Dr. Massarotti has received consulting fees from UCB, Roche, Pfizer, and Medco Health Solutions (less than $10,000 each) and honoraria from the American College of Rheumatology; she also receives royalties as an author for Up To Date.
Brigham and Women's Hospital, Boston, Massachusetts
Prior research demonstrates that hydroxychloroquine (HCQ) lowers glycosylated hemoglobin (HbA1c) in diabetes patients without rheumatic disease. We examined medical records of patients with diabetes mellitus (DM) and concomitant rheumatic illness to measure changes in HbA1c after starting HCQ or methotrexate (MTX).
We used electronic medical records to identify patients beginning treatment with either HCQ or MTX who had a diagnosis of DM (or a pretreatment HbA1c value of ≥7%) and at least 1 HbA1c measurement both before and within 12 months after initiation of treatment. Using a structured medical record abstraction, we examined rheumatic disease diagnosis, cumulative steroid use, duration (months) between drug initiation and lowest HbA1c value, a change in DM medication, body mass index (BMI), age, and sex. Adjusted linear regression models determined changes in HbA1c from pretreatment values to the lowest posttreatment values within 12 months.
We identified 45 patients taking HCQ and 37 patients taking MTX who met the inclusion criteria. Rheumatoid arthritis had been diagnosed in approximately half of the patients in each group. Age, sex, and mean pretreatment HbA1c levels were similar across groups. The mean BMI of those taking HCQ (35.4 kg/m2) was slightly higher than that of those taking MTX (32.2 kg/m2) (P = 0.13). Glucocorticoid use appeared more common in those taking MTX (46%) than in those taking HCQ (29%) (P = 0.17). The mean reduction in HbA1c from pretreatment values to the lowest posttreatment values was 0.66% (95% confidence interval [95% CI] 0.26, 1.05) in those taking HCQ compared with 0.11% (95% CI −0.18, 0.40) in those taking MTX. In fully adjusted analyses, the reduction in HbA1c among those taking HCQ was 0.54% greater than the reduction among those taking MTX (P = 0.041).
HCQ initiation was associated with a significantly greater reduction in HbA1c as compared with MTX initiation among diabetes patients with rheumatic disease.
Patients with rheumatic diseases, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), are at an increased risk of developing cardiovascular disease (CVD) (1–4). CVD is a leading cause of death in patients with rheumatic diseases; however, the risk factors for CVD in this population are not clear. Both traditional risk factors and inflammation likely contribute to CVD (5–7). Current management guidelines for CVD in rheumatic disease suggest measures applicable to the general population, with the addition of slightly more aggressive risk stratification (8–10). It would be ideal if management strategies for CVD and its risk factors could be tailored for rheumatic disease patients.
Several risk factors—both traditional and those specific to rheumatic conditions—may indicate an elevated risk of CVD in rheumatic disease patients (5–7). Although there is no consensus regarding the risk of diabetes mellitus (DM) in RA (11, 12), it is clear that patients with rheumatic disease have a substantially elevated risk of insulin resistance (13, 14). Insulin resistance refers to a state of impaired insulin sensitivity and glucose metabolism, which commonly precedes the development of DM (15). It is strongly associated with the metabolic syndrome, defining 1 of the World Health Organization criteria for this constellation of CVD risk factors, and predicts future CVD events (16).
It has been shown that inflammation directly influences insulin and glucose metabolism through cytokines such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) (13, 17–19). Considering this, several disease-modifying antirheumatic drugs (DMARDs)—agents prescribed primarily to treat rheumatic diseases—have also been tested as interventions to improve insulin and glucose metabolism. Anakinra, an IL-1 receptor antagonist approved by the Food and Drug Administration (FDA) for the treatment of RA, was examined as a therapy for DM and was associated with significantly lower levels of glycosylated hemoglobin (HbA1c) (20). Several TNFα antagonists have been shown to improve insulin metabolism in patients with RA or ankylosing spondylitis (17–19). In addition, hydroxychloroquine (HCQ), an FDA-approved DMARD for the treatment of RA and lupus, has been shown in at least 2 randomized controlled trials to improve diabetes control in patients without rheumatic disease (21, 22). One large epidemiologic study also showed that HCQ reduces the risk of DM among patients with RA (23).
It is unclear whether the effects of HCQ seen among diabetes patients would generalize to rheumatic disease patients. Further, it is not clear whether other, more potent DMARDs such as methotrexate (MTX) would affect HbA1c. Considering these questions, we compared the effect of HCQ with that of MTX on HbA1c in adults with diabetes who were receiving treatment for a rheumatic condition.
PATIENTS AND METHODS
Adult patients were identified from a large academic medical center's clinical data repository. This clinical data repository includes information on patients' charges, diagnoses, procedures, laboratory values, prescribed medications, medical history, and sociodemographics.
