|Year : 2020 | Volume
| Issue : 4 | Page : 184-193
Glycemic efficacy and safety of hydroxychloroquine in type 2 diabetes mellitus: A systematic review and meta.analysis of relevance amid the COVID-19 pandemic
Rimesh Pal1, Mainak Banerjee2, Ashok Kumar3, Sanjay Kumar Bhadada1
1 Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, India
3 Department of National Institute of Nursing Education, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||23-Sep-2020|
|Date of Acceptance||28-Oct-2020|
|Date of Web Publication||31-Dec-2020|
Prof. Sanjay Kumar Bhadada
Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Aims: Hydroxychloroquine (HCQ) is approved for use as an oral anti-diabetic drug (OAD) in patients with uncontrolled type 2 diabetes mellitus (T2DM); however, robust data are lacking. The present meta-analysis was conducted to provide precise effect estimates regarding the efficacy and safety of HCQ in patients with T2DM.
Methods: PubMed/Cochrane Library and grey literature were systematically searched till August 25, 2020, to identify randomized controlled trials (RCTs) with duration =12 weeks, evaluating the efficacy and safety of HCQ (400 mg/day) in patients with T2DM and glycated hemoglobin (HbA1c) =7.0%–7.5% already on a combination of metformin/sulfonylurea compared to either placebo or another OAD.
Results: We identified eight eligible RCTs, pooling data retrieved from 1763 patients with T2DM. HCQ resulted in significant decrease in HbA1c by 0.88% (95% confidence interval [CI]: -1.01 to - 0.75) compared to placebo and by 0.32% (95% CI: -0.37 to -0.26) compared to an OAD. Besides, there were significant reductions in fasting blood glucose, postprandial blood glucose, body weight, triglycerides, and low-density lipoprotein. A small but significant increase in high-density lipoprotein was also noted. An increase in the risk of any episode of symptomatic hypoglycemia (whether documented or not) was observed (risk ratio = 1.34 [95% CI: 1.10–1.63]). No other safety issues were identified.
Conclusions: The meta-analysis suggests that HCQ, used as an add-on drug in patients with T2DM exerts significant beneficial effects on glycemic control, body weight, and lipid profile, however, increasing the risk for symptomatic hypoglycemia. HCQ might be useful amid the ongoing pandemic, as the drug has also been found to be beneficial in COVID-19.
Keywords: Hydroxychloroquine, oral anti-diabetic drug, type 2 diabetes mellitus, uncontrolled diabetes mellitus
|How to cite this article:|
Pal R, Banerjee M, Kumar A, Bhadada SK. Glycemic efficacy and safety of hydroxychloroquine in type 2 diabetes mellitus: A systematic review and meta.analysis of relevance amid the COVID-19 pandemic. Int J Non-Commun Dis 2020;5:184-93
|How to cite this URL:|
Pal R, Banerjee M, Kumar A, Bhadada SK. Glycemic efficacy and safety of hydroxychloroquine in type 2 diabetes mellitus: A systematic review and meta.analysis of relevance amid the COVID-19 pandemic. Int J Non-Commun Dis [serial online] 2020 [cited 2022 Sep 25];5:184-93. Available from: https://www.ijncd.org/text.asp?2020/5/4/184/306000
| Introduction|| |
Metformin remains the first-line pharmacotherapy for the management of type 2 diabetes mellitus (T2DM). The American Diabetes Association (ADA) emphasizes on sodium-glucose transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) as second-line anti-diabetic drugs especially in patients with established atherosclerotic cardiovascular disease (ASCVD) or high risk of ASCVD. However, in a developing country like India that harbors nearly 77 million patients with diabetes mellitus, most patients are unable to afford SGLT2i and GLP-1 RA as these classes of drugs are exorbitantly priced. In a recent audit of endocrine practice from India that analyzed the records of 403 patients with T2DM, sulfonylureas (SUs) were the most commonly prescribed second-line drug class. SUs, however, do not address the issue of declining β-cell function and most patients initially responding to metformin and SUs lose their effectiveness with time. Hence, the majority of the patients require a third-line anti-diabetic drug to achieve glycemic targets.
