Does Hydroxychloroquine Improve Glycemic Status and Lipid Pro(cid:2510)ile in Rheumatoid Patients with Diabetes Mellitus – An Observational Study

Rheumatoid arthritis is an autoimmune disease, causing chronic in(cid:977)lamma-tion of small joints in hands and feet. The chronic in(cid:977)lammation and corticosteroid use in rheumatoid patients predispose them to insulin resistance and diabetes. Hydroxychloroquine, a proven drug in rheumatoid arthritis, seems to be bene(cid:977)icial in diabetes and also reduces the risk of cardiovascular events. This study was done to (cid:977)ind out the role of hydroxychloroquine on the glycemic status and lipid pro(cid:977)ile in Rheumatoid patients having treatment with Diabetes mellitus. 50 patients with both RA and DM in the middle age group were categorized into HCQ and Non-HCQ group. Both the groups were followed up for 6 months. Their glycemic status and lipid pro(cid:977)ile were compared by mea-suring FBS, PPBS, HbA1C, triglycerides, total cholesterol, VLDL, LDL and HDL. Statistical analysis was done by student t test. The mean FBS, PPBS, HbA1C values in HCQ Group patients decreased signi(cid:977)icantly from 155.16, 200.12 and 8.26 to 135.80, 174.60 and 7.49 respectively in the follow-up period. In the Non-HCQ group, there was no signi(cid:977)icant change in mean FBS and PPBS after 6 months. Mean HbA1C increased from 8.13 to 8.33 in Non-HCQ group. Triglycerides, total cholesterol, VLDL and LDL also were found to be reduced in patients who had taken HCQ. In Rheumatoid patients with diabetes, use of HCQ improves their glycemic status and reduces the lipid abnormalities.


INTRODUCTION
Rheumatoid arthritis (RA) is a chronic musculoskeletal disease with an autoimmune origin. It affects 1% of the adult population in the world (Silman and Pearson, 2002). The symmetric polyarticular synovial in lammation typically affects small joints of hands and feet. The in lammatory pannus formation leads to relentless joint damage with multiple deformities and functional loss.
These patients lead a sedentary lifestyle due to pain and disability, resulting in obesity which is a risk factor for diabetes mellitus (Mokdad et al., 2001). The chronic in lammation and corticosteroid use predispose them to insulin resistance and diabetes. Many immunoregulatory components like IL-6 have been associated in the common pathophysiological pathways of RA and DM.
Hydroxychloroquine (HCQ) is commonly used in the management of RA. It has relatively low toxicity and is well tolerated with long term usage. Hypoglycemia is an uncommon side effect of therapy with hydroxychloroquine. The incidence of diabetes reduces by more than 75% in patients who use HCQ more than 4years for RA.
This study was aimed at inding out the role of hydroxychloroquine in patients with rheumatoid arthritis and diabetes mellitus. The association between the laboratory indices and HCQ was studied to ind out their relationship. We hypothesized that use of HCQ lowers fasting glucose, improves glycemic status and lipid pro ile in rheumatoid patients.

MATERIALS AND METHODS
An Observational comparative study was done during the period March 2017-March 2020 in the Orthopaedics department. All patients registered with both rheumatoid arthritis and diabetes mellitus were included in the study. 50 patients in the age group, 30-60 years, were selected based on the exclusion and inclusion criteria.
The irst group of patients had been taking 200 mg of HCQ twice daily, along with other anti-rheumatoid and oral hypoglycaemic drugs. The second group of patients were on similar anti-rheumatoid drugs and oral hypoglycemic drugs except for HCQ. Age, sex, body mass index, diabetic history and past medications, other signi icant co-morbid illnesses were noted. ESR, CRP, RA Factor, glycaemic indices such as FBS, PPBS and HbA1C, and lipid pro ile of all patients were done and recorded using a structured proforma during the initial visit. The patients were followed up for 6 months, and the studies were repeated. The treatment courses were connected to research participation.

Patients diagnosed to have both DM and RA
within one year of study.

Age 30-60 years
The exclusion criteria in this study was Ethical committee clearance was obtained from the institution. Informed written consent was obtained from all the patients. Statistical analysis was done by student t-test using SPSS software version 21. Statistical tests were considered signi icant if P-value was <0.05 at a con idence interval of 95%. Descriptive statistics such as mean, the standard deviation for each continuous variable were used to summarize the demographic data.

