Effects of niacin on the incidence of new onset diabetes and cardiovascular events in patients with normoglycaemia and impaired fasting glucose

Authors

Errata

This article is corrected by:

  1. Errata: Erratum Volume 67, Issue 12, 1361, Article first published online: 19 November 2013

  • Disclosures Vasilisa Sazonov and Christine McCrary Sisk are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA, and may hold stock/stock options in the company. Darbie Maccubbin is a former employee of Merck Sharp & Dohme Corp., and may hold stock/stock options in the company. Paul L. Canner has received research grants from Merck Sharp & Dohme Corp.


Christine McCrary Sisk, Merck Sharp & Dohme Corp., 126 E. Lincoln Ave., POBox 2000 Ry34-B290, Rahway, NJ 07065-0900, USA
Tel: +1 732 594 2704
Fax: +1 732 594 9868
Email: christine_sisk@merck.com

Summary

Background:  This post hoc analysis from the Coronary Drug Project (CDP) evaluated the effects of niacin vs. placebo on the incidence of new onset type 2 diabetes mellitus (T2DM) and cardiovascular event rates in patients with normal and impaired fasting glucose (IFG).

Methods:  The CDP was a randomised, placebo-controlled clinical trial of lipid-modifying agents in men with previous myocardial infarction. Normoglycaemia and IFG were defined as fasting plasma glucose (FPG) < 5.6 mmol/l and FPG ≥ 5.6 but < 7.0 mmol/l, respectively. New onset T2DM was defined by ≥ 1 of the following: clinical diagnosis of T2DM, use of an antihyperglycaemic therapy, or two FPG values ≥ 7.0 mmol/l.

Results:  The incidence of new onset T2DM was higher in patients with IFG (16.5%) compared with those with normoglycaemia (5.4%), and was slightly higher with niacin vs. placebo in both normoglycaemic (6.8% vs. 4.9%; p = 0.07) and IFG (19.8% vs. 15.2%; p = 0.05) patients. Consistent with previous analyses, the cardiovascular benefit of niacin was independent of baseline glycaemic status (normal, IFG, T2DM) and change in fasting glucose level from baseline to year 1.

Conclusion:  Despite a modest increase in risk of new onset T2DM with long-term niacin therapy, there is a potential cardiovascular benefit of niacin.

What’s known

Cardiovascular disease is a major cause of death in patients with diabetes and multiple lipid abnormalities are common. Niacin is an effective agent for the treatment of the dyslipidaemia associated with diabetes and has been shown to reduce cardiovascular events in high-risk patients.

What’s new

We analysed CDP data to evaluate the effects of niacin vs. placebo on new onset diabetes and cardiovascular events among patients with normal and IFG. New onset diabetes was higher among IFG vs. normoglycaemic patients, and slightly higher with niacin than placebo for both groups. Cardiovascular benefits with niacin were independent of baseline glycaemic status and change in glucose over year 1.

Introduction

Niacin effectively improves the lipid abnormalities associated with cardiovascular disease, such as lowering low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and raising high-density lipoprotein cholesterol (HDL-C) levels (1,2). The Coronary Drug Project (CDP), a randomised, placebo-controlled clinical trial in men with previous myocardial infarction, showed that relative to placebo, niacin produced modestly favourable effects on cardiovascular outcomes (3). Further analyses suggest that this effect is independent of baseline or on-treatment fasting plasma glucose (FPG) levels or the presence of metabolic syndrome (4,5). Nevertheless, because niacin produces small increases in FPG in some patients (6), there is a reluctance to use it among patients with impaired fasting glucose (IFG) who are at high risk of developing type 2 diabetes mellitus (T2DM) (1,7). The present report describes the results of a post hoc analysis from CDP assessing the effects of niacin vs. placebo on the incidence of new onset T2DM and cardiovascular event rates in normoglycaemic and IFG patients.

Methods

The methods used in the CDP have been previously described (3). In brief, CDP was a multicenter, randomised, double-blind, placebo-controlled clinical trial of lipid-modifying agents in men with previous MI, consisting of five initial monthly visits plus three follow-up visits each year for at least 5 years. Oral glucose tolerance tests (one-hour post 75 g glucose load) and FPG tests were performed at baseline and every third follow-up (annual) visit. For the present analysis, the total study population consisted of niacin 3 g (= 1,119) and placebo-treated patients (= 2,789). Baseline normoglycaemia and IFG were defined as FPG < 5.6 mmol/l and FPG ≥ 5.6 but < 7.0 mmol/l, respectively, and no clinical diagnosis of T2DM and no current treatment with antihyperglycaemic medications at baseline. Baseline T2DM was defined as either clinical diagnosis of T2DM or use of antihyperglycaemic medication or FPG ≥ 7.0 mmol/l at baseline. New onset T2DM was defined as either clinical diagnosis of T2DM, use of an antihyperglycaemic therapy, or at least two FPG values ≥ 7.0 mmol/l during the first 5 years of follow up.