In most cases, the third-line drug is a dipeptidyl-peptidase 4 inhibitor (DPP4i), pioglitazone, alpha-glucosidase inhibitor, SGLT2i, or insulin. When used as a third-line agent, DPP4i can lower glycated hemoglobin (HbA1c) only modestly hence might not be sufficient in patients with uncontrolled T2DM. Although pioglitazone has a good HbA1c lowering efficacy, the drug is fraught with adverse effects; hence, its use in India has reduced. Alpha-glucosidase inhibitors, although effective in lowering postprandial glycemic excursions and well-suited for the typical carbohydrate-rich Indian diet, multiple dosing and gastrointestinal intolerance are some of the drawbacks. Insulin therapy is not only costly but the need for parenteral administration compromises patient compliance. Thus, an effective, safe and affordable third-line anti-diabetic drug after metformin and SU/DDP4i remains an elusive goose in the Indian scenario.
Hydroxychloroquine (HCQ) was approved for the management of T2DM by the Drug Controller General of India at a dose of 400 mg/day as an adjunct to diet and exercise to improve glycemic control in patients on a combination of metformin and SU. The drug was also endorsed by the Research Society for the Study of Diabetes in India clinical practice recommendations as a third-line drug for the management of T2DM. Few randomized controlled trials (RCTs) and prospective observational studies have evaluated the role of HCQ as an anti-diabetic drug in patients with uncontrolled T2DM; however, to date, no meta-analysis exists in this regard. Besides, amid the ongoing pandemic, HCQ has been found to have some beneficial role in the treatment and prophylaxis of COVID-19., Thus, a drug that is useful in the management of COVID-19, as well as T2DM, would be a boon as COVID-19 tends to be severe and fatal in patients with T2DM.,,
Hence, the present systematic review was undertaken to identify, critically appraise and summarize all the relevant RCTs and provide precise effect estimates regarding the efficacy and safety of adding HCQ as a third-line anti-diabetic drug in patients with T2DM.
| Systematic Review and Meta-Analysis|| |
This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic reviews and Meta-analyses statement.
A systematic review of the literature was performed across PubMed and Cochrane Library from inception till August 25, 2020, using the following keywords: “Hydroxychloroquine,” “diabetes mellitus,” “diabetes,” and “T2DM” with interposition of the Boolean operator “AND”/”OR.” Besides, grey literature was searched for nonindexed studies. The studies published in the English language were only included. References of the included studies were also manually searched for relevant articles. The search was conducted independently by two investigators (RP and MB). For missing data, the corresponding authors of the included studies were contacted wherever possible.
Eligibility and exclusion criteria
Eligibility criteria were set as follows:
- All studies had to be RCTs irrespective of study design (parallel/cross-over), study blinding (single-blind, double-blind, or open-label), and sample size
- All the participants should have been patients of T2DM
- The intervention group should have been treated with HCQ at a dose of 400 mg/day, the recommended anti-diabetic dose
- The comparator could have been either a placebo or another oral anti-diabetic drug (OAD) (active comparator)
- The minimum duration of the study should have been 12 weeks
- The studies should have provided at least one of the following treatment outcomes: HbA1c, fasting blood glucose (FBG), postprandial blood glucose (PPBG)
- The data should have been presented in mean ± standard deviation (SD).
Exclusion criteria were set as follows:
- Observational studies
- Reviews, abstracts, and animal studies
- Studies involving patients without T2DM
- Studies involving patients with diabetes mellitus and coexisting rheumatological disorders
- Incompleteness in data
- Errors in statistical methods.
Two investigators (RP and MB) independently scanned titles and/or abstracts to exclude duplicate studies and studies that failed to meet the aforementioned eligibility criteria. Studies hence selected were reviewed and the following data were extracted from full-text reports for further assessment: study characteristics, participants' baseline characteristics, baseline treatment, and comparators along with key efficacy and safety outcomes. Our primary efficacy outcome was the glycemic efficacy of HCQ compared to the placebo/active comparator, as assessed by the absolute change in HbA1c levels (%). Secondary efficacy outcomes were the absolute changes in FBG (mg/dl), PPBG (mg/dl), body weight (kg)/body mass index (BMI, kg/m2), triglycerides (mg/dl), low-density lipoprotein (LDL, mg/dl) and high-density lipoprotein (HDL, mg/dl). Major safety outcomes that were assessed included any episode of symptomatic hypoglycemia (whether documented or not), gastrointestinal adverse events, diabetic retinopathy, and death. For trials reporting glycemic efficacy at multiple time points (=12 weeks), we used the data with the longest duration of intervention.
Risk of bias assessment
Two investigators (RP and MB) independently assessed the risk of bias in the following domains using the corresponding Cochrane Collaboration's tool: Random sequence generation, allocation concealment, blinding of participants and staff, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting. Each domain was rated as “low,” “unclear” or “high” risk of bias. A study was rated as being of low risk of bias in the presence of adequate procedures in all the domains; on the contrary, an inadequate procedure in at least one domain rated a study as being of a high risk of bias. In any other case, a study was labeled as being of unclear risk of bias. Any discrepancy was solved by a discussion with a third senior investigator (SKB).
