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Efficacy and safety of hydroxychloroquine for managing glycemia in type-2 diabetes: A systematic review and meta-analysis D Dutta1, R Jindal2, D Mehta3, M Kumar4, M Sharma51 Department of Endocrinology, CEDAR Superspeciality Clinics, Dwarka, New Delhi, India 2 Department of Endocrinology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India 3 Department of Gastroenterology, CEDAR Superspeciality Clinics, Dwarka, New Delhi, India 4 Department of Endocrinology, CEDAR Superspeciality Clinics, Zirakpur, India 5 Department of Rheumatology, CEDAR Superspeciality Clinics, Dwarka, New Delhi, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_301_21
Keywords: Hydroxychloroquine, inflammation, meta-analysis, retinopathy, type-2 diabetes
Hydroxychloroquine (HCQ) has been extensively used in different rheumatologic disorders for more than half a century now.[1] The studies in patients with lupus, Sjogren syndrome, and rheumatoid arthritis have highlighted the mild anti-hyperglycemic properties of HCQ.[1],[2] People with autoimmune disorders on HCQ receiving glucocorticoids had a lower incidence of diabetes.[1],[2] A reduction in systemic inflammation, a favorable impact on adipocytokines, and a reduction in insulin degradation are some of the possible mechanisms attributed to the glycemic benefits of HCQ.[3] HCQ has also been used as an immunomodulator for the treatment and prophylaxis in the recent coronavirus 2019 (COVID-19) pandemic.[4] HCQ retinopathy is a dreaded, but, fortunately, a rare complication of the HCQ therapy, typically seen in people on HCQ for decades at doses more than 5 mg/kg/day.[3] HCQ has been recently approved as a third-line agent for managing glycemia in people with type-2 diabetes (T2DM) in India.[3] However, it must be realized that no other country in this world has included HCQ in their guidelines for managing T2DM or has made a recommendation for the use of HCQ in T2DM. T2DM is a chronic disorder needing decades of treatment, especially in a country like India, where the peak incidence of T2DM is nearly two decades earlier than in the western world.[5] With the peak incidence of T2DM in India being in the thirties, and the average life span of the Indians being 75 years, many of the people living with T2DM may end up receiving HCQ for up to 40 years.[6],[7] A few randomized controlled trials (RCTs) and reviews have been published evaluating the role of HCQ for managing glycemia in T2DM.[8] However, a literature search reveals that to date, no Cochrane meta-analysis with the grading of evidence is available which holistically evaluated the efficacy and safety of HCQ in managing T2DM. We undertook this meta-analysis to address this knowledge gap.
The meta-analysis was carried out according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.[9] The predefined protocol has been registered with the international prospective register of systematic reviews (PROSPERO) having registration number: CRD42021227109. All the RCTs satisfying the inclusion criteria, published till December 2020 were considered This meta-analysis has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).[10] Since ethical approval already exists for the individual studies included in the meta-analysis, no separate approval was required for this study. The Population, Intervention, Comparison, Outcomes and Study type (PICOS) criteria were used to screen and select the studies for this meta-analysis with patients (P) being individuals with T2DM; intervention (I) being use of HCQ over the background of standard care for T2DM; control (C) being the patients with T2DM on standard care for managing glycemia but not receiving HCQ; outcomes (O) being evaluated, and study type (S) being RCTs for this meta-analysis. Only those RCTs which had at least two arms were included, with the intervention arm receiving HCQ on the background of standard care for T2DM and the non-intervention or control arm receiving placebo or any other approved medication for T2DM were considered. The primary outcome of the meta-analysis was to evaluate the changes in HbA1c. The secondary outcomes of this study were to evaluate the alterations in fasting plasma glucose (FPG), 2 h post-prandial glucose (PPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C), bodyweight change, discontinuation of medication due to adverse events, and any