RESULTS
The age for both groups had a mean of 55 years, and female patients outnumbered males in both groups. Mean height, weight and BMI of the groups were comparable to each other. The duration of disease and treatment was 5.6 years in the HCQ group and 6.08 years in Non-HCQ group. These parameters were not statistically signi icant between the groups. All patients selected were RA factor positive and Anti-CCP positive. Comparing both the groups, as shown in Table 3 LDL, VLDL and triglycerides did not show signi icant change. But, changes in mean total cholesterol and HDL were signi icant. The reduction in these lipid values in the HCQ group, even though statistically signi icant from the values of that of the non-HCQ group, were lesser compared to the glycemic status improvement in the same group.

DISCUSSION
Rheumatoid patients are at increased risk of impaired glucose tolerance due to increased proin lammatory cytokines. They may eventually develop type 2 DM. The link between insulin resistance and rheumatoid arthritis shows clearly that chronic in lammation plays a role in the development of these conditions. Their insulin sensitivity improves when their disease process is adequately controlled. The severity and duration of RA is an important factor which in luences the risk of developing type 2 DM.
Antimalarials have been commonly used in rheumatoid arthritis for a long time now. They have a superior safety pro ile than the other conventional drugs, even though their disease-modifying ability is not so dramatic as the other treatment options. This has led to its use in mild to moderate disease and in combination therapy for rheumatoid arthritis. They do not have any increased risk of malignancy or infection. They are well-tolerated, and no routine laboratory monitoring is needed. Their toxicity is rare, and yearly ophthalmologic examinations are recommended.
Hydroxychloroquine is safely used in many autoimmune disorders, most commonly rheumatoid arthritis. Antimalarials are noted to produce hypoglycaemia as a serious but relatively uncommon side effect in diabetic as well as nondiabetic individuals. The exact mechanism by which hydroxychloroquine exerts its hypoglycaemic action is not clear, and it's a known fact that the in lammatory cytokines alter the sugar levels. The hypoglycaemic action of chloroquine is attributed by its effect on slowing down the insulin clearance by stabilising the lysosomes and slowing down the lysosome-receptor complex breakdown in the cytoplasm (Emami et al., 1998). Weber and Levitz demonstrated that Chloroquine regulates TNF production by inhibiting its transcription through mitogen-activated protein kinase pathways. HCQ modulates immune response by these effects on TNF production (Weber and Levitz, 2000). Hydroxychloroquine also reduces the action of insulin metabolising enzyme, hence increasing insulin levels in blood (Emami et al., 1999). Chloroquine increases C-peptide response, thereby improving beta cell functioning leading to hypoglycaemia (Powrie, 1991;Gerstein et al., 2006). In obese non-diabetic patients, 6 weeks of HCQ use was associated with signi icantly increased insulin sensitivity and reduction in insulin resistance in the study by Mercer (Mercer et al., 2012).
Ramser indicated that HCQ has an antiproliferative effect in tissues by induces autophagy of ibroblasts (Ramser et al., 2009). Their observations suggest HCQ has a regulatory effect on homeostasis of cellular energy. Jin and White stressed that cellular autophagy under stress plays an important role in malignancies (Jin et al., 2017). So, the role of HCQ as an adjunct to conventional therapies for solid tumours is being studied.