Statistical analysis was performed using the RevMan 5.4 software. For continuous outcome variables, we calculated the mean differences (MD) with 95% confidence intervals (CIs), using an inverse variance weighted fixed-effects model. Regarding dichotomous safety variables, differences were calculated with the use of risk ratio (RR) with 95% CI after implementation of the Mantel-Haenszel fixed-effects formula. Studies where the change in outcome SDs was not reported, the same was calculated from baseline and final SDs using the formula:
where r represents the correlation coefficient. As a conservative strategy, r was considered to be 0.5. The same strategy has been employed in prior meta-analyses of interventions in T2DM.
Statistical heterogeneity among studies was assessed using I2 statistics. Heterogeneity was quantified as low, moderate, and high with upper limits of 25%, 50%, and 75% for I2, respectively. A P < 0.05 was considered to be statistically significant.
| Results|| |
After a scrupulous literature search and a meticulous study selection process, we included 8 RCTs in our meta-analysis pooling data retrieved from 1763 patients with T2DM in total [Figure 1].,,,,,,, Two of the 8 studies had used placebo as a comparator,, while the rest had used an active comparator, namely, pioglitazone,, vildagliptin, sitagliptin, teneligliptin, SU, and metformin. The study by Baidya and Ahmed had three arms: Group A (metformin 2000 mg + glimepiride 2 mg), Group B (metformin 1000 mg + glimepiride 2 mg + HCQ 400 mg) and Group C (metformin 1000 mg + glimepiride 4 mg). Hence, for this meta-analysis, we separately compared both Group A and Group C with Group B (separate comparisons between HCQ 400 mg with metformin 1000 mg and between HCQ 400 mg with glimepiride 2 mg).
As presented in [Table 1], all the studies had included adult patients with T2DM with an HbA1c ≥7.0%–7.5% on a stable combination of metformin ≥500 mg/day (maximum 2000 mg/day) and glimepiride ≥2–4 mg/day (or gliclazide ≥160 mg/day) with/without insulin. Except for the study by Chakravarti and Nag and Hsia et al., the study duration extended over 24 weeks. The risk of bias assessment of the selected studies has been presented in [Supplementary Table 1]. The results of the meta-analysis have been presented below.
|Table 1: Overview of the randomized controlled trials included in the meta-analysis|
Click here to view
Addition of HCQ at a dose of 400 mg/day led to a significant decrease in HbA1c compared placebo (MD - 0.88% [95% CI: -1.01 to -0.75], P < 0.001, I2 = 74%) [Figure 2]a. Compared to any active comparator, HCQ was also associated with a significant decrease in HbA1c (MD - 0.32% [95% CI: -0.37 to -0.26], P < 0.001, I2 = 87%) [Figure 2]b.
|Figure 2: (a and b) Forest plots showing the effect of hydroxychloroquine on glycated hemoglobin levels as compared to placebo (a) or other oral anti-diabetic drugs (b). GP - Glimepiride, Met - Metformin, Vilda - Vlidagliptin, Pio - Pioglitazone, Sita - Sitagliptin, Teneli - Teneligliptin|
Click here to view
Fasting blood glucose
Compared to placebo, addition of HCQ led a significant decrease in FBG (MD 29.67 mg/dl [95% CI: -36.02 to -23.31], P < 0.001, I2 = 59%) [Figure 3]a. Similarly, when compared to an OAD, HCQ was also associated with a decrease in FBG (MD - 8.21 mg/dl [95% CI: -9.97 to -6.45], P < 0.001, I2 = 32%) [Figure 3]b.
|Figure 3: (a and b) Forest plots showing the effect of hydroxychloroquine on fasting blood glucose levels as compared to placebo (a) or other oral anti-diabetic drugs (b). GP - Glimepiride, Met - Metformin, Vilda - Vlidagliptin, Pio - Pioglitazone, Sita - Sitagliptin, Teneli - Teneligliptin|
Click here to view
Postprandial blood glucose
HCQ was associated with a decline in PPBG compared to placebo (MD - 66.34 mg/dl [95% CI: -74.84 to -57.84], P < 0.001, I2 = 97%) [Figure 4]a. Compared to an OAD, HCQ still demonstrated a significant decline in PPBG (MD - 13.84 mg/dl [95% CI: -16.32 to -11.35], P < 0.001, I2 = 26%) [Figure 4]b.