other adverse events as described by the authors and death (all-cause). The RCTs whose outcomes evaluated the primary end-point or at least two secondary end-points were included in the meta-analysis. A sub-group analysis was done based on whether the control group received an active comparator (another anti-diabetes medication)—labeled here as the active control group (ACG) or a placebo—labeled as the passive control group (PCG). Search method for identification of studies A detailed search of the electronic databases of Medline (via PubMed), Embase (via Ovid SP), Cochrane central register of controlled trials (CENTRAL) (for trials only), ctri.nic.in, clinicaltrials.gov, global health, and Google Scholar was done using a Boolean search strategy: ((hydroxychloroquine) OR (chloroquine*)) AND ((diabetes) OR (“diabetes mellitus”) OR (glycemia) OR (glucose) OR (insulin)). Data extraction and study selection Data extraction was carried out independently by two authors using the standard data extraction forms. The details have been elaborated in another meta-analysis carried out by our group and published elsewhere.[11] Assessment of risk of bias in the included studies Three authors independently assessed the risk of bias using the risk of the bias assessment tool in the Review Manager (RevMan) version 5.3 (The Cochrane Collaboration, Oxford, UK, 2014) software. We specifically looked for selection bias, performance bias, detection bias, attrition bias, reporting bias and any other bias like publication bias. The details of how risk of bias assessment was done has already been elaborated elsewhere.[11] Quality assessment of the included studies was also conducted using the Jadad scale which consisted of three domains: randomization (0–2 points), blinding (0–2 points), and an account of all the patients (0–1 point). We classified the quality of RCTs as good (4–5 points), fair (3 points), or poor (0–2 points).[12] Measures of treatment effect For continuous variables, the outcomes were expressed as MD. The final results were presented both in conventional units as well as SI units. For dichotomous outcomes the results were expressed as risk ratio (RR) with 95% CI. Assessment of heterogeneity Heterogeneity was initially assessed by studying the forest plot generated. Subsequently, heterogeneity was analyzed using a Chi-square test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test.[7] The detail of assessment and interpretation of heterogeneity has already been elaborated elsewhere.[11]
An overall grading of the evidence related to each of the primary and secondary outcomes of the meta-analysis was done using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach.[13] The details of how grading of the study results was done and how the summary of findings (SoF) table was developed [Table 1], has been elaborated elsewhere.[11] We specifically looked for publication bias by plotting the Funnel Plot. Presence of one or more study outside the inverted funnel plot was proof of significant publication bias [Supplementary Figure 1].
Data synthesis Data were pooled as a random effect model for the analysis of outcomes which were expressed as 95%CI. Forrest plots were plotted with the left side of the graph favoring HCQ and the right side of the graph favoring control using the RevMan 5.3 software.
A total of 471 articles were found after the initial search [Figure 1]. Following the screening of the titles, abstracts, the search was reduced down to 21 studies whose full texts were evaluated in detail for inclusion in this meta-analysis [Figure 1]. Eleven RCTs in people with T2DM which fulfilled all criteria were analyzed in this meta-analysis (eight from India, one each from the USA, Canada, and Italy).[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] The remaining 10 studies were evaluated in detail but were excluded as they did not fulfill the inclusion criteria of this meta-analysis.[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] One RCT in prediabetes and another RCT focusing on dyslipidemia instead of glycemia were excluded.[26],[27] The studies by Gupta A,[28] Baidya A et al. (2018),[29] Baidya A et al. (2018a),[32] and Chandra AK et al.[33] evaluating HCQ in T2DM were excluded as they did not have valid control groups. The study by Jagnani VK et al.[31] was excluded as it was a retrospective study without an appropriate control group.