The count and percentage of new onset T2DM was tabulated by treatment group among patients with normoglycaemia and IFG. The comparisons between treatment groups were made using the Cox proportional hazards model with the PROC PHREG procedure (SAS 8.2; SAS Institute, Cary, NC) in each subgroup. A hazard ratio was calculated for outcome comparisons between the niacin and placebo groups, with a value < 1.0 indicating that the event rate with niacin was less than that with placebo. Per CDP study design, the FPG and one-hour glucose levels were only tested at annual follow-up visits; thus, the new onset T2DM identified by the FPG could only be diagnosed at annual follow-up visits and thus were interval censored. Given the discrete nature of this outcome, the EXACT method (i.e., to use option of ‘TIES = EXACT’ under MODEL statement in PROC PHREG) was used in estimating the hazard ratio from the Cox proportional hazards model.

The summary statistics (including 95% confidence intervals) of change from baseline in FPG were assessed at years 1, 2, 3, 4 and 5 by treatment among patients with normoglycaemia and IFG and T2DM.

All-cause and coronary heart disease (CHD) mortality and cardiovascular events [non-fatal MI (NFMI) and CHD death or NFMI (CD/MI)] were analysed using a similar statistical method as that used for new onset T2DM. The Exact method was used for NFMI because this outcome was interval-censored. In addition to the same subgroups with normoglycaemia and IFG, this outcome was examined in additional subgroups (1-year FPG < 5.6 mmol/l, ≥ 5.6 and < 7.0 mmol/l, and ≥ 7.0 mmol/l and change from baseline to 1 year of treatment in FPG < 0 mmol/l, 0–0.55 mmol/l, and ≥ 0.56 mmol/l).

Results

Of the 3906 patients in the analysis cohort, 2194 had normal glycaemic status, 1242 had IFG and 470 had T2DM at baseline (Table 1). Compared with the normoglycaemic cohort, the IFG and T2DM groups had slightly higher mean BMI, TG and blood pressure (Table 1). As expected, mean FPG at baseline was highest in the T2DM group and lowest in the normoglycaemic group (Table 1).

Table 1. Baseline characteristics
CharacteristicNormoglycaemic (= 2194)Impaired fasting glucose (= 1242)Type 2 diabetes mellitus (= 470)
Age, mean years ± SD51.9 ± 7.353.1 ± 7.054.1 ± 6.7
Body mass index, kg/m2 ± SD25.6 ± 3.126.6 ± 3.227.1 ± 3.9
Race, non-Caucasian, % ± SD5.9 ± 23.67.0 ± 25.510.8 ± 31.1
Systolic blood pressure, mmHg ± SD128.4 ± 17.9131.4 ± 19.4134.4 ± 20.6
Diastolic blood pressure, mmHg ± SD81.1 ± 10.782.8 ± 11.183.2 ± 10.9
Total cholesterol, mmol/l ± SD6.5 ± 1.26.5 ± 1.26.5 ± 1.4
Triglycerides, mmol/l ± SD1.9 ± 1.42.1 ± 1.62.6 ± 2.8
Fasting plasma glucose, mmol/l ± SD5.1 ± 0.35.9 ± 0.37.7 ± 2.7

Compared with placebo, niacin increased FPG among patients in the baseline normoglycaemic, IFG and T2DM cohorts (Figure 1). Progression to new onset T2DM over time was observed in both the niacin and placebo treatment groups (Table 2). New onset T2DM was more prevalent among IFG vs. normoglycaemic patients, and was slightly higher with niacin vs. placebo in both normoglycaemic and IFG group (Table 2). The relationship of 15-year mortality to progression or non-progression to T2DM is illustrated in Figure 2.

Figure 1.

 Mean change from baseline in glucose (mmol/l) ± SE by glycaemic status (normoglycaemic, impaired fasting glucose, and type 2 diabetes mellitus) and treatment over 5 years

Table 2. New onset diabetes by baseline glycaemic status and treatment group over 5 years
Baseline glycaemic statusNiacin n/N (%)Placebo n/N (%)Hazard ratio95% CIp-value
Normoglycaemic43/634 (6.8)76/1560 (4.9)1.410.97, 2.050.07
Impaired fasting glucose70/354 (19.8)135/888 (15.2)1.341.00, 1.800.05
Figure 2.

