0.05) (Table 2). The Fig. 2 continued 1328 Diabetes Ther (2018) 9:1317–1334 percentage changes in TG and HDL-C levels with DM and 13.0% (n = 211) of those without were similar regardless of DM status. DM, and upper respiratory tract infection, From baseline to week 12, alirocumab dosing reported in 7.9% (n = 55) and 6.6% (n = 107), regimens of 150 mg Q2W and 75/150 mg Q2W respectively. Among alirocumab-treated indi- were associated with improved levels of Apo B, viduals, 3.7% (n = 26) of those with DM and Lp(a), non-HDL-C, TGs, and HDL-C in subjects 8.7% (n = 141) of individuals without DM with or without DM (Supplementary Table 1). reported injection-site reactions (Table 3). In persons with and without HeFH, similar Overall, 20.3% (alirocumab) and 23.9% (pla- alirocumab efficacy was observed at week 12, cebo) of subjects in the DM group and 15.0% regardless of DM status and alirocumab dosing (alirocumab) and 14.3% (placebo) of those regimen, except for lower Apo B and non-HDL- without DM experienced treatment-emergent C levels in individuals with HeFH in the alir- serious adverse events. Discontinuation rates ocumab 75/150 mg group with DM (interaction were 5.6% (alirocumab) and 8.0% (placebo) in p value \ 0.05 between persons with DM and individuals with DM, and 5.4% (alirocumab) those without) (Supplementary Tables 2 and 3). and 5.7% (placebo) in those without DM Reduced levels of other lipids were observed (Table 3). Occurrence of adverse events of spe- from week 4 and maintained for up to 78 weeks cial interest in alirocumab-treated individuals in individuals with and without DM in the on- was generally similar regardless of DM status treatment population (Fig. 2b–f). The lipid (Table 3). Overall, the median exposure to ran- levels for the ITT population were similar domized treatment was 78 weeks in both the (Supplementary Fig. 2B–F). In the HeFH group, alirocumab and control groups, regardless of improvements in other lipids from baseline to DM status. Mean HbA1c and FPG levels week 24 were seen in individuals with DM and remained unchanged in both groups through- without, regardless of alirocumab dosing (Sup- out the treatment period regardless of DM status plementary Table 4). No differences between (Supplementary Table 6). subjects with and without DM were observed in the non-HeFH group either, except for lower DISCUSSION mean percentage reductions in Apo B levels in subjects with DM in both alirocumab groups Across all studies in the ODYSSEY program, and lower mean percentage reductions in non- individuals with hypercholesterolemia experi- HDL-C levels in subjects with DM in the alir- enced significant LDL-C reductions from base- ocumab 150 mg Q2W pool (interaction line compared with either placebo or ezetimibe p value \ 0.05 between persons with DM and following alirocumab treatment with back- those without; Supplementary Table 5). ground statin therapy (± other lipid-lowering No correlation was found between baseline therapies) [16–19]. Similar reductions were seen HbA1c levels and LDL-C reductions in alir- with alirocumab treatment in individuals with ocumab-treated individuals with DM at week 24 or without DM, and were maintained for up to (Supplementary Fig. 3). 78 weeks. In the present analysis, alirocumab 150 mg Safety Analysis Q2W resulted in 58.5% and 62.1% reductions in LDL-C levels versus placebo at week 24 with no Overall, the incidence of TEAEs was similar significant difference being observed between between groups, occurring in 79.9% with DM those with and those without DM, respectively. and 79.8% without DM in alirocumab-treated Furthermore, LDL-C levels of \ 70 mg/dL were individuals versus 82.0% and 81.0% in the pla- achieved by the majority of persons receiving cebo groups, respectively (Table 3). The most this dose regardless of DM status (76.9–77.7%), common TEAEs occurring in C 5% of individ- with mean achieved LDL-C levels of uals treated with alirocumab were nasopharyn- 50.2–52.3 mg/dL, regardless of DM status. gitis, reported in 11.5% (n = 80) of individuals Diabetes Ther (2018) 9:1317–1334 1329 Table 3 Adverse events in persons with and without DM (safety population) n (%) DM (n = 1051) No DM (n = 2441) Alirocumab Placebo Alirocumab Placebo (n = 696) (n = 355) (n = 