Of the 11 studies included, in 3 studies (Chakravarti et al.[15]Gerstein et al.[16] and Quatraro et al.[19]), the control groups were receiving placebo, and hence, have been sub-grouped under the passive control sub-group (PCS). The duration of the follow-up of 12, 24, and 24 weeks in the studies by Chakravarti et al.[15], Gerstein et al.[16] and Quatraro et al.[19], respectively, was used for analysis. In the remaining eight studies, the control groups were receiving anti-diabetes medication as the comparator agent, and hence, have been sub-grouped under the active control sub-group (ACS). The active comparator was pioglitazone 15 and 45mg/d in the studies by Pareek et al. [17] and Hsia et al.[18] respectively. The duration of the follow-up was 24 and 16 weeks in the studies by Pareek et al.[17] and Hsia et al.[18] respectively. Vildagliptin 100mg/d was the active comparator in the study by Baidya et al.[20] Teneligliptin 20mg/d was the active comparator in the studies by Ranjan et al.[22] and Kumar (2019) et al.[23]Sitagliptin 100mg/d was the active comparator in the studies by Kumar (2018) et al.[21] Singh (2018) et al.[24] and Singh (2018a) et al.[25] The duration of the follow-up was 24 weeks in the studies by Baidya et al. (2018c),[20] Kumar et al. (2018),[21] Kumar et al. (2019),[23] Ranjan et al.[22] Singh et al.(2018),[24] and Singh et al. (2018a).[25] The dose of HCQ used in the studies by Chakravarti et al.[15], Pareek et al.[17], Hsia et al.[18], Baidya et al. (2018c)[20], Ranjan et al.[22], Kumar (2018) et al.[21], Kumar (2019) et al.[23], Singh (2018) et al.[24] and Singh (2018a) et al.[25] was 400mg/d. In the studies by Gerstein et al.[16] and Quatraro et al.[19], the dose of HCQ used was 300–600 and 600mg/d, respectively. The details of all the RCTs included have been elaborated in [Supplementary Table 1]. The characteristics of the studies excluded are given in [Supplementary Table 2]. Risk of bias in the included studies The summaries of the risk of bias of the 11 studies included in the meta-analysis have been elaborated in [Figure 2]a, and [Figure 2]b. The random sequence generation bias was judged to be low risk in 5 out of the 11 RCTs (45.45%). The allocation concealment and reporting bias were judged to be at low risk of bias in all the 11 RCTs (100%). The performance bias (blinding of participants and investigators) and detection bias (blinding of outcome assessors) were judged to be at low risk of bias in 4 out of 11 studies (36.36%). Attrition bias was low risk in 8 out of 11 studies (72.72%). The source of funding, especially pharmaceutical, authors from the pharmaceutical organizations, and conflict of interests were looked into the “other bias” section. The other bias was judged to be at a low risk in 10 out of 11 studies (90.90%) [Figure 2]a, [Figure 2]b. Among the 11 trials evaluated in this study, four were of good quality, one of fair quality, and six trials (54.54%) were of poor quality as evaluated by the Jadad scale [Supplementary Table 3].
Effect of HCQ on the primary outcomes: Efficacy HbA1c Data from eight studies involving 2,334 patients were analyzed to find out the impact of HCQ on HbA1c in the ACG. The reduction in HbA1c after 16-24 weeks was significantly greater in the HCQ group as compared to the active controls (MD -0.17% [95%CI: -0.30 – -0.04; P=0.009; I2=89%][considerable heterogeneity]); [Figure 3]a; very low certainty of evidence (VLCE); [Supplementary Table 1]]. Data from three studies involving 284 patients with T2DM were analyzed to find out the impact of HCQ on HbA1c in the PCG. The reduction in HbA1c after 12-24 weeks was significantly greater in people receiving HCQ as compared to those receiving placebo in the PCG (MD -1.35% [95% CI: -2.10 – -0.59; P = 0.005; I2 = 74%] [moderate heterogeneity]); [Figure 3]b].
Effect of HCQ on the secondary outcomes: Efficacy Fasting glucose Data from eight studies involving 2,334 patients were analyzed to find out the impact of HCQ on fasting glucose in the ACG. The reduction in the fasting glucose after 16-24 weeks was significantly greater in the HCQ as compared to the active controls (MD -16.63 mg/dL [0.9 mmol/L] [95% CI: -25.99 – -7.28 mg/dL] [-1.4 - -0.4 mmol/L]; P < 0.001; I2 = 97% [considerable heterogeneity]; [Figure 3]c; VLCE; [Table 1]). Data from only one study involving 112 patients with T2DM were analyzed to find out the impact of HCQ on fasting glucose in the PCG, which was significantly higher in the HCQ as compared to those receiving placebo in the PCG (MD -22.00 mg/dL [-1.2 mmol/L] [95% CI: -32.47 – 11.53 mg/dL] [-1.8 - -0.6 mmol/L]; P < 0.001; [Figure 3]d). Post-prandial Glucose Data from seven studies involving 2,312 patients were analyzed to find out the impact of HCQ on 2-hour PPG in the ACG. The reduction in the 2-h PPG was significantly greater in the people receiving HCQ as compared to the ACG (MD -8.41 mg/dL [-0.5 mmol/L] [95% CI: -14.71 – -2.12 mg/dL] [-0.8 - -0.1 mmol/L]; P = 0.009; I2 = 87% [considerable heterogeneity]; [Figure 4]a; VLCE; [Table 1]). Data from one study involving 112 patients (Chakravarti et al[14]) with T2DM was analyzed to find out the impact of HCQ on 2-h PPG in the PCG. The reduction in 2-h PPBG was significantly higher in the people receiving HCQ as compared to those receiving placebo in the PCG (MD -41.00 mg/dL [-2.3 mmol/L] [95% CI: -55.64 – 26.36 mg/dL] [-3.1 - -1.5 mmol/L]; P < 0.001).
