Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes

From Pubdrug

Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial (ADVENT)
Authors	Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, et al.
Journal	Archives of Internal Medicine
Year/Volume(Issue)/Pages	2002;162(14):1568-1576
Original Article Abstract
This page is not completed and has not been reviewed for accuracy. You are reading a non-certified PubDrug document. This document is incomplete and not ready for final editing, review, and certification. Until this document is certified, any registered PubDrug user may edit its content.

Contents 1 Quick Summary 2 Hypothesis/Objectives 3 Methods/Design 3.1 Inclusion criteria 3.2 Exclusion criteria 3.3 Design 4 Results 4.1 Baseline characteristics 4.2 Primary endpoint results 4.3 Other 5 Limitations

Quick Summary

• Niacin may be effective in the management of diabetic dyslipidemia since it can potentially lower triglycerides and decrease the small, dense LDL particles, and also increase HDL levels. However, high doses have been reported to increase fasting blood glucose (FBG) levels.
• The primary aim of this study was to evaluate the ER formulation of niacin on A1C, HDL, and triglyceride levels.
• After a 16-week follow up, 1500mg daily of ER niacin was found to significantly decrease triglycerides, but also increase A1C by a mean of 0.29% compared to placebo. Both ER niacin groups were associated with significant increases in HDL levels compared to placebo.

Hypothesis/Objectives

Use of immediate release (IR) niacin is limited due to patient intolerance to flushing,and over-the-counter slow-release niacin has been associated with increased risk of hepatotoxicity and reduced efficacy on HDL levels. The objective of this study was to evaluate the safety and efficacy of low-dose ER niacin for the treatment of dyslipidemia in patients with type 2 diabetes.

Methods/Design

		Y	Randomized?
		Y	Controlled?
		Y	Placebo-controlled?
		Y	Prospective?
		U	Double-blind?
		*U = not reported

Inclusion criteria

• Men and women >21 years
• Stable type 2 diabetes:
  • FBG less than or equal to 200 mg/dL
  • AND A1C less than or equal to 9% on two separate occasions
• History of diabetes controlled by diet, oral hypoglycemic agents (sulfonylureas, metformin, acarbose; thiazolidinediones excluded), or insulin
• Lipid levels:
  • Patients currently receiving an HMG-CoA reductase inhibitor:
    • LDL at least 130 mg/dL
    • HDL no greater than 40 mg/dL
    • OR triglycerides of at least 200 mg/dL
  • Patients not currently receiving an HMG-CoA reductase inhibitor:
    • LDL no greater than 130 mg/dL
    • HDL no greater than 40 mg/dL
    • OR triglycerides of at least 200 mg/dL
• Baseline aspartate aminotransferase and alanine aminotransferase no greater than 1.3 times the upper limit of the reference range
• Willing to continue treatment for the study duration
• Women were not breastfeeding or planning on becoming pregnant
• Chronic stable conditions, like history of hypertension or previous myocardial infarction (MI) (>6 months prior), unless being treated with medication that might affect lipid levels

Exclusion criteria

• Clinically significant history of:
  • psychiatric illness
  • substance abuse
  • liver disease
  • gout
  • peptic ulcer disease
  • other conditions that could be adversely affected by participation in the study

Design

The 148 included participants were randomized to treatment with placebo (n=49), ER niacin 1000mg daily (n=47), or ER niacin 1500mg daily (n=52). All patients completed 4 weeks of treatment with an appropriate diet, and a 4 week drug washout phase, where all lipid-lowering medications (except HMG-CoA reductase inhibitors) were discontinued. During the first 4 weeks of treatment, ER niacin was titrated as follows: week 1: 375mg daily at bedtime, week 2: 500mg daily, week 3: 750mg daily, week 4: 1000mg or 1500mg daily as per treatment assignment. Use of aspirin 325mg up to 30 minutes prior to treatment was allowed. Patients were followed up every 4 weeks, with periodic measurements of blood pressure, pulse, weight, lipid profiles, A1C, and serum chemistries, for a total of 16 weeks.