One author (LRR) abstracted the medical records of potentially eligible patients, using a structured review. Items of interest included age, sex, body mass index (BMI), rheumatic disease diagnosis, DM diagnosis, history of use of insulin or noninsulin DM medication, and history of oral corticosteroid use.
We searched the repository for patients age ≥18 years with a diagnosis of DM (or a pretreatment HbA1c value of ≥7%) (24) with ≥2 HbA1c values available and who began treatment either with HCQ but not MTX or with MTX but not HCQ. From this group of 537 potentially eligible patients, we reviewed full medical records and excluded those without 1 pretreatment HbA1c value and without 1 posttreatment HbA1c value (n = 391), those taking both HCQ and MTX (n = 26), and those who lacked a pretreatment HbA1c value of ≥7% or a clinical diagnosis of DM (n = 38). The Partners HealthCare System Institutional Review Board approved all aspects of this study.
The exposures of interest were initiation of either HCQ or MTX; patients who were receiving HCQ and MTX concomitantly were excluded. Information about HCQ or MTX initiation was derived from physician notes as well as the electronic medication list. We made no distinctions based on the dosage of these medications. While simultaneous use of HCQ and MTX was not permitted, patients were commonly prescribed other antirheumatic therapies during the same period; these patients were included. In addition, glucocorticoid use was not excluded.
Outcome of interest.
The primary outcome of interest was change in the HbA1c value, from the measurement most proximal prior to HCQ or MTX initiation to at least 12 weeks after initiation (HbA1cPRE − HbA1cPOST). Two different postexposure HbA1c values were examined: the most proximal to HCQ or MTX initiation and the lowest within 12 months following initiation of treatment. The HbA1c values were derived from routine clinical laboratory practice, in which a Tosoh HLC-723G8 Analyzer instrument is used to measure HbA1c (coefficient of variation <0.5%) (25).
Descriptive statistics such as the mean, median, and SD for each continuous variable and frequencies for each categorical variable were used to summarize the data. The normality of the distribution of primary outcomes of interest was examined with a normal probability plot. Two-sample t-tests, chi-square tests, Fisher's exact tests, or nonparametric tests were used for baseline comparisons between the 2 exposure groups when applicable. The change in the HbA1c value was calculated separately for the HCQ and MTX groups, as was HbA1cPRE – HbA1cPOST. First, the change in HbA1c within each group was assessed using paired t-tests or Wilcoxon's signed rank tests. We then compared changes in HbA1c across drugs using general linear regression adjusted for rheumatic disease diagnosis, cumulative steroid use, duration (months) between drug initiation and lowest HbA1c value, a change in DM medication, BMI, age, and sex. Data analyses were performed using SAS 9.2 (SAS Institute).
The baseline characteristics of the 82 patients (45 taking HCQ and 37 taking MTX) who were included in the analyses are shown in Table 1. The mean age for both groups was 61 years, and most patients were female (82% in the HCQ group and 73% in the MTX group). RA was diagnosed in approximately one-half of the patients in each treatment group (53% in the HCQ group and 57% in the MTX group); 7% of the HCQ-treated patients had SLE, compared with 0% of the MTX-treated patients. There was a trend toward more frequent oral glucocorticoid use in the 12 months following drug initiation in the MTX group (46%) than in the HCQ group (29%) (P = 0.17), as well as a slightly higher mean ± SD cumulative dose in the MTX group (612 ± 982 gm) than in the HCQ group (464 ± 809 gm) (P = 0.46). The mean BMI for those taking HCQ (35.4 kg/m2) was slightly higher than that for those taking MTX (32.2 kg/m2) (P = 0.13). A physician's diagnosis of DM was recorded in 89% of those taking HCQ and in 97% of those taking MTX, with roughly 30% in both groups prescribed insulin therapy and close to 60% in both groups prescribed noninsulin DM medication.
Table 1. Baseline characteristics of the diabetes patients with rheumatic disease at the time of initiation of HCQ or MTX*
HCQ group (n = 45)
MTX group (n = 37)
Except where indicated otherwise, values are the percent of patients. There were no significant differences between the groups.
Refers to the 12 months after initiation of hydroxychloroquine (HCQ) or methotrexate (MTX).
Mean pretreatment HbA1c values were similar in both groups (7.71% in the HCQ group and 7.38% in the MTX group; P = 0.35) (Table 2). The HbA1c values recorded most proximally after drug initiation were similar (7.28% in the HCQ group and 7.47% in the MTX group; P = 0.58), as were the lowest absolute HbA1c values within 12 months after treatment initiation (7.05% in the HCQ group and 7.27% in the MTX group; P = 0.49). However, a comparison of the change in HbA1c from pretreatment values to the lowest posttreatment values revealed a significant reduction with HCQ (0.66% [95% confidence interval 0.26, 1.05]) compared with the reduction observed with MTX (0.11% [95% confidence interval −0.18, 0.40]; P = 0.04) (Table 2 and Figure 1). In adjusted analyses, this drop in HbA1c among those taking HCQ was 0.54% greater than that among those taking MTX (P = 0.041).