Effect of HCQ on secondary outcomes: Lipid parameters Data from four studies involving 1,154 patients with T2DM was analyzed to find out the impact of HCQ on TC and LDL cholesterol in the ACG. The reduction in the TC was significantly greater in the HCQ as compared to those receiving any other anti-diabetes medication in the ACG (MD -5.78 mg/dL [-0.15 mmol/L] [95% CI: -9.52 – -2.04 mg/dL] [-0.25 - -0.05 mmol/L]; P = 0.002; I2 = 35% [low heterogeneity]; [Figure 4]b; moderate certainty of evidence (MCE); [Table 1]). The reduction in LDL cholesterol was significantly greater in HCQ as compared to the ACG (MD -4.38 mg/dL [-0.11 mmol/L] [95% CI: -6.41 – -2.34 mg/dL] [-0.17 - -0.06 mmol/L]; P < 0.001; I2 = 26% [low heterogeneity]; [Figure 4]c; MCE). Data from three studies involving 854 patients were analyzed to find out the impact of HCQ on HDL cholesterol in the ACG which was not significantly different (MD -0.36 mg/dL [-0.01 mmol/L] [95% CI: -2.99 – 2.47] [-0.08 – 0.06 mmol/L]; P = 0.79; I2 = 60% [moderate heterogeneity]; [Figure 4]d). Data from three studies involving 854 patients were analyzed to find out the impact of HCQ on serum triglycerides in the ACG. Serum triglycerides was significantly lower in people receiving HCQ as compared to those receiving any other anti-diabetes medication in the ACG (MD -5.99 mg/dL [-0.07 mmol/L] [95% CI: -6.91 – -5.06 mg/dL] [-0.08 - -0.06 mmol/L]; P < 0.001; I2 = 0% [low heterogeneity]; [Figure 4]e; MCE). The effect of HCQ on secondary outcomes: HbA1c <7% (53 mmol/mol) Data from three studies involving 854 patients were analyzed to find out the impact of HCQ on the percentage of people achieving HbA1c <7% (53 mmol/mol) in the ACG. The percentage of people achieving HbA1c <7% (53 mmol/mol) was not different in the patients receiving HCQ as compared to the ACG (odds ratio [OR] 0.78 [95% CI: 0.06 – 10.58]; P = 0.85; I2 = 69% [moderate heterogeneity]; [Figure 4]f). Effect of HCQ on secondary outcomes: Safety Data from 11 studies involving 2,723 patients were analyzed to evaluate the impact of HCQ on the occurrence of adverse events. The adverse events reported were primarily minor with gastrointestinal adverse events being the most common (gastritis, flatulence, constipation). Two patients noticed hyperpigmentation. In a study by Pareek et al.,[16] two deaths were reported from the HCQ group (one due to acute myocardial infarction and the other due to acute pulmonary edema), and were believed to be unrelated to the drug as per the investigators.[14] Three reports of non-proliferative diabetic retinopathy (NPDR) were noted from the same study (two in the pioglitazone ACG and one in the HCQ group).[14] In the study by Gerstein et al.,[15] one patient in the HCQ group developed proliferative retinopathy (PDR) requiring laser therapy after 18 months of treatment.[13] Another patient in the HCQ group developed abnormal visual fields from drusen in both eyes and macular edema after 7 months of therapy. One patient in the placebo control group developed macular degeneration after 10 months of follow-up.[13] The occurrence of total adverse events (TAEs) was not statistically different in patients receiving HCQ as compared to the controls (RR 0.93 [95% CI: 0.68 – 1.28]; P = 0.65; I2 = 66% [considerable heterogeneity]; [Figure 5]a; low certainty of evidence [LCE]; [Table 1]).
