Evaluation of Comparative Efficacy and Pleiotrophy of the Available Three SGLT2 Inhibitors in Type 2 DM Subjects

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a chronic disease that is associated with obesity and the progressive development of hyperglycemia. Increased body fat is associated with the development of insulin resistance in muscle and in the liver, particularly if excess fat is deposited in these tissues . Initially, the pancreas is able to overcome this insulin resistance by producing more insulin, but in diabetes there is a progressive failure of β-cell output, resulting first in glucose intolerance and then overt T2DM. In addition to these established factors, it is now known that multiple defects, involving numerous metabolic pathways and organ systems, contribute to the progression of hyperglycemia in T2DM. It include adipocytes (accelerated lipolysis), the gastrointestinal tract (incretin deficiency/resistance), pancreatic α-cells (hyperglucagonemia), the brain (insulin resistance), and the kidneys (increased glucose reabsorption).1 Diabetes is a worldwide growing public health problem with high risks of severe micro vascular and macrovascular complications. Diabetic nephropathy (DN) is a major burden among the chronic complications of diabetes, given that it affects the 30% of patients with diabetes. Indeed, DN is the most common cause of end-stage renal disease . Known risk factors for DN include hyperglycemia, hypertension, dyslipidemia, smoking, and obesity as well as ethnic, familial, and genetic predispositions. Thus, large intervention trials on the impact of long-term intensified glucose control on chronic diabetes complications, both in type 1 and type 2 diabetes, have documented the critical role of glycemic control in preventing the development of early DN as well as in slowing its progression; In contrast, the clinical trials with renin-angiotensin-aldosterone system (RAAS) blockade versus other antihypertensive agents in primary prevention of DN have provided conflicting results , when albuminuria is the primary outcome, by the rapid but reversible decreases in urinary albumin excretion rate and by the differences in blood pressure control. AIM OF THE STUDY: To observe the blood sugar lowering and other pleiotropic effects like changes in body weight and BMI, systolic and diastolic BP changes in type 2 diabetes mellitus subjects with the latest anti diabetic agents of the class SGLT2 inhibitors namely Canagliflozin, Dapagliflozin and Empagliflozin over a minimum period of 3 months. OBJECTIVES OF THE STUDY: To assess the number of hypoglycaemic events. 1. To assess the effect on body weight. 2. To determine macrovascular complication in type 2 DM 3. To compare and assess effect of drugs on type 2 DM and the role in renal protection. SUBJECTS: It is decided to recruit 35 subjects of Type 2 DM, male and female, taking any one of the three SGLT2 inhibitors that are available in the indian pharmaceutical market namely canagliflozin, Dapagliflozin and Empagliflozin attending the outpatient services of the Madurai Institute of Diabetes and Endocrine (MIDE) practice and research at 89A,East veli street and 96,Nakkeerar street, Madurai. INCLUSION CRITERIA: Subjects should be suffering from Type 2 Diabetes Mellitus as per the usual clinical and laboratory criteria that is followed at MIDE. They should all be adults above the age 18 years. Even though it is only an observational study informed consent was obtained from all subjects. Most of the patients were already on one or two insulin secretagogues and one or two insulin sensitizers. Somewhere on alpha glucosidase inhibitors. Subjects with cardiovascular risks were on appropriate anti platelet therapy and any one statin, hypertensives were on appropriate anti hypertensives. No dosage adjustments or alterations of these drugs were made during the 3 months study period. EXCLUSION CRITERIA: Drug naive patients who were not on adequate doses of insulin secretagogues or sensitizers, subjects who had moderate to severe renal failure, mild, moderate, severe liver disease and acute coronary syndrome, infarct, stroke or ketoacidosis or suffering from any acute or chronic infections. METHODOLOGY In this observational study we did not disturb the routine of the patients or the physicians in the clinic. We tried to collect atleast 10 subjects in each group with a total of 30 subjects in all. we recruited 35 subjects in all out of which 6 were excluded due to reasons of inadequate length of treatment. The parameters which we studied with a view to compare head to head the three agents are body weight, BMI, systolic and diastolic and 2 hours post prandial blood sugar values Clinical evaluation regarding age, gender, duration of disease, age onset, any other complication and family history evaluation were done in all the cases. Patient were received after the treatment measurement. The observed parameter were analysed. Discussion was held with Diabetologist for the interpretation of collected data. The efficacy of each group was determined and conclusion was drawn. Finally patient were counselled regarding the importance of strict glycemic control attained by diabetic diet & regular exercise with proper drug treatment. CONCLUSION: This study has limitations because of the small number, being only observational and pilot study. Only the age group of the subjects and body weight were in the same range in the three groups. However the following conclusions can be made from the observed data. 1.Body weight and BMI fell in all the three groups with Canagliflozin 100mg/day, Dapagliflozin 10mg/day, and Empagliflozin 25mg/day. The best fall has observed with Empagliflozin 2.Fall in the systolic and diastolic blood pressure did not reach significance in all the three groups. The Empagliflozin group which had high levels to start with should greater fall. 3.The blood sugar reductions at 2 hour post prandial blood sugar value were statistically significance in all the three groups. The higher reductions are seen with the Empagliflozin group. 4.Thus it can be considered that Empagliflozin among the 3 available SGLT2 inhibitor at maximum permitted doses appears slightly more efficacious however the differences were not statistically efficient