Table 2. Change in HbA1c values with initiation of HCQ or MTX in diabetes patients with rheumatic disease*
Values are the mean ± SD percent. See Table 1 for other definitions.
From general linear regression adjusted for rheumatic disease diagnosis, cumulative steroid use, duration (months) between drug initiation and lowest glycosylated hemoglobin (HbA1c) value, a change in diabetes mellitus medication, body mass index, age, and sex.
Reports suggest that HCQ may have unique hypoglycemic effects in addition to its remittive actions on rheumatic diseases. To better understand whether the hypoglycemic effects of HCQ are in part related to its antiinflammatory properties or to another mechanism, we examined the potential hypoglycemic benefits of MTX, another DMARD commonly used to treat RA and other rheumatic diseases. In this study, we examined the change in HbA1c among rheumatic disease patients beginning treatment with either drug; all patients had DM and a pretreatment HbA1c value of ≥7%. Comparing pretreatment levels with those within 1 year following drug initiation, HCQ produced a reduction in HbA1c that was significantly larger than the change associated with MTX. Patients starting MTX did not experience a significant reduction in HbA1c, but relatively few patients starting MTX were studied.
While inflammation is known to be associated with impaired glucose control, the mechanism by which HCQ exerts a hypoglycemic effect is not entirely clear. Chloroquine has been shown to increase the C peptide response, which Gerstein et al cite as a potential effect of improved beta cell functioning with decreased blood glucose (22, 26). Additionally, the inhibitory effect of HCQ on insulin metabolism has been demonstrated in animal models, with effects including reductions in intracellular insulin degradation and increases in insulin accumulation (27, 28). Whether due to a novel mechanism or to the established antiinflammatory effect of this therapy, the results from the present study align with the clinically observed responses detailed in epidemiologic studies and case reports.
Data from our study represent novel findings, highlighting the potential ability of HCQ to decrease HbA1c in diabetes patients with systemic inflammatory disease. Several previous studies in non–rheumatic disease patients with DM have demonstrated the hypoglycemic effect of HCQ as well. HCQ therapy contributed to significant improvements in type 2 DM management, as compared with a placebo, in a small group of patients with treatment-refractory disease in a randomized trial (21). Subsequently, HCQ was shown in another randomized trial to improve glucose control and high-density lipoprotein cholesterol in a larger cohort of patients with type 2 DM (22). In addition, a large epidemiologic study among patients with RA showed that HCQ was associated with a reduced risk of incident DM, even after controlling for disease activity and glucocorticoid use (23). Considering these prior data and the significant effect we observed with HCQ, our findings generate interesting questions about the potential long-term role of this therapy, apart from its effect on arthritis symptoms, in treating systemic rheumatic disease.
Our study has several limitations. Because the study is a nonrandomized retrospective chart review, there is the possibility for confounding by unmeasured factors, including changes in diabetes medications and BMI. The data were collected on a limited number of patients at 1 academic medical center, potentially limiting generalizability. In addition, information on rheumatic disease activity was not collected, and only extremely limited data were available on concomitant glucocorticoid use. Finally, the study was small and not specifically powered to detect a difference in MTX; the null effect may be an artifact of the small sample size.
In the last decade, there has been a growing awareness of the increased cardiovascular morbidity associated with RA and SLE. The reasons for this observation are in part related to inflammation as well as to traditional risk factors such as DM and impaired insulin resistance. We wanted to better understand whether HCQ might improve glucose control in rheumatic disease patients and to begin to explore whether the effects of HCQ were related to a reduction in inflammation or to another, independent effect of HCQ. We examined the effects of HCQ and MTX, 2 commonly used DMARDs, on HbA1c among rheumatic disease patients. HCQ significantly lowered HbA1c levels; MTX did not, but the sample size was limiting. These findings add to existing literature suggesting beneficial effects of HCQ on insulin and glucose metabolism, perhaps distinct from those of MTX. Comprehensive, larger, and prospective studies are clearly warranted to determine the potential role of HCQ in mitigating cardiovascular morbidities in patients with systemic rheumatic diseases.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Solomon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Rekedal, Massarotti, Garg, Gleeson, Lu, Solomon.
Acquisition of data. Rekedal, Bhatia, Gleeson.
Analysis and interpretation of data. Rekedal, Lu, Solomon.