 Fifteen-year mortality for patients who either progressed or did not progress from normoglycaemia or impaired fasting glucose at baseline to confirmed type 2 diabetes mellitus over 5 years, including all deaths from year 2 to year 15

Compared with placebo, niacin reduced the risk of NFMI to a greater extent in patients at all levels of baseline glycaemic status, particularly among patients with T2DM (Table 3). The risk of all death, CHD death and CD/MI was similar in the niacin and placebo groups across all levels of baseline glycaemic status (Table 3). Compared with placebo, niacin reduced the risk of NFMI and CD/MI similarly in patients at all year one FPG levels and levels of change in FPG (Table 3). The effect of niacin on these outcomes was not diminished, even among patients with the highest year one FPG levels and greatest increase in FPG. The risk of all death and CHD death was similar in the niacin and placebo groups across the cohorts of patients with year 1 FPG levels < 5.6 mmol/l and from 5.6 to < 7.0 mmol/l, and those with changes in FPG of < 0 mmol/l and from 0 to < 0.56 mmol/l (Table 3). The relative effect of niacin vs. placebo on these outcomes was greater in the cohorts of patients with year 1 FPG ≥ 7.0 mmol/l and those with changes in FPG ≥ 0.56 mmol/l (Table 3).

Table 3. Mortality and cardiovascular morbidity outcomes by baseline glycaemic status, year 1 fasting plasma glucose and change in fasting plasma glucose from baseline to year 1 in the niacin and placebo groups
CohortOutcomeNiacin %Placebo %Hazard ratio95% CIp-value
  1. *Sample sizes of the niacin and placebo groups, respectively. CHD, coronary heart disease; NFMI, non-fatal myocardial infarction; CD/MI, CHD death or NFMI. Portions of Table 3 have been reprinted from Canner et al.; Am J Cardiol 2005; 95: 254–7 with permission from Elsevier.

Baseline glycaemic status      
Normoglycaemic (= 6,341,560)*5-year total mortality18.420.00.910.74, 1.130.40
CHD death14.416.80.840.66, 1.070.16
NFMI9.912.80.790.59, 1.040.09
CD/MI22.427.00.810.67, 0.980.03
15-year total mortality48.353.80.860.75, 0.980.02
Impaired fasting glucose (= 354,888)*5-year total mortality22.919.71.190.91, 1.550.20
CHD Death17.816.61.100.82, 1.470.54
NFMI7.911.30.700.46, 1.060.10
CD/MI23.726.10.920.71, 1.180.49
15-year total mortality52.560.50.840.71, 0.990.04
Type 2 diabetes mellitus (n = 131,339)* 5-year total mortality29.830.40.990.69, 1.430.96
CHD death27.524.21.150.78, 1.700.48
NFMI7.614.20.520.26, 1.030.06
CD/MI32.134.80.900.63, 1.280.55
15-year total mortality67.971.40.920.72, 1.170.49
Year 1 fasting plasma glucose       
 < 5.6 mmol/l  (= 4,051,394)*5-year total mortality14.615.10.960.72, 1.280.77
CHD death10.412.60.820.59, 1.150.25
NFMI7.910.50.750.51, 1.100.15
CD/MI16.521.30.760.59, 0.990.05
15-year total mortality44.451.50.830.70, 0.970.02
 5.6–6.9 mmol/l  (= 456,900)*5-year total mortality17.116.01.080.82, 1.420.58
CHD death13.613.41.020.75, 1.390.89
NFMI5.912.00.480.32, 0.740.0008
CD/MI18.023.70.750.58, 0.970.03
15-year total mortality49.357.00.820.70, 0.960.01
 ≥ 7.0 mmol/l  n = 104,177)5-year total mortality18.326.60.630.37, 1.080.09
CHD death15.420.30.700.39, 1.260.24
NFMI9.610.70.820.38, 1.760.60
CD/MI24.028.80.770.48, 1.250.29
15-year total mortality56.774.60.630.46, 0.850.003
Change in fasting plasma glucose from baseline to year 1       
 < 0 mmol/l  (= 3,181,165)*5-year total mortality17.315.01.160.86, 1.570.33
CHD death14.212.91.110.79, 1.550.55
NFMI6.010.50.570.35, 0.930.02
CD/MI19.221.60.880.66, 1.160.36
15-year total mortality49.455.00.880.74, 1.050.17
 0–0.55 mmol/l (= 346,941)*5-year total mortality15.315.70.970.71, 1.330.86
CHD death11.612.50.920.64, 1.320.65
NFMI7.211.00.650.42, 1.010.06
CD/MI16.821.60.760.57, 1.020.07
15-year total mortality45.451.90.820.69, 0.980.03
 ≥ 0.56 mmol/l  (= 301,365)*5-year total mortality16.021.60.710.50, 1.020.06
CHD death11.617.50.640.42, 0.970.03
NFMI8.312.90.590.36, 0.960.03
CD/MI18.329.00.600.43, 0.820.002
15-year total mortality49.864.10.690.56, 0.850.0004