|Figure 4: (a and b) Forest plots showing the effect of hydroxychloroquine on postprandial blood glucose levels as compared to placebo (a) or other oral anti-diabetic drugs (b). GP - Glimepiride, Met - Metformin, Vilda - Vlidagliptin, Pio - Pioglitazone, Sita - Sitagliptin, Teneli - Teneligliptin|
Click here to view
Body weight/body mass index
Use of HCQ as an add-on OAD was associated with a decrease in body weight as compared to placebo (MD - 4.09 kg [95% CI: -5.75 to -2.42], P < 0.001, I2 = 80%) [Figure 5]a. Compared to an OAD, HCQ was also associated with a small but significant decline in body weight (MD - 1.10 kg [95% CI: -1.74 to -0.46], P < 0.0007, I2 = 0%) [Figure 5]b. For studies reporting BMI, HCQ also showed a significant decline compared to active comparator (MD - 1.88 kg/m2 [95% CI: -2.33 to -1.42], P < 0.001, I2 = 0%) [Figure 5]c.
|Figure 5: (a-c) Forest plots showing the effect of hydroxychloroquine on body weight as compared to placebo (a) or other oral anti-diabetic drugs (b). Likewise, forest plot showing effect of hydroxychloroquine on body mass index as compared to other oral anti-diabetic drugs. (c) GP - Glimepiride, Met - Metformin, Pio - Pioglitazone, Sita - Sitagliptin, Teneli - Teneligliptin|
Click here to view
Data on change in triglycerides were reported in 3 studies, all involving OADs as comparators.,, The addition of HCQ was found to be associated with a significant reduction in triglycerides as compared to other OADs (MD - 11.47 mg/dl [95% CI: -17.13 to -5.82], P < 0.001, I2 = 0%) [Supplementary Figure 1].
Data on change in LDL cholesterol were available from 4 studies, all involving active comparators.,,, HCQ led to a significant decline in LDL compared to other OADs (MD - 9.76 mg/dl [95% CI: -12.74 to -6.77], P < 0.001, I2 = 64%) [Supplementary Figure 2].
Change in HDL with treatment was reported in 3 studies involving pioglitazone, metformin 1000 mg, and glimepiride 2 mg as comparators.,, HCQ was found to be associated with a significant increase in the levels of HDL cholesterol compared to other OADs (MD 2.31 mg/dl [95% CI: 1.05–3.56], P value = 0.0003, I2 = 78%) [Supplementary Figure 3].
Any episode of symptomatic hypoglycemia (whether documented or not) was considered for the meta-analysis. Four studies with optimum reporting of hypoglycemic events were included.,,, The use of HCQ was associated with an increased risk of any hypoglycemic event compared to another OAD by 34% (RR: 1.34 [95% CI: 1.10–1.63], P = 0.004, I2 = 68%) [Figure 6]. Episodes of severe hypoglycemia were inconsistently reported across the included studies. While Ranjan et al., Chakravarti and Nag, and Baidya and Ahmed, did not report any episode of severe hypoglycemia in the HCQ treated patients, Kumar et al. reported 32 episodes of hypoglycemia with documented capillary blood glucose ≥50 mg/dl.
|Figure 6: Forest plot showing the effect of hydroxychloroquine on the risk of any episode of symptomatic hypoglycemia as compared to other oral anti-diabetic drugs. GP - Glimepiride, Met - Metformin, Vilda - Vlidagliptin, Pio - Pioglitazone, Sita - Sitagliptin|
Click here to view
Other safety outcomes
Compared to placebo, the use of HCQ was associated with increased gastrointestinal disturbances (1 patient in placebo arm vs. 16 patients in HCQ arm). The number of patients having diarrhea/dyspepsia was almost similar in the pioglitazone and HCQ arms (3 in pioglitazone vs. 4 in HCQ). On the contrary, Baidya and Ahmed reported that the incidence of gastrointestinal adverse events was more in the high-dose metformin group compared to the HCQ group, although not statistically significant. The rise in creatinine phosphokinase levels was reported in only 1 patient from 2 studies., Nonproliferative diabetic retinopathy (NPDR) was reported in only 1 patient receiving HCQ, the rest of the studies did not report any ophthalmology-related adverse events in the HCQ treatment arm.,, Only three deaths were reported from 2 studies, one each was attributed to acute myocardial infarction, acute pulmonary edema, and malignant lung neoplasm; none was deemed related to the use of HCQ., There were no reports of arrhythmia in any of the included RCTs.
| Discussion|| |
In the present meta-analysis, we have demonstrated that the addition of HCQ to the ongoing metformin and SU combination in patients with T2DM and HbA1c above the ADA recommended glycemic target of 7.0% results in a significant decrease in glycemic parameters, namely, HbA1c, FBG and PPBG when compared to placebo or other OAD. Besides, HCQ is associated with a significant reduction in weight/BMI, triglycerides, LDL, and a small but significant increase in HDL. However, the use of HCQ led to an increase in the odds of any symptomatic hypoglycemic event by 34%.