1622) (n = 819) TEAEs 556 (79.9) 291 (82.0) 1295 (79.8) 663 (81.0) Treatment-emergent SAEs 141 (20.3) 85 (23.9) 244 (15.0) 117 (14.3) TEAEs leading to 56 (8.0) 20 (5.6) 88 (5.4) 47 (5.7) discontinuation TEAEs leading to death 7 (1.0) 5 (1.4) 9 (0.6) 8 (1.0) Adverse events of special interest HLT: injection site reactions 26 (3.7) 10 (2.8) 141 (8.7) 52 (6.3) General allergic TEAE 63 (9.1) 28 (7.9) 163 (10.0) 77 (9.4) (CMQ) Neurocognitive disorders 9 (1.3) 6 (1.7) 12 (0.7) 3 (0.4) Adjudicated cardiovascular 37 (5.3) 27 (7.6) 57 (3.5) 19 (2.3) events ALT [ 3 9 ULN, n/N (%) 11/689 (1.6) 14/349 (4.0) 34/1610 (2.1) 7/815 (0.9) TEAEs occurring in C 5% of persons Nasopharyngitis 80 (11.5) 35 (9.9) 211 (13.0) 107 (13.1) Upper respiratory infection 55 (7.9) 36 (10.1) 107 (6.6) 58 (7.1) Injection-site reaction 26 (3.7) 10 (2.8) 141 (8.7) 52 (6.3) Bronchitis 33 (4.7) 27 (7.6) 79 (4.9) 31 (3.8) Urinary tract infection 49 (7.0) 26 (7.3) 79 (4.9) 39 (4.8) Arthralgia 27 (3.9) 26 (7.3) 91 (5.6) 50 (6.1) Influenza 39 (5.6) 19 (5.4) 108 (6.7) 44 (5.4) Back pain 33 (4.7) 17 (4.8) 90 (5.5) 53 (6.5) Headache 29 (4.2) 16 (4.5) 90 (5.5) 48 (5.9) Diarrhea 33 (4.7) 17 (4.8) 90 (5.5) 40 (4.9) Myalgia 21 (3.0) 11 (3.1) 90 (5.5) 35 (4.3) ALT alanine aminotransferase, CMQ custom MedDRA query, DM diabetes mellitus, HLT high-level term, MedDRA Medical Dictionary of Regulatory Activities, SAE serious adverse event, TEAE treatment-emergent adverse event, ULN upper limit of normal In the pool of studies where per-protocol were changed by - 43.8% (individuals with dose increase from 75 mg to 150 mg Q2W DM) and - 49.7% (individuals without DM) in occurred if LDL-C goals were not reached at the alirocumab groups (placebo, ? 0.3% and week 8, the week 24 LDL-C levels from baseline ? 5.1%, respectively), with these changes being 1330 Diabetes Ther (2018) 9:1317–1334 consistent regardless of DM status. Possibly as a Fewer injection-site reactions were reported result of the higher LDL-C levels at baseline, in individuals with DM, a difference that may in alirocumab dose was increased at week 12 in a part be due to a greater familiarity and tolerance higher proportion of subjects without DM, associated with glucometer and/or which was associated with a greater magnitude injectable medication use in the DM population of LDL-C reduction at week 24 in that group (27.8% and 72.2% of persons with DM were (absolute LDL-C change, - 66.3 mg/dL) versus receiving antihyperglycemic injectable and the DM group (absolute LDL-C change, non-injectable medication at baseline, respec- - 58.3 mg/dL); however, similar LDL-C levels tively). However, as previously reported, (63.1–71.1 mg/dL) were achieved in both administration by injection does not deter per- groups. In the subgroup without HeFH, the sons from self-administration of alirocumab percentage of individuals requiring dose [23]. The ODYSSEY OUTCOMES study increase was similar regardless of DM status. (NCT01663402) will help to further establish if Therefore, this analysis indicates that the higher DM status has an influence on the frequency of proportion of individuals in the subgroup injection-site reactions [24]. without DM who received alirocumab dose Mean HbA1c and FPG measurements in increase versus the subgroup with DM could be individuals with DM were comparable between explained by more individuals with HeFH with alirocumab and placebo for up to 78 weeks of higher baseline LDL-C being included in the treatment. These variables were comparable subgroup without DM. between alirocumab and placebo in individuals At baseline, the differences in prevalence of without DM, as previously reported [25]. On the HeFH, ASCVD, and high-intensity statin use, basis of these results, alirocumab treatment does and baseline LDL-C levels between individuals not appear to affect blood glucose, which is very with and without DM may reflect discrepancies reassuring given that statins modestly raise the in selection criteria between the studies inclu- risk of DM [26], and recent genetic publications ded in the analysis. Furthermore, consistent have suggested that the PCSK9 pathway might with previous studies [21, 22], fewer individuals be relevant to glycemia levels [27, 28]. In a with HeFH had DM (12.2–15.5%) compared