Discussion

Niacin is associated with a decrease in cardiovascular risk, but is known to cause mild increases in blood glucose levels in some patients via mechanisms that are not completely understood (6). Niacin-induced hyperglycaemia is believed to be caused by an increase in insulin resistance (8). As a result, caution has been urged about new onset T2DM in niacin-treated patients, particularly among those with abnormal glucose metabolism (1,7). Two prior post hoc analyses of the CDP have demonstrated that niacin treatment reduced cardiovascular events in patients with elevated baseline and follow-up plasma glucose levels and in patients with metabolic syndrome (4,5).

Two prospective studies have demonstrated the safety and efficacy of niacin in dyslipidemic patients with T2DM. The Arterial Disease Multiple Intervention Trial (ADMIT) was a prospective, placebo-controlled trial that evaluated the effect of niacin, antioxidant vitamins, and low-dosage warfarin on plasma lipoproteins and glycaemic control in patients with peripheral artery disease (9). Overall, 125 of the 468 participants enrolled in ADMIT had T2DM. Patients were randomised in a double-blind fashion to crystalline nicotinic acid 3000 mg/day (64 patients with and 173 without T2DM) or placebo (61 patients with and 170 without T2DM) for 48 weeks. For patients with and without T2DM, niacin was associated with an HDL-C increase of 29% in both groups; TG reductions of 23% and 28%, respectively; and LDL-C reductions of 8% and 9%, respectively (p < 0.05 for all comparisons between niacin and placebo). In patients with and without T2DM in the placebo group, HDL-C increased by 0% and 2%, respectively; TG levels increased by 7% and 0%, respectively; and LDL-C increased by 1% in both groups. Among patients with T2DM, no changes in haemoglobin A1c were observed with niacin (compared with a 0.3% reduction in the placebo group), and there were no significant differences between niacin and placebo with respect to discontinuation rates, insulin dosage or hypoglycaemic therapy.

In a multicenter, double-blind study, 148 patients with T2DM and dyslipidaemia were randomly assigned to extended-release niacin (given as Niaspan) 1000 or 1500 mg/day or placebo for 16 weeks (10). Enrolment was limited to patients with T2DM who had HDL-C levels < 40 mg/dl or TG levels > 200 mg/dl, or patients receiving a statin who had LDL-C levels > 130 mg/dl. Approximately half of enrolled patients were receiving a statin at baseline. Mean lipid levels at study entry were HDL-C 41 mg/dl, LDL-C 105 mg/dl, and TG 264 mg/dl. In the 1000 mg, 1500 mg, and placebo groups, respectively, HDL-C increases of 20%, 24% and 4%, and TG reductions of 15%, 29% and 5% were observed. Haemoglobin A1c levels were largely unchanged. Global assessment of diabetes status was improved or the same in 80%, 71% and 88%, respectively, of patients in the 1000 mg, 1500 mg and placebo groups.

The present analysis evaluated the effects of niacin on progression to T2DM and cardiovascular event rate in patients with IFG at baseline according to published guidelines from the American Diabetes Association. The findings confirm those from the CDP and other studies regarding the effects of niacin on glucose and cardiovascular outcomes. The observed increases in glucose levels and new onset T2DM with niacin did not translate into any deleterious effects with regard to cardiovascular events or mortality risk. Because of the post hoc nature of this analysis, these results should be interpreted with caution because of multiple subgroups, with some containing small numbers of patients and multiple end-points.

In conclusion, niacin produced favourable effects on clinical outcome in patients with evidence of IFG or overt T2DM.

Acknowledgements

Funding for this post hoc analysis was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. The authors are grateful for the contributions of Baishali Ambegaonkar (Merck & Co., Inc.) for technical assistance and Jennifer Rotonda (Merck & Co., Inc.) for editorial assistance.

Author contributions

All authors had access to study data and contributed to the design, drafting, revision and approval of this article.

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