Elsevier

The American Journal of Medicine

Volume 129, Issue 7, July 2016, Pages 753.e13-753.e22
The American Journal of Medicine

AJM online
Clinical research study
Effects of Extended-Release Niacin Added to Simvastatin/Ezetimibe on Glucose and Insulin Values in AIM-HIGH

https://doi.org/10.1016/j.amjmed.2016.02.039Get rights and content

Abstract

Background

Niacin is an antidyslipidemic agent that may cause blood sugar elevation in patients with diabetes, but its effects on glucose and insulin values in nondiabetic statin-treated subjects with cardiovascular disease and at high risk for diabetes are less well known.

Methods

This was a prespecified, intent-to-treat analysis of the Atherothrombosis Intervention in Metabolic syndrome with low high-density lipoprotein/high triglycerides: Impact on Global Health outcomes trial which randomized 3,414 participants at 92 centers in the US and Canada to extended-release niacin (ERN) plus simvastatin/ezetimibe (ERN) or simvastatin/ezetimibe plus placebo (Placebo). Baseline and annual fasting glucose and insulin values were measured. Those experiencing an adverse event indicative of diabetes or starting medications for diabetes were considered to have confirmed diabetes. In addition, nondiabetic subjects with 2 annual follow-up glucose measurements were categorized into normal, impaired fasting glucose or newly diagnosed diabetes (presumed or confirmed) states.

Results

Compared with placebo, ERN increased annual fasting glucose from baseline to 1 year in both those with normal (7.9 ± 15.8 vs 4.3 ± 10.3 mg/dL; P < .001) and impaired fasting glucose (4.1 ± 18.7 vs 1.4 ± 14.9; P < .02) and increased insulin levels. Both effects waned over the next 2 years. There were less consistent effects in those with baseline diabetes. There was an increased risk of progressing from normal to presumed or confirmed impaired fasting glucose (ERN 197/336) cases (58.6%) vs placebo 135/325 cases (41.5%; P < .001) over time, but no difference in diabetes development in the 2 treatment groups except in those with normal fasting glucose at baseline.

Conclusions

The addition of ERN to simvastatin/ezetimibe had marginal effects on glycemia in those with diabetes at baseline, and there was a trend toward increased development of new-onset diabetes. In addition, ERN increased the risk of developing impaired fasting glucose, which may have deleterious consequences over time and warrants further study.

Section snippets

Study Design

AIM-HIGH was a randomized, placebo-controlled clinical trial designed to test the hypothesis that in patients with atherosclerotic cardiovascular disease and atherogenic dyslipidemia, treatment with ERN (Niaspan, AbbVie, Inc, North Chicago, IL) to raise baseline levels of high-density lipoprotein cholesterol (HDL-C) would decrease the rate of cardiovascular endpoints (coronary artery disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome or

Baseline Status

Of the 3414 randomized participants, all but 2 could be classified by glycemic status at baseline. Approximately 34% (n = 1158) had previously diagnosed diabetes; a further 164 (4.8%) were found to have diabetes by baseline FG testing, making a total of 1322 subjects (38.7%) with baseline diabetes. Almost 30% (n = 1010) had IFG and 32% (n = 1080) had NFG. Those with diabetes at baseline were older and had higher HbA1c but lower LDL-C levels than those without diabetes, and participants with

Discussion

The principal findings of this analysis of the AIM-HIGH population comparing the effects of ERN vs Placebo added to simvastatin/ezetimibe over a mean 3-year follow-up period on glucose and insulin levels, were that FG levels increased modestly but significantly more in the ERN than the Placebo group, irrespective of whether participants had NFG, IFG, or diabetes at baseline. This difference was accompanied by a significant worsening of insulin resistance as assessed by insulin and HOMA-IR

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  • Cited by (15)

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      In some cases, the effect on glycemic metabolism was negative. The addition of extended-release niacin to statins had deleterious effects on glycemia in those with diabetes at baseline, and there was a trend toward increased development of new-onset diabetes [5]. In other cases, the effect was neutral.