Effects of Usage
Petri et al. concluded HCQ was found to be associated with a reduction in blood glucose levels in SLE patients (Petri and Yoo, 1994). Shojania, in their case report in 1999, found the insulin requirements were lesser in a patient with RA and Diabetes by the use of HCQ (Shojania et al., 1999). In 2007, Wasko in their large multicentre study in 4905 patients with 21.5 years followed up found that the development of diabetes was reduced by 77% in rheumatoid patients on HCQ therapy for more than 4 years (Wasko et al., 2007). Compared to those not on HCQ, the adjusted relative risk of developing diabetes was 0.23.
In a retrospective study done on 1127 patients over 5 years, Bili found a favourable outcome with regards to the incidence of diabetes among those on HCQ compared with nonusers (Bili et al., 2011). Their indings support the fact that HCQ attenuates the risk of diabetes in rheumatoid patients.
In their study on the safety and ef icacy comparing hydroxychloroquine and pioglitazone in uncontrolled diabetic patients, Pareek reported a signi icant reduction in glycaemic parameters from baseline in both groups at 12 and 24 weeks (Pareek et al., 2014). Total cholesterol and LDL-C reduction was signi icant in the HCQ group. At week 24, both groups showed a signi icant reduction in triglycerides level. There was no change in Mean HDL-C. So, they concluded that HCQ could be a safe treatment option for T2DM. In our study, mean total cholesterol, triglycerides, and LDL showed a reduction with the use of HCQ. In contrast to the above study, mean HDL also increased in 6 months followup in the HCQ group (Table 1).
Jagnani, in their study on HCQ on refractory diabetic patients, found signi icant improvement in glycaemic control when it is prescribed as an add-on therapy. Its ef icacy in controlling blood sugar was comparable to agents like Teneligliptin. So, they suggested HCQ may be used in uncontrolled T2 DM patients as an add-on drug (Jagnani et al., 2017;Quatraro, 1990;O'Dell et al., 1996). In our study too, HCQ group had better glycemic control than the Non-HCQ group as evidenced by the decrease in FBS, PPBS and HbA1C.

Effects in Rheumatoid Arthritis and Diabetes Mellitus
In their study on 135 obese patients, Gerstein demonstrated the impact of HCQ on quality of life and its glucose-lowering ef icacy when used as an add on an agent in sulfonylurea refractory type 2 diabetes (Gerstein et al., 2006). Rekedal found that the baseline HbA1c reduced by 0.66% in patients with both diabetes and RA on HCQ (Rekedal et al., 2010). They compared the effects of HCQ and MTX on this factor and concluded that HCQ significantly lowered glycated haemoglobin in comparison to MTX. Our results also showed a signi icant decrease in HbA1C in 6 months. On prolonged usage of HCQ, the glycemic status will have a better beneicial effect.
Quatraro, from their study among patients with refractory diabetes, concluded that glycaemic control was better in those who took HCQ (Quatraro, 1990). Serum C-peptide levels were not changed, indicating that the insulin secretion was not increased. In another study by Powrie done in 20 diabetic patients, they found that the chloroquine reduces insulin clearance as well as increases its secretion in the circulation (Powrie, 1991).

Effect on Lipid Pro ile and Cardiovascular Diseases
Rheumatoid arthritis imparts higher mortality and morbidity due to cardiovascular disorders. The bene icial effect on the reduction of cardiovascular risk factors by antimalarials have been shown (Tam et al., 2000;Petri, 1996;Booth et al., 2006). Tam found favourable lipid pro ile in patients who take antimalarials and prednisone concomitantly in 123 patients with Lupus (Tam et al., 2000). Usage of HCQs was associated with lesser damage in SLE patients (Akhavan et al., 2013). Wasko noted that HCQ showed lower LDL and total cholesterol values than nonusers in SLE women (Wasko et al., 2007).
Signi icant reduction in LDL, total cholesterol and triglycerides was noted in the HCQ group in our study. Morris concluded from their results that HCQ is an important adjunct therapy in Rheumatoid patients who are at high risk for CVD (Morris et al., 2011). Restrepo, in their prospective cohort study over a period of 14 years in RA patients, found a signi icant reduction in TC, TG and LDL and an increase in HDL (Restrepo et al., 2017). HDL increase has been shown to play a signi icant role in reducing the cardiovascular events, especially in postmenopausal women. We also found an increase in HDL in HCQ group, which will bene it rheumatoid patients prone for cardiovascular morbidity and mortality. Considering their bene icial effects on the reduction of risk factors for Coro-nary vascular diseases like diabetes and hyperlipidaemias, antimalarials can reduce the risk of cardiovascular events. Further work is needed to ind out patients' subsets who will be particularly bene icial from HCQ.

CONCLUSIONS
HCQ is a relatively safe, a cheaper drug used commonly in treatment autoimmune diseases like RA and SLE. HCQ improves glycaemic status and lipid pro ile in diabetic patients with RA. These indings clearly show a protective role for them in the prevention of cardiovascular diseases in them.