subgroup analysis of 11,031 individuals with with those without HeFH (44.4–46.3%). Possi- DM in FOURIER (median follow-up, 2.2 years), bly as a result of this imbalance, fewer individ- neither HbA1c nor incidence of DM was uals in the cohort with DM had a history of increased in the evolocumab groups versus the ASCVD and received high-intensity statin placebo groups [29]. In contrast, a recent meta- compared with the cohort without DM. The analysis of phase 2/3 randomized PCSK9 inhi- lower rate of high-intensity statin use in indi- bitor clinical studies (excluding FOURIER) sug- viduals with DM indicates that this high-risk gested that PCSK9-mediated lowering of LDL-C population is undertreated. does increase risk for DM [30]. Taking all of Overall, alirocumab treatment was generally these publications into consideration, it is not well tolerated with no particular differences yet clear whether LDL-C reduction per se or the observed in incidence of TEAEs, serious adverse means of attaining lower LDL-C levels influence effects, or deaths compared with placebo in DM risk. In the ODYSSEY and FOURIER studies, individuals with or without DM. Overall, mean most individuals received statin therapy, which exposure to randomized treatment was similar may mask the glycemic effect of PCSK9 inhibi- (78 weeks) in individuals with or without DM tors [29, 31]. The results of ODYSSEY OUT- regardless of treatment status. This analysis does COMES will provide key additional data not allow for conclusive safety observations to relevant to this important issue. be made, in particular for rare adverse events Overall efficacy and safety findings from such as adjudicated cardiovascular events. As a these placebo-controlled studies were consistent consequence, safety results should be consid- with findings from studies comparing alir- ered in the context of the overall ODYSSEY ocumab with ezetimibe and employing back- program. ground statin therapy [32, 33]. A recently Diabetes Ther (2018) 9:1317–1334 1331 and Desmond Thompson; Sanofi: Corinne published study of the efficacy and safety of Hanotin, Michael Howard, L. Veronica Lee, alirocumab in individuals with type 2 DM and Guillaume Lecorps, Laurence Merlet, Christelle mixed dyslipidemia (defined as non-HDL- Lorenzato, and Jonas Mandel. C C 100 mg/dL; TGs C 150 mg/dL and \ 500 mg/dL) showed similar responses for non-HDL-C (37.7% reduction) and TGs (13.0% Funding. This analysis as well as journal reduction) at week 24 compared to the larger article processing charges were funded by Sanofi group of individuals with type 1 and 2 DM in and Regeneron Pharmaceuticals, Inc. The the present analysis [15]. In the DM-INSULIN sponsor was involved in the study design, col- phase 3b study, alirocumab demonstrated simi- lection, analysis, and interpretation of data, as lar results in reducing LDL-C and other lipids in well as data checking of information provided insulin-treated type 1 DM and type 2 DM indi- in the manuscript. The authors had unrestricted viduals [14]; all individuals were at high car- access to data, were responsible for all content diovascular risk and received maximally and editorial decisions, and received no hono- tolerated statin therapy. raria related to the development of this This analysis was limited by the non-ran- publication. domized nature of DM status in subgroups, which could introduce bias to the analyses. Medical Writing and Editorial Assis- Nevertheless, this placebo-controlled analysis of tance. Medical writing support was provided by up to 78 weeks adds to the body of evidence on Susanne Ulm, PhD, and Rachel Wright, PhD, of PCSK9 inhibitor use in people with DM [34]. Prime (Knutsford, UK), funded by Sanofi and Regeneron Pharmaceuticals Inc. according to Good Publication Practice guidelines. CONCLUSION Authorship. All named authors meet the On the basis of these data from placebo-con- International Committee of Medical Journal trolled phase 3 studies, DM status does not Editors (ICMJE) criteria for authorship for this appear to meaningfully affect lipid-modifying article, take responsibility for the integrity of efficacy or safety of alirocumab treatment, nor the work as a whole, and have given their does alirocumab appear to significantly affect approval