Most patients with T2DM require pharmacotherapy with two or more anti-diabetic drugs to achieve optimum glycemic control. Metformin remains the first-line anti-diabetic drug in patients with T2DM in the developed as well the developing nations, like India., As a second-line drug, SUs rank first in India mostly because of their high HbA1c lowering efficacy, widespread availability, and low cost. Most patients initially respond to a combination of metformin and SU, however, they lose their effectiveness with time, necessitating the addition of a third oral agent or insulin. However, the use of insulin in the Indian scenario is limited due to its relatively high cost, poor compliance, and clinical inertia in initiating insulin on part of the physicians. Among oral agents, DPP4i, pioglitazone, alpha-glucosidase inhibitors, and SGLT2i are viable third-line options. DPP4i are safe and relatively inexpensive; however, their efficacy as a third-line agent is low-to-modest. Pioglitazone is inexpensive and efficacious, however, is associated with a myriad of adverse events such as weight gain, fluid retention, macular edema, worsening of heart failure, and increased risk of osteoporosis and fragility fractures, hence, should be used cautiously. Alpha-glucosidase inhibitors require multiple dosing and are associated with significant gastrointestinal disturbance, hence, are usually not preferred. Sodium-glucose transporter-2 inhibitors, apart from lowering HbA1c, promote weight loss, offer cardio-protection and reno-protection in patients with T2DM; however, they are highly priced and are unaffordable for patients belonging to a developing nation like India.
HCQ, the metabolite of the anti-malarial drug, chloroquine, is a safe and age-old disease-modifying anti-rheumatic drug used widely for the management of rheumatoid arthritis (RA) and systemic lupus erythematosus. The role of HCQ in preventing the development of diabetes mellitus was highlighted in a prospective observational study of 4905 adults with Over a follow-up period of 21.5 years, the use of HCQ was associated with a reduced risk of diabetes. Patients who took HCQ for >4 years had a significant 77% lower risk of developing diabetes mellitus compared with HCQ nonusers (RR 0.23; 95% CI: 0.11–0.50). This serendipitous finding supported a favorable action of HCQ on glucose metabolism. Besides, in a 13-week study in nondiabetic adults, HCQ was found to improve insulin sensitivity and β-cell function. Improvement in insulin sensitivity was also associated with a significant increase in plasma adiponectin levels. Taking cues from these studies and considering the pleiotropic effects of HCQ in patients with rheumatological disorders (lipid-lowering and anti-thrombotic),, the drug was further investigated as an OAD.
Although two RCTs with HCQ as an anti-diabetic drug in patients with treatment-refractory T2DM had been conducted as long back as 1990 and 2002, respectively, the studies had either involved a very limited number of patients or had used HCQ at a dose different from that presently recommended., The first substantial RCT using HCQ at a dose of 400 mg/day was conducted by Pareek et al. in 2014. Thereafter, a handful of prospective/retrospective observational studies,, and RCTs,,,,,, had been conducted with HCQ being compared head-to-head with either placebo or other OAD drugs. However, to date, there had been no meta-analysis assessing the glycemic efficacy of the drug.
