To evaluate the effect of Ranolazine on Fasting Plasma Glucose in patients of Type – II Diabetes Mellitus with Stable Angina as add on therapy

Department of Pharmacology, S.H.K.M. Govt. Medical College, Mewat, Haryana, India Department of Pharmacology, Major SD Singh Medical College, Farrukhabad, India Department of Pharmacology, S.N. Medical College, Agra, India Department of Gynecology & Obstetrics,S.H.K.M. Govt. Medical College, Mewat, Haryana, India Department of Community Medicine, S.H.K.M. Govt. Medical College, Mewat, Haryana, India


Introduction
Prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide.Nowadays over 360 million people are suffering from diabetes and it is expected that its prevalence reach a staggering 552 million by 2030 . 1 Diabetes mellitus(DM) substantial associated with cardiovascular morbidity and mortality. 2][4][5] Patients with diabetes have a 2-to 4-fold higher risk of CVD death compared with patients without diabetes; approximately 65% of deaths in patients with diabetes, of which type 2 diabetes predominates, are a result of CVD . 6The treatment options for diabetic patients with coronary artery disease (CAD) currently have several safety concerns.Several clinical trials have shown that patients with CAD treated with β-blockers and calcium channel blockers have consistently and significantly higher rates of newly diagnosed diabetes because of the prodiabetic effects of these medications. 71] Studies of Ranolazine effect on FPG are lacking.Therefore, the objective of the present study is to evaluate the effect of Ranolazine on FPG in patients of Type -II Diabetes Mellitus with Stable Angina as add on therapy.

Material and Methods
An open-labeled, randomized, controlled parallel group study was conducted in the Department of Pharmacology in collaboration with other departments from November 2009 to July 2011 in diagnosed patients of Type -II Diabetes Mellitus with Stable Angina attending the Medicine OPD, Cardiology OPD, Diabetic Clinic and admitted in Medical wards of S.N.Medical College and Hospital, Agra.The Institutional Ethical Committee approved the study protocol and informed consent was obtained from all patients before enrollment after detailed explanation of possible adverse effects of the drug.187 patients were screened of these, 80 willing participants were recruited on the the basis of inclusion and exclusion criteria.Inclusion criteria: Patients of either gender in the age group of 30-70 years had a documented history of both T2DM and CAD and treated with stable doses of drugs for at least 3 months, Patients ready for therapy after knowing adverse effects of the test drug.Key exclusion criteria were: Acute coronary syndrome in the prior 2 months, planned coronary revascularization during the study period, stroke or transient ischemic attack within 6 months prior to screening, uncontrolled hypertension, hepatic impairment, Renal impairment, patients on Insulin Therapy, New York Heart Association functional class III to IV heart failure symptoms, Pregnant females, Nursing mother, Age <30 years and >70 years, prior treatment with Ranolazine, Patients with history of Torsades de pointes or QTc > 500 milliseconds and those receiving agents that are known to prolong QT c interval and Patients with Current treatment with potent inhibitors of CYP3A (ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir).
Four patients out of the selected eighty patients refused to take part in study after written consent.The remaining 76 selected patients on the basis of inclusion and exclusion criteria were randomly assigned in a1:1 fashion into 2 groups by computer generated randomization chart: Control group (Group 1): was on their regular therapy during the 8-week study period.
Test group (Group 2): was on Ranolazine 500mg BD (orally) in addition to their regular therapy during the 8-week study period.
After selecting the patient, a detailed medical history and findings of clinical examination including demographic data were recorded in a Performa.After that all patients were subjected to investigations which include-Hb, TLC, DLC, ESR, Blood sugar, Weight of patient, SGPT/ SGOT, Serum creatinine, Urine analysis.The investigations were done at baseline, repeated after 4weeks and after end of treatment(i.e at 8week).Patients were followed at 4 th week and 8 th week.Each patient served its own control and patient's baseline values were compared with values after 4 weeks and 8 weeks.Number and doses of concomitant medications were kept stable during the study period.Compliance to the therapy was monitored by receiving back the empty wrappers of the supplement at weekly follow-ups and telephonic communications.
Under aseptic conditions, venous blood samples were drawn in the morning after an overnight (8-12 hours) fast.Fasting Plasma Glucose (FPG) was determined by using modified Glucose Oxidase-Peroxidase method. 12