Results

Baseline characteristics

Participants in the ER niacin 1000mg daily group had significantly higher baseline weight and BMI, and significantly lower HDL levels compared to the 1500mg daily ER niacin or placebo groups (p<0.001). There were no other statistically significant differences between the three groups. 81% of participants were also using drugs for diabetes control, and 47.3% were also using HMG-CoA reductase inhibitors. In the placebo group 59% were using HMG-CoA reductase inhibitors, 42% in the 1000mg daily ER niacin group, and 40% in the 1500mg daily ER niacin group.

Primary endpoint results

The primary safety endpoint was the change from baseline to week 16 in A1C. The mean A1C values at week 16 for placebo, 1000mg daily ER niacin and 1500mg daily ER niacin were 7.1%, 7.4%, and 7.5%, respectively, which corresponds to mean changes of -0.02%, +0.07%, and +0.29%. The change in A1C was significant for the 1500mg ER niacin group compared to placebo (p=0.048), but may not be clinically significant.

The primary efficacy endpoints were change from baseline to week 16 of HDL and triglyceride levels. HDL levels were found to increase significantly in both ER niacin treatment groups compared to placebo (p<0.05). The mean absolute increase in HDL levels at week 16 was found to be: 1.6 mg/dL for the placebo group, 7.6 mg/dL in the 1000mg daily ER niacin group, and 11.0 mg/dL in the 1500mg daily ER niacin group. The decrease in triglyceride levels seen was not significant between the placebo and 1000mg ER niacin groups, but was significant for the 1500mg ER niacin group compared to placebo (p<0.05): median percentage of change for the placebo group was -5% to -8%, and was -28% to -36% for the 1500mg daily ER niacin group.

Other

Secondary safety endpoints included measurement of FBG levels, serum transaminase concentrations, and self-reported adverse events. Between weeks 4 and 8, there was a significant increase in FBG levels for the 1000mg daily ER niacin group compared to baseline (p<0.05), but this was not significant at week 16. No other secondary safety endpoints were found to be statistically significant. However, 73% of placebo patients, 69% of 1000mg daily ER niacin patients, and 77% of 1500mg daily ER niacin patients reported adverse events. Flushing did occur in two-thirds of the ER niacin treated patients, and in 10% of placebo patients which was significantly different.

Secondary efficacy endpoints included total cholesterol and LDL levels, ratio of total cholesterol to HDL, lipoprotein (a) levels, high-sensitivity C-reactive protein (hsCRP), and LDL particle size. LDL levels were found to be significantly decreased at weeks 12 and 16 for the 1500mg daily ER niacin group compared to placebo (p<0.05): mean change from baseline at 16 weeks was +9% for placebo, and -7% for the 1500mg daily ER niacin group. Total cholesterol:HDL was significantly decreased from baseline in both ER niacin treatment groups compared to placebo (p<0.01): mean change at week 16 for 1000mg daily ER niacin -12%, -22% for 1500mg daily ER niacin and not reported for placebo. There were no other significant findings for any of the secondary efficacy endpoints.

Although there is no statistical analysis available to determine significance, 11.1% more patients were using insulin compared to baseline at the end of the study in the 1500mg daily ER niacin group. There was a 0.5% increase in insulin use in the 1000mg daily ER niacin group and a 6.4% increase in the placebo group.

Limitations

• Specific p-values were not reported for the majority of the results, they were only given as "<0.05" or "<0.01".
• The study was supported by Kos Pharmaceuticals, the manufacturer of ER niacin (Niaspan).
• 48 patients (32.4%) dropped out of the study due to lack of blood glucose control, adverse events, or unknown reasons.
• 47.3% of the included patients were also using an HMG-CoA reductase inhibitor, which could account for the significant changes seen in the lipid profiles.