In this meta-analysis that had included 8 hitherto available RCTs, the addition of HCQ as a third-line OAD drug in patients already on metformin and SUs and still having an HbA1c ≥7.0%–7.5% was found to significantly lower the HbA1c, FBG, and PPBG as compared to placebo as well other OAD agents, notably, DPP4i, pioglitazone, and glimepiride. The glucose lowering effect of HCQ is attributed to reduced insulin degradation and improved insulin sensitivity. In normal physiology, following the binding of insulin to cell surface insulin receptor, the insulin-insulin receptor is endocytosed and subsequently, the insulin moiety is destroyed by endosomal insulin-degrading enzymes. HCQ, an acidophilic drug, selectively concentrates in the intracellular endosomes increasing the pH. Increased endosomal pH inhibits the action of insulin-degrading enzymes, and thus there is less insulin degradation. Insulin is thus re-released into circulating which is free to act on another insulin receptor. Consistent with its immunomodulator property, HCQ also reduces pro-inflammatory cytokines, notably tumor necrosis factor alpha and interleukin 6, as well as other inflammatory markers like hsCRP, thereby decreasing insulin resistance., Secondary to improvement in insulin sensitivity, HCQ was also found to reduce body weight/BMI by 4.09 kg as compared to placebo and 1.10 kg as compared to other OAD drugs. Weight loss would be highly desirable as most of the commonly used anti-diabetic agents in India, namely, SUs, pioglitazone, and insulin, lead to weight gain. Weight gain secondary to glucose-lowering agents has shown to be associated with a relative increase in the risk of heart failure. Besides, the use of HCQ is associated with a reduction in the doses of insulin which can further contribute to weight loss.,
The herein demonstrated glucose-lowering effect of HCQ would be a boon amid the ongoing COVID-19 pandemic. The novel coronavirus disease tends to be more severe and fatal in patients with DM.,, Patients with DM are more likely to require intensive care unit admissions and eventually die due to COVID-19. In this scenario, HCQ holds a unique position. The drug has been found to be beneficial in patients with COVID-19 both in terms of treatment and prophylaxis.,, Thus, initiation of HCQ as an add-on drug in patients with uncontrolled T2DM would theoretically help take care of glucose control and even perhaps reduce the risk of contracting the virus.,,
Besides its glycemic efficacy, HCQ was also found to have a beneficial effect on lipid profile, notably reduction in LDL and triglycerides and an increase in HDL. Part of the improvement in lipid profile could be attributed to a reduction in insulin resistance. In addition, the upregulation of hepatic LDL receptors has been proposed as one of the underlying mechanisms., In a double-blinded, randomized study conducted in 328 patients with primary dyslipidemia, a fixed-dose combination of atorvastatin (10 mg) and HCQ (200 mg) led to more number of patients achieving LDL and total cholesterol goals compared to atorvastatin (10 mg) alone.
Regarding safety outcomes, the use of HCQ was associated with an increased risk of any episode of symptomatic hypoglycemia by 34% compared to comparator anti-diabetic drugs. However, the majority of the studies did not report any episode of severe hypoglycemia.,,, The frequency of hypoglycemic episodes can probably be reduced by a concomitant reduction in the dose of the already ongoing SU. In addition to hypoglycemia, patients treated with HCQ had a higher frequency of gastrointestinal adverse events compared to placebo. Nevertheless, none of the included RCTs reported any episode of arrhythmia or major adverse cardiovascular event. The use of HCQ has been associated with cardiac toxicity, namely, bundle branch block, atrioventricular block, QT prolongation, torsades de pointes, and sudden cardiac death., Prior history of cardiovascular disease and chronic kidney disease are associated with an increased risk of QT prolongation and torsades de pointes., Most of the RCTs included in the present meta-analysis had excluded patients with preexisting cardiovascular disease and abnormal kidney function; besides, none had performed routine electrocardiographic assessments of cardiac rhythm; hence, detection of asymptomatic QT prolongation would have been virtually impossible.
Ocular toxicity is another important concern linked with the chronic use of HCQ. The development of retinopathy associated with HCQ depends on the dose and duration of exposure. At a recommended dose of 5 mg/kg real body weight (which would approximately amount to a dose of 400 mg/day in a typical obese patient with T2DM), the risk of toxicity up to 5 years is <1% and up to 10 years is <2%. Hence, expectedly, HCQ-associated retinopathy was not reported in any of the study participants included in the meta-analysis. However, it is recommended that patients planned for long-term use of HCQ should be screened at baseline for the presence of preexisting retinopathy and thereafter annually after 5 years of chronic use. Nevertheless, patients with T2DM are already on routine ophthalmological screening and hence are in a better position for early detection of HCQ-associated retinopathy. It might still be prudent to avoid HCQ in patients with moderate-severe NPDR and proliferative diabetic retinopathy as the same might make clinical screening for HCQ-related retinopathy difficult.