for this version to be published. blood glucose control in individuals with or without DM. The results presented here provide Author Contributions. Henry N. Ginsberg, support for the recent recommendation by the Michel Farnier, and Jennifer G. Robinson con- American Diabetes Association that PCSK9 tributed to study design or concept, data inhibitor therapy may be considered for indi- acquisition, analysis and interpretation of the viduals with DM and ASCVD [8]. The ODYSSEY data, and critically reviewed and edited the OUTCOMES study is expected to provide an manuscript. Christopher P. Cannon, Marie T. opportunity to evaluate the effect of alirocumab Baccara-Dinet, Maja Bujas-Bobanovic, Michael in a larger sample of individuals with DM [24]. J. Louie, and Helen M. Colhoun contributed to study design or concept, analysis and interpre- tation of the data, and critically reviewed and edited the manuscript. Naveed Sattar and Alexia ACKNOWLEDGEMENTS Letierce contributed to analysis and interpreta- tion of data, and critically reviewed and edited The authors would like to thank study individ- the manuscript. uals and investigators, and the following per- sons from sponsors for their contributions to Disclosures. Henry N. Ginsberg has received data collection and analysis, assistance with other research support from Genzyme (Sanofi), statistical analysis, or critical review of the Merck, Sanofi, Regeneron Pharmaceuticals Inc., manuscript: Regeneron Pharmaceuticals Inc.: and Amgen; and is a consultant and on the Eva-Lynne Greene, Carol Hudson, Rita Samuel, 1332 Diabetes Ther (2018) 9:1317–1334 advisory board for Amarin, Amgen, AstraZe- Boehringer Ingelheim, and AstraZeneca LP, and neca, Bristol Myers Squibb, GlaxoSmithKline, shareholding in Bayer and Roche. IONIS, Janssen, Kowa, Merck, Novartis, Sanofi, Compliance with Ethics Guidelines. All Regeneron Pharmaceuticals, Inc., and Pfizer. study protocols were approved by the appro- Michel Farnier has received research support priate institutional review boards, and all par- from and participated in a speakers’ bureau for ticipants provided informed, written consent. Amgen, Merck, and Sanofi; received honoraria All trials were performed in accordance with the from Abbott/Mylan, Akcea/Ionis, Eli Lilly, and ethical principles that have their origin in the Pfizer; and acted as a consultant/advisory panel Declaration of Helsinki and all applicable member for Amgen, AstraZeneca, Roche, Kowa, amendments laid down by the World Medical Merck, Pfizer, Sanofi, and Servier. Jennifer G. Assemblies and the International Conference Robinson has received research grants from Harmonisation guidelines for Good Clinical Amarin, Amgen, AstraZeneca, Daiichi-Sankyo, Practice. Eli Lilly, Esai, Genentech/F. Hoffman La Roche, GlaxoSmith Kline, Merck, Pfizer, Regeneron Open Access. This article is distributed Pharmaceuticals, Inc./Sanofi, and Zinfandel/ under the terms of the Creative Commons Takeda; and is a consultant and on the advisory Attribution-NonCommercial 4.0 International board for Akcea/Ionis, Amgen, Eli Lilly, F. License (http://creativecommons.org/licenses/ Hoffman LaRoche, Merck, Pfizer, and Sanofi/ by-nc/4.0/), which permits any noncommercial Regeneron Pharmaceuticals, Inc. Christopher P. use, distribution, and reproduction in any Cannon has received research grants from Acc- medium, provided you give appropriate credit umetrics, Arisaph, AstraZeneca, Boehringer to the original author(s) and the source, provide Ingelheim, GlaxoSmithKline, Janssen, Merck, a link to the Creative Commons license, and Takeda, Amgen, BMS, American College of indicate if changes were made. Cardiology, and Sanofi/Regeneron Pharmaceu- ticals, Inc; and is a consultant and on the advisory board for Boehringer Ingelheim CSL Behring, Essentialis, GlaxoSmithKline, Merck, REFERENCES Kowa, Takeda, BMS, Pfizer, Sanofi, Regeneron Pharmaceuticals, Inc., and Lipimedix. Alexia 1. Catapano AL, Graham I, De Backer G, et al. 2016 Letierce is an employee and a stockholder of ESC/EAS guidelines for the management of dyslip- Sanofi. 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Journal

Diabetes TherapySpringer Journals

Published: May 19, 2018

References

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