Statistical Analysis
All data obtained were expressed as mean ± standard deviation (SD).All statistical tests were conducted at the 5% significance level.A two-tailed, un-paired student's t-test was used to test differences between control and test groups.The differences in observations before and after therapy in same group were studied using student's two-tailed, paired t-test.A statistical significance was reported at a two-tailed p value of <0.05.All tests were done online at www.graphpad.com.

Results
All the 76 selected patients completed the study without any significant adverse drug reaction.1, there were no significant differences among the groups.All subjects continued with their medical therapy as prescribed by their treating physicians.2, in group I Fasting Plasma Glucose (FPG) concentration was 139.59 ± 8.96 mg/dl at 0 week, 138.82 ± 8.76 at 4 week and 139.76 ± 8.87 at the end of 8 week, whereas for group II, it was 140.86 ± 14.70 at 0 week, 137.89 ± 10.25 at 4 week and 134.84 ± 8.42 at the end of 8 week.There was decrease in FPG in Group II and this decrease was statistically significant with P value < 0.05 in comparison to group I at end of 8 week after treatment.IJBAR (2013) 04 (10)  www.ssjournals.com

Discussion
In our study, we have analyzed the effect of Ranolazine on FPG in patients of Type -II Diabetes Mellitus with Stable Angina as add on therapy with their ongoing regular therapy.Patients were in the age group of 30-70 years of either sex in both groups.During study period there was negligible changes in FPG concentration in group I but there was decrease in FPG concentration in Ranolazine add on group.The decrease in FPG was statistically insignificant with P value > 0.05 in comparison to group I at 4 week but it was statistically significant with P value < 0.05 in comparison to group I at end of 8 week.
The above results are similar to previous studies, in which patients with moderate/severe hyperglycemia, Ranolazine treatment was associated with a reduction (25.7 mg/dl) in fasting plasma glucose (FPG) after 4 months of treatment 11,13 but in contrast with the MERLIN-TIMI 36 randomized controlled trial, in which no difference in fasting glucose values were found between the 2 treatment groups (P≥0.32 at each time point). 14om above finding it seems that T2DM patients with angina may receive greater benefit from Ranolazine therapy -both in terms of its antianginal and glucose-lowering effects as Hyperglycemia may worsen myocardial perfusion through microvascular and endothelial dysfunction, enhanced platelet aggregation and prothrombotic state, and increased oxidative stress-detrimental effects that may be reduced with better glucose control. 15e mechanism of action of Ranolazine to lower FPG is not clear and currently being investigated, however preliminary data from studies using rat and human pancreatic islets suggests that Ranolazine may promote glucosestimulated insulin secretion. 16There may be role of other possible mechanism as Ranolazine effect on FPG takes times, which should be determined in further studies.
Results from the present study show evidence for the antidiabetic effects of Ranolazine.In this context, Ranolazine is a promising choice for patients of Type -II Diabetes Mellitus with Stable Angina as It provide significant Antihyperglycemic activity together with Antianginal activity which are beneficial in diabetic patients because increase in cardiovascular morbidity and mortality relate to the synergism of hyperglycemia with other cardiovascular risk factors.However, more studies are needed to further characterize the potential antidiabetic effect of Ranolazine.

Conclusion
Our Study signifies the future scope, for the use of Ranolazine in the patients of Type -II Diabetes Mellitus with Stable Angina as add on therapy in addition to their regular therapy as it significantly reduced FPG.Moreover further studies are needed to show the definite effect of Ranolazine on FPG.