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)

Abstract

Objective: The epidemic of T2DM is rising across the globe. Systemic inflammation plays a pivotal role in the pathogenesis and complications of T2DM. Combination of two or more oral hypoglycemic agents (OHA) is widely prescribed in patients with T2DM, however many patients have poor glycemic control despite receiving combination therapy. The new antidiabetic drugs are relatively costly or many patients have anxiety over the use of injectable insulin. The objective of this observational study was to investigate the effectiveness and tolerability of hydroxychloroquine (HCQ) in T2DM patients uncontrolled on multiple OHA and despite high sugar level not willing to initiate insulin therapy in a real-world clinical setting. Methods: A prospective, investigator-initiated, observational, single-centred study was conducted where 250 patients (18-65 years) with T2DM for more than 5 years, with uncontrolled glycemia despite on a combination of multiple OHA, HbA1c between ≥7% and <10.5%, FPG >130 mg/dL or PPG >180 mg/dL and BMI between >25 and <39 kg/m2, were prescribed hydroxychloroquine sulphate 400 mg once daily for 48 weeks. Percentage of drugs used at the baseline were as follows: metformin 2000 mg (100%), glimepiride 4 mg (100%), pioglitazone 30 mg (100%), sitagliptin 100 mg (100%), canagliflozin 300 mg (52.4%), empagliflozin 25 mg (22.8%), dapagliflozin 10 mg (17.6%) and voglibose 0.3 mg (62%). Mean change in HbA1c, blood glucose and hs-CRP at baseline, week 12, 24 and 48 were assessed using the paired t-test. Results: After 48 weeks of add-on treatment with HCQ, almost all SGLT-2 inhibitors were withdrawn; metformin dose was reduced to 1000 mg, glimepiride reduced to 1 mg and sitagliptin reduced to 50 mg OD. Patients continued to have good glycemic control. HbA1c was reduced from 8.83% to 6.44%. Reduction in FPG was 40.78% (baseline 177.30 mg/dL) and PPG was reduced by 58.95% (baseline 329.86 mg/dL). Change in mean body weight was -4.66 Kg. The reduction in glycemic parameters and mean body weight was significant (p < 0.0001). Hs-CRP was significantly reduced from 2.70±1.98 mg/L to 0.71±0.30 mg/L 9 (p < 0.0001). More reduction in glycemic parameters and body weight was observed among the patients with higher hs-CRP (> 3 mg/L) as compared to patients with baseline hs- CRP ≤ 3 mg/L. Most common adverse events reported with the drug therapy were GI irritation (3.6%) and hypoglycemia (2%). None of the patients required medical assistance for hypoglycemia. Conclusion: Add-on treatment of HCQ effectively improved glycemic control in T2DM patients uncontrolled on multiple antidiabetic drugs. By virtue of its antidiabetic and anti-inflammatory properties, it may emerge as a valuable therapeutic intervention for the patients with T2DM.

Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection

“…24 Among 250 patients with poorly controlled type 2 diabetes who were unwilling to start insulin, hydroxychloroquine (400 mg/d) was associated with marked reductions in fasting plasma glucose, hemoglobin A 1c and body weight, whereas hypoglycemia developed in 2% of participants over the 48-month study period. 25 Physicians should warn patients who are being treated with chloroquine or hydroxychloroquine about the possibility of hypoglycemia and describe its manifestations. Management of hypoglycemia involves cessation of the drug and administration of supplemental glucose or parenteral dextrose as needed.…”

Antihyperglycemic properties of hydroxychloroquine in patients with diabetes: Risks and benefits at the time of COVID‐19 pandemic

“…Furthermore, patients with higher baseline hs-CRP levels also exhibited higher (although not significant) baseline levels of HbA1c, fasting-and postprandial glucose levels. (5) The previously mentioned study by Wasko et al (4) conducted in non-diabetic overweight or obese subjects also found that HCQ (at a dose of 400 mg/day) significantly increased plasma levels of the adipokine adiponectin, which plays a key role in insulin resistance and metabolic syndrome by exerting anti-inflammatory actions and increasing insulin sensitivity. (31)(32)(33) Importantly, HCQ use up to 24 weeks (at a dose of up to 600 mg/day) in patients with T2D has also led to an improved lipid profile, which consisted of a significant reduction in total cholesterol, LDL-cholesterol and non-HDL cholesterol in different studies.…”

“…Different studies have shown the safety and efficacy of HCQ use (at a dose ranging from 400 to 600 mg/day) in patients with T2D over a short-term period (up to 18 months). (5,11,12,14,15) In 2014, HCQ (at a dose of 400 mg/day) has been approved in India as an addon hypoglycemic agent for patients with inadequately controlled type 2 diabetes despite lifestyle management associated with sulfonylurea and metformin combination therapy. Nevertheless, concerns on long-term safety of HCQ in patients with T2D still persist due to the lack of robust data.…”

“…HCQ is a well-known anti-inflammatory and immunomodulatory agent able to reduce the production of pro-inflammatory cytokines, and is therefore used as a DMARD for the treatment of several inflammatory rheumatic diseases. (1,30) With regard to the anti-inflammatory effects of HCQ in T2D, Amit Gupta (5) has recently shown that diabetic patients with higher baseline levels of highsensitivity C-reactive protein (hs-CRP >3 mg/L) exhibited a more pronounced, although not significant, improvement in glucose control from baseline to 48 weeks after the initiation of HCQ therapy, as compared to patients with lower baseline levels of hs-CRP (≤ 3 mg/L). Furthermore, patients with higher baseline hs-CRP levels also exhibited higher (although not significant) baseline levels of HbA1c, fasting-and postprandial glucose levels.…”

“…(11) Moreover, a retrospective study conducted in diabetic patients with concomitant rheumatic diseases (RA and SLE) showed that HCQ, when compared to methotrexate, was associated with a significantly greater reduction in HbA1c from pre-treatment baseline to its lowest value within 12 months of treatment initiation. (13) More recently, a 24-week prospective randomized trial (14) and two real-world, prospective observational studies of short duration (up to 24-48 weeks) (5,15) conducted in India have shown that the use of HCQ (400 mg/day) as an add-on treatment in patients with T2D uncontrolled on a combination of two or more oral hypoglycemic agents (including metformin, sulfonylureas, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors, and alpha-glucosidase inhibitors) was welltolerated and led to a significant improvement of glucose control (assessed by HbA1c, fasting-and postprandial blood glucose) from baseline (without occurrence of severe hypoglycemia). This article is protected by copyright.…”