Data from 10 studies involving 1,974 patients were analyzed to evaluate the impact of HCQ on the occurrence of hypoglycemic events. The occurrence of hypoglycemia was not statistically different in patients receiving HCQ as compared to the controls (RR 0.78 [95% CI: 0.39 – 1.59]; P = 0.50; I2 = 66% [considerable heterogeneity]; [Figure 5]b; LCE; [Table 1]). A reduction in the insulin dose was noted in the patients receiving HCQ in the studies by Gernstein et al[15]. Quatraro et al[18] and Kumar et al.[20] Once, the patient in the HCQ group in the study by Gernstein et al[15]. had severe hypoglycemia, necessitating a significant reduction in the total daily dose of insulin.[13] There were no other reports of severe hypoglycemia. Data from seven studies involving 2,046 patients were analyzed to evaluate the impact of HCQ on the bodyweight, which was not significantly different (MD -0.54 kg [95% CI: -1.11 – 0.03]; P = 0.06; I2 = 91% [considerable heterogeneity]; [Figure 5]c; LCE; [Table 1]).
A meta-analysis has been published on December 31, 2020, evaluating the glycemic efficacy and safety of HCQ in T2DM.[36] That study included data from eight RCTs (1,763 patients).[36] The authors noted that HCQ use over 6 months was associated with HbA1c reduction of -0.88% (95% CI: -1.01 to - 0.75) compared to placebo and by -0.32% (95% CI: -0.37 to -0.26) compared to other oral diabetes agents.[36] Our meta-analysis is a more updated version having included data from three more RCTs which were missed in the prior analysis. We evaluated data from 11 RCTs (three having placebo as controls and eight having anti-diabetes medications as controls involving 2,723 patients). Ours is the first Cochrane meta-analysis to holistically analyze the efficacy and safety of HCQ in managing glycemia in people with T2DM with rigorous grading of the results. In our meta-analysis, HCQ use over 6 months was associated with HbA1c reduction of -1.35% (95% CI:-2.10 to -0.59) compared to placebo and by -0.17% (95% CI:-0.30 to -0.04) compared to other oral anti-diabetes agents. When compared to active controls, the additional benefit with HCQ with regards to HbA1c reduction was much more tempered in our analysis as compared to the previous observations.[36] The results of a meta-analysis are as good as the quality of the studies evaluated in it. These observations are clouded by the high data heterogeneity and the very low quality of evidence generated, which raises questions, if the same can be replicated in the real-world scenario. Hence, this meta-analysis highlights the poor quality of data evaluating the short-term glycemic efficacy of HCQ as the performance and detection bias was high in 60% of the studies, with >50% of the RCTs being of poor quality as per the Jadad scale. The issues of poor data quality and high heterogeneity were also noted previously.[36] A marginally better weight reduction seen with HCQ in this meta-analysis may be an indirect consequence of the use of pioglitazone in some of the studies as the active comparator agent, which is well known to cause weight gain. This meta-analysis highlights that the current safety data with regard to the use of HCQ for managing diabetes is primarily limited to 6 months. There is a glaring lack of long-term safety data with regard to the use of HCQ in T2DM. Hence, it is surprising that the research society for the study of diabetes in India (RSSDI) has recommended the use of HCQ as a third-line agent in the management of T2DM.[37] Till definitive further long-term data are available, it may be said that the good clinical practices with the long-term use of HCQ include ensuring that the total daily dose should not cross 400 mg, preferable to keep a daily dose <5 mg/kg/day, keep the total lifetime cumulative dose to less than 1,000 mg, restrict the total duration of therapy to less than 6 months in accordance with the current available safety and efficacy data in the use of HCQ in T2DM, and to reduce the risks of retinal toxicity.[8],[38] It must be remembered that diabetes per se is a risk factor for retinal injury. A recent study from India involving more than 51,000 patients reported a 19% (95% CI: 18.9-19.5) prevalence of diabetic retinopathy.[39] The potential issues regarding long-term cardiovascular safety and ocular safety can only be established with long-term large multi-centric RCTs. To conclude, it may be said that the current evidence with regards to the use of HCQ in managing T2DM remains sketchy in view of the predominantly short-term studies of poor quality and high heterogeneity. The routine use of HCQ for managing T2DM cannot be recommended based on the current available data. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1]
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