Our meta-analysis does have certain limitations. First, some of the included RCTs did have a high risk of bias in one or more domains. However, due to the scarcity of available literature, all the RCTs were included. Second, the comparator OAD drugs were highly variable across the included RCTs. Third, the observed heterogeneity can be considered as moderate-to-high. However, considering the myriad of anti-diabetic drugs with variable efficacy being used as a comparator, such heterogeneity was not unexpected. Due to the small number of included trials, we were not able to perform subgroup or meta-regression analyses for investigation of the heterogeneity.
| Conclusions|| |
To conclude, the addition of HCQ at a dose of 400 mg/day in patients with T2DM already on a combination of the maximum tolerated doses of metformin and SUs leads to improvement in glycemic parameters. Besides, HCQ also leads to weight loss and improvement in dyslipidemia. Apart from a modest increase in the risk of hypoglycemic episodes, the use of HCQ was found to be relatively safe over the study period. Considering its widespread availability, low cost, once-daily dosing, modest HbA1c lowering efficacy, and favorable side-effect profile, HCQ can be considered as a viable third-line anti-diabetic agent in Indian patients with uncontrolled T2DM. Preexisting cardiovascular disease, renal/hepatic disease, and diabetic retinopathy should be ruled out before initiating HCQ.
Ethical approval statement
Being a meta-analysis, ethical approval was not required.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2020. Diabetes Care 2020;43:S98-110.
Singla R, Bindra J, Singla A, Gupta Y, Kalra S. Drug prescription patterns and cost analysis of diabetes therapy in India: Audit of an endocrine practice. Indian J Endocrinol Metab 2019;23:40-5.
Kumar A. Second line therapy: Type 2 diabetic subjects failing on metformin GLP-1/DPP-IV inhibitors versus sulphonylurea/insulin: For GLP-1/DPP-IV inhibitors: Incretins superior to SU/Insulin in T2DM on metformin. Diabetes Metab Res Rev 2012;28:21-5.
Hayati F, Hazim A, Sasongko TH, Siew Hua G, Wan Mohamed WM, Daud J, et al
. Efficacy and safety of sitagliptin as a third therapeutic agent in the treatment of type 2 diabetes mellitus. J Diabetes Res Clin Metab 2014;3:10.
Kalra S, Sahay R, Schnell O, Sheu WH, Grzeszczak W, Watada H, et al
. Alpha-glucosidase inhibitor, acarbose, improves glycamic control and reduces body weight in type 2 diabetes: Findings on Indian patients from the pooled data analysis. Indian J Endocrinol Metab 2013;17:307.
Das AK, Kalra S, Tiwaskar M, Bajaj S, Seshadri K, Chowdhury S, et al
. Expert group consensus opinion: Role of anti-inflammatory agents in the management of type-2 diabetes (T2D). J Assoc Physicians India 2019;67:65-74.
Bajaj S. RSSDI clinical practice recommendations for the management of type 2 diabetes mellitus 2017. Int J Diabetes Dev Ctries 2018;38:1-115.
Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, et al
. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396-403.
Chatterjee P, Anand T, Singh K, Rasaily R, Singh R, Das S, et al. Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19. Indian J Med Res 2020;151:459-467.
] [Full text]
Pal R, Bhansali A. COVID-19, diabetes mellitus and ACE2: The conundrum. Diabetes Res Clin Pract 2020;162:108132.
Pal R, Bhadada SK. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diabetes Metab Syndr 2020;14:513-7.
Pal R, Bhadada SK. Should anti-diabetic medications be reconsidered amid COVID-19 pandemic? Diabetes Res Clin Pract 2020;163:108146.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al
. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009;339:b2700.
Higgins J, Sterne J, Savovic J, Page M, Hróbjartsson A, Boutron I, et al
. A revised tool for assessing risk of bias in randomized trials. Cochrane Database Syst Rev 2016;10:29-31.
Batson S, Burton H. A systematic review of methods for handling missing variance data in meta-analyses of interventions in type 2 diabetes mellitus. PLoS One 2016;11:e0164827.
Higgins JP. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Townsend D, Eynatten M, Norton J. A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of hydroxychloroquine in patients with type 2 diabetes mellitus. Glob J Endocrinol Metab 2018;2:GJEM.000543.
Chakravarti HN, Nag A. Efficacy and safety of hydroxychloroquine as add-on therapy in uncontrolled type 2 diabetes patients who were using two oral antidiabetic drugs. J Endocrinol Invest 2020;1-12.
Pareek A, Chandurkar N, Thomas N, Viswanathan V, Deshpande A, Gupta OP, et al
. Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: A double blind, randomized comparison with pioglitazone. Curr Med Res Opin 2014;30:1257-66.
Baidya A, Ahmed R. Effect of early addition of hydroxychloroquine in type 2 diabetic patients inadequately controlled on metformin and sulfonylurea combination therapy. Int J Res Med Sci 2018;6:2626.
Baidya A, Kumar M, Pathak S, Ahamed R. Study of comparative effect of hydroxychloroquine and vildagliptin on glycemic efficacy and HbA1c in type 2 diabetes patients who were inadequately controlled with metformin and glimepiride duel therapy. J Med Sci Clin Res 2018;6:409-15.