    • Metabolic syndrome cluster does not provide incremental prognostic information in patients with stable cardiovascular disease: A post hoc analysis of the AIM-HIGH trial

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      However, our analysis showed that in AIM-HIGH participants without MS at baseline, ERN did not affect the rate of subsequent MS. This could be explained by the previously mentioned unfavorable effect of niacin on insulin resistance and the potential concern that developing DM on ERN might have offset the positive effect on lipids. Recent AIM-HIGH data demonstrate that ERN increased development of DM and impaired fasting glucose.18 This was a post hoc analysis of a clinical trial, which has the potential for inherent selection bias as well reduced power to demonstrate difference.

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      Though limited by its size, design as a dose-finding trial, and lack of randomization or comparison to placebo, this study provides an early look at the safety, tolerability, and potential therapeutic use of niacin in pediatric patients. A recent prespecified secondary intention to treat (ITT) analysis of the 2011 AIM-HIGH trial sought to elucidate the effect of extended release niacin (Niaspan) on fasting glucose (FG) and insulin levels in statin-treated nondiabetic patients with a history of cardiovascular disease [7MC]. Patients included in this trial were 45 years or older had established cardiovascular disease, low HDL-C, triglycerides 100–400 mg/dL, and LDL-C < 180 mg/dL.

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      Analysis of subpopulations also provided further support of the neutral findings as well as some concerns for ERN use. When diabetes was present at baseline, ERN appeared to be associated with only marginal effects on glycemia.23 However, there was a significant increase in fasting blood glucose levels at 1 year in those participants with normal or impaired fasting glucose levels at baseline, as well as a 17% absolute increase in diabetes in those with normal baseline glucose values.

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    Funding: The Atherothrombosis Intervention in Metabolic syndrome with low high-density lipoprotein/high triglycerides: Impact on Global Health (AIM-HIGH) study was supported by the National Heart, Lung, and Blood Institute (U01 HL081616 and U01 HL081649) and by an unrestricted grant from AbbVie, Inc. AbbVie donated the extended-release niacin, the matching placebo, and the ezetimibe; Merck donated the simvastatin. Neither of these companies had any role in the oversight or design of the study or in the analysis or interpretation of the data.

    Conflict of Interest: RBG reports receiving consultancies from Sanofi. VAB reports grant funding for clinical trials from Janssen Pharma, Pfizer, and Bayer Healthcare; participation in trials funded by Astra Zeneca, Sanofi/Regeneron, and Amgen; consultancies for Eli Lilly, Amarin, Novartis, and Amgen. RLD and JLF report no conflicts of interests. GG reports grant funding from Merck, NovoNordisk, Eli Lilly, Lexicon, Medtronic, and Astra Zeneca; and speakers bureau participation for NovoNordisk, Sanofi, Janssen, Eli Lilly, Boehringer Ingelheim, and GlaxoSmithKline. JRG reports grant funding from Regeneron, Sanofi, Amgen, Amarin, Genzyme, Synageva; and consultancies with Regeneron, Sanofi, and Amgen. LAL reports grant funding, consultancies, and honoraria from Aegerion, Amgen, Astra Zeneca, Eli Lilly, Merck, Pfizer, Regeneron, Valeant, and Sanofi. RM reports grant funding from AbbVie, Inc (AIM-HIGH funding only). JGR reports grant funding from Amarin, Amgen, Astra-Zeneca, Eli Lilly, Esai, GlaxoSmithKline, Merck, Pfizer, Sanofi/Regeneron, and Takeda, as well as consultancies from Akcea/Isis, Amgen, Eli Lilly, Esperion, Merck, Pfizer, and Sanofi/Regeneron. DLS reports no conflicts of interest. CW reports consultancies with Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, NovoNordisk, and Sanofi. PX and WEB report no conflicts of interest.

    Authorship: All authors had access to the data and a role in writing the manuscript. All authors have reviewed and approved of this article prior to submission.

    Trial Registration: Niacin Plus Statin to Prevent Vascular Events (AIM-HIGH); https://clinicaltrials.gov/ct2/show/NCT00120289 (Clinicaltrials.gov Identifier NCT00120289.

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