The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas—a randomized trial

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Abstract

Aim: To assess the glucose-lowering efficacy, responsiveness, duration of action and impact on quality-of-life of hydroxychloroquine (HXCHL), when added as an antihyperglycemic agent to patients with sulfonylurea-refractory type 2 diabetes. Methods: One hundred and thirty-five obese patients with type 2 diabetes (mean age 57.5 years) and a glycated hemoglobin (GHb) ≥11% despite maximum sulfonylureas were randomly allocated to the addition of HXCHL (up to 300 mg bid) or placebo and followed for up to 18 months. Randomization was stratified by baseline GHb (<13.5% versus ≥13.5%). The primary outcome was ‘blinded’ withdrawal of study drug due to unacceptable glycemic control; GHb, glucose tolerance, lipids, and quality of life were also assessed. Results: Those on placebo were more likely to be withdrawn from study drug because of unacceptable glycemic control than patients randomized to HXCHL (95.5 and 69.6% given placebo and HXCHL, respectively; P=0.0001). During the first 6 months, HXCHL decreased GHb by an absolute amount of 1.02% more than placebo (95% CI 0.24, 1.81). Glucose tolerance and LDL cholesterol improved during the first 3 months of therapy. No significant adverse effects were noted. Factors that predicted responsiveness included an initial GHb <13.5%, early responsiveness to study drug, and no prior metformin use. Lower GHb levels at baseline predicted a better response; the hazard of withdrawal increased 36% (95% CI 11%, 66%) for every 1% increase in GHb even in patients whose baseline GHb was <13.5%. Conclusions: HXCHL improves glycemic control in sulfonylurea-refractory patients with poorly controlled type 2 diabetes.

Introduction

Type 2 diabetes affects up to 10% of all adults in the general population and up to 20% of people over age 65 [1], and is a major risk factor for cardiovascular, eye, kidney, and nerve disease. Effective treatment of hyperglycemia improves well-being and reduces the risk of these other diseases [2], [3], [4]. Whereas most patients initially respond to sulfonylureas and/or metformin, these agents lose their effectiveness with time [2], [5]; comparable long-term data is not yet available for the alpha glucosidase inhibitors, the meglitinides and the thiazolidinediones. Oral agents that will reduce hyperglycemia when added to refractory patients with type 2 diabetes are therefore needed.

Hydroxychloroquine (HXCHL) is an antimalarial drug that may have antihyperglycemic properties in patients with diabetes. One previous 6 month blinded study reported that HXCHL decreased glycated hemoglobin (GHb) by an absolute amount of 3.3% [6] when added to patients with type 2 diabetes who were refractory to high doses of insulin or pills. Other smaller studies of HXCHL or the parent drug chloroquine have also been shown to reduce both glucose and lipid levels in people with diabetes [7], [8], [9], and there has been at least one report of hypoglycemic coma in an individual with type 2 diabetes who was prescribed HXCHL [10].

We therefore conducted a randomized double-blind placebo controlled trial to assess the efficacy, duration of action and impact on quality-of-life of HXCHL and to characterize the type of patient most likely to respond to this drug.

Section snippets

Study sample

Patients with type 2 DM and poor glycemic control on maximal doses of sulfonylurea, who were reluctant to begin insulin therapy, were recruited for the study. Eligible participants were 35–80 years old, had a body mass index >25 and had a GHb level that was ≥11% (normal range 5.5–7.5%) despite at least 2 months therapy on maximal doses of sulfonylurea either alone or in combination with metformin. Patients with a history of diabetic retinopathy requiring laser therapy, evidence of an imminent

Results

A total of 135 patients (mean age 57.5 years, 58% male) with poorly controlled type 2 diabetes (mean GHb 13.4%) were randomized to either HXCHL or placebo (Table 1). Follow-up data for one or more post-randomization visits until study drug withdrawal was available in 134/135 (99.3%) participants (69 participants on HXCHL and 65 participants on placebo). By the end of the study, 120 participants had been eligible for the full 18 months of follow-up, 12 participants had been eligible for 15

Discussion

This study clearly shows that the addition of HXCHL improves glycemic control in sulfonylurea- refractory patients with type 2 diabetes. HXCHL was not effective if the baseline GHb was ≥13.5% (180% of the upper limit of normal). In patients whose GHb was between 11 and 13.5%, HXCHL was effective for a mean period of 1 year and lowered the GHb by an absolute amount of 1% more than placebo. Even within this group, however, the hypoglycemic effect waned as the baseline GHb increased; this suggests

Acknowledgements

This project was supported by the Medical Research Council of Canada Grant# MA11784. HXCHL drug and placebo were provided by Sanofi Winthrop, Accucheck 3M monitors were provided by Boehringer Mannheim, and insulin used for testing was provided by Lilly pharmaceuticals. Dr Patricia Harvey's ophthalmologic collaboration, Dr Diane Finegood's assistance with the minimal model analyses, Dr Fakhreddin Jamali's measurement of HXCHL levels and Mr Daniel Pericak's contribution to the statistical

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