Kumar V, Singh MP, Singh AP, Pandey MS, Kumar S, Kumar S. Efficacy and safety of hydroxychloroquine when added to stable insulin therapy in combination with metformin and glimepiride in patients with type 2 diabetes compare to sitagliptin. Int J Basic Clin Pharmacol 2018;7:1959.
Ranjan P, Ahsan S, Bhushan R, Kumar B, Tushar, Gupta A, et al
. Comparison of efficacy and safety of Hydroxychloroquine and teneligliptin in type 2 diabetes patients who are inadequately controlled with glimepiride, metformin and insulin therapy: A randomized controlled trial with parallel group design. Ann Clin Endocrinol Metab 2017;2:033-40.
Hsia SH, Duran P, Lee ML, Davidson MB. Randomized controlled trial comparing hydroxychloroquine with pioglitazone as third-line agents in type 2 diabetic patients failing metformin plus a sulfonylurea: A pilot study. J Diabetes 2020;12:91-4.
Montvida O, Shaw J, Atherton JJ, Stringer F, Paul SK. Long-term trends in antidiabetes drug usage in the U.S.: Real-world evidence in patients newly diagnosed with type 2 diabetes. Diabetes Care 2018;41:69-78.
Wangnoo SK, Maji D, Das AK, Rao PV, Moses A, Sethi B, et al
. Barriers and solutions to diabetes management: An Indian perspective. Indian J Endocrinol Metab 2013;17:594-601.
Wasko MCM, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, et al
. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA 2007;298:187.
Wasko MC, McClure CK, Kelsey SF, Huber K, Orchard T, Toledo FG. Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: A randomised trial. Diabetologia 2015;58:2336-43.
Morris SJ, Wasko MC, Antohe JL, Sartorius JA, Kirchner HL, Dancea S, et al
. Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2011;63:530-4.
Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 2011;13:77-80.
Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, Ceriello A, et al
. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug? Ann Intern Med 1990;112:678-81.
Gerstein HC, Thorpe KE, Wayne Taylor D, Brian Haynes R. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas-a randomized trial. Diabetes Res Clin Pract 2002;55:209-19.
Gupta A. Real-world clinical effectiveness and tolerability of hydroxychloroquine 400 Mg in uncontrolled type 2 diabetes subjects who are not willing to initiate insulin therapy (HYQ-Real-World Study). Curr Diabetes Rev 2019;15:510-9.
Baidya A, Chakravarti HN, Saraogi RK, Gupta A, Ahmed R, Banerjee A, et al
. Efficacy of maximum and optimum doses of hydroxychloroquine added to patients with poorly controlled type 2 diabetes on stable insulin therapy along with glimepiride and metformin: association of high-sensitive C-Reactive protein (Hs-CRP) and glycosylated haemoglobin (Hba1c). Endocrinol Metab Syndr 2018;7:283.
Singh UP, Baidya A, Singla M, Jain S, Kumar S, Sarogi RK, et al
. Efficacy and safety of substituting teneligliptin with hydroxychloroquine in inadequately controlled type 2 diabetes subjects with combination therapy of teneligliptin, metformin and glimepiride with or without other antidiabetic therapy: The TENE-HYQ SHIFT Study. Clin Diabetol 2018;7:209-14.
Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: A meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2015;3:356-66.
Pal R, Bhadada SK. COVID-19 and non-communicable diseases. Postgrad Med J 2020;96:429-30.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al
. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949.
Pal R, Bhadada SK. Managing common endocrine disorders amid COVID-19 pandemic. Diabetes Metab Syndr 2020;14:767-71.
Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: Reversal of deleterious effects of steroids on lipids. Am J Med 1990;89:322-6.
Pareek A, Chandurkar N, Thulaseedharan NK, Legha R, Agarwal M, Mathur SL, et al
. Efficacy and safety of fixed dose combination of atorvastatin and hydroxychloroquine: A randomized, double-blind comparison with atorvastatin alone among Indian patients with dyslipidemia. Curr Med Res Opin 2015;31:2105-17.
Hooks M, Bart B, Vardeny O, Westanmo A, Adabag S. Effects of hydroxychloroquine treatment on QT interval. Heart Rhythm 2020;17:1930-1935.
Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila) 2006;44:173-5.
Malviya A. Ventricular arrhythmia risk due to chloroquine hydroxychloroquine treatment for COVID-19: Should it be given. Indian Heart J 2020;72:131-2.
Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology 2016;123:1386-94.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]