Research Journal of Recent Sciences _________________________________________________ ISSN 2277-2502 Vol. 3(ISC-2013), 403-407 (2014) Res. J. Recent. Sci. International Science Congress Association 403 Study of Adverse Effects of Vildagliptin and Insulin Treatment in Diabetes Mellitus Patients Priya E. and Mallika JainuResearch and Development Centre, Bharathiar University, Coimbatore – 641046, INDIA Department of Biomedical Engineering, SriSiva Subramaniya Nadar College of Engineering, Kalavakkam, Chennai -603110, INDIAAvailable online at: www.isca.in, www.isca.me Received 30th November 2013, revised 23rd June 2014, accepted 6th July 2014 AbstractThe defective response of the body tissues to insulin leads to Diabetic condition in human beings. The central nervous system which controls the entire motor unit, suffers degeneration that leads to many complications, of which Diabetes Mellitus disease lies most widespread in India. Present-day medicine such as insulin injection and vildagliptin (Dipeptidyl peptidase-4 inhibitor) treatment are associated with serious neuromuscular side effects and nervous impairment. Within this context, aim of our research was to evaluate, by analysing the myocardial dysfunction complexity, the adverse effects induced by vildagliptin in combination with other antidiabetic treatment. Blood glucose level, glycosylated hemoglobin, serum insulin, systolic and diastolic blood pressure, heart rate, myocardial enzymes such as LDH, CK-MB, AST and ECG signals were measured before and after the insulin and vildagliptin treatment in patients. All the above mentioned parameters were altered significantly after the treatment with insulin and vildagliptin. This study may provide evidence to the medical society about the cardiac dysfunction complexity caused by autonomic failure of hypoglycemic actions upon combination therapy of insulin with vildagliptin in diabetes mellitus. Keywords: Vildagliptin, Diabetes Mellitus, cardiac markers. Introduction Type-2 diabetes mellitus is one of the most challenging non-communicable diseases world wide and will be the most challenging health problems in the 21st century. It has been estimated that the world prevalence of diabetes mellitus in the age groups between 20-79 years will be affecting 439 million adults by 2030. Thus in addition to lifestyle changes effective treatments are also necessary for treating diabetes. So far metformin has been recommended by American diabetes association as a treatment of choice for diabetes mellitus. However underlying pathogenic factors requires additional glucose lowering drugs in addition to it. So the treatment of diabetes has gone towards combining metformin with other drugs with a different mechanism of action. Oral antidiabetic medications can be used in combination with metformin or alone include Dipeptidyl peptidase inhibitors which act by improving Alpha and Beta cell sensitivity to glucose by improving concentrations of active GLP-1. Vildagliptin has been shown to act effectively in combination with metformin. In some cases the patient was found to have low tolerance towards the drug vildagliptin. There are many side effects some of which may include tremors, fatigue, hypoglycemia, blistering of the skin, ulcer in foot, rapid heart rate, low blood pressure and hypotension. The results of the analyses of different DPP-4 inhibitor group of drugs are not entirely comparable but most of them have got deleterious effect on the cardiovascular events3,4 The present analyses shows that vildagliptin not only increases the cardiovascular risk but it may produce other side effects also in diabetic patients. The prespecified design of the present analyses included the blinded adjudication of the cardiovascular events which may strengthen the current findings. This analysis was based on individual patient data from a large clinical development programme. This allows derivation of endpoints and minimizes between study heterogeneity of unrelated studies. The present analyses shows that vildagliptin treatment increases cardiovascular risk and may even yield other side effects in patients with type-2 diabetes mellitus. However the prespecified design of the present meta analyses involved prospective and blinded adjudication of cardiovascular events which should strengthen the validity of the current findings. In addition, this meta-analysis was based on individual patient data from a consistently designed, large clinical development programme this allows consistent derivation of endpoints and extensive subgroup analyses and minimizes between study heterogeneity that can confound analyses of unrelated studies. Since, till date, there were no studies have been done on the adverse effect of vildagliptin treatment on cardiovascular dysfunction. Within this context, aim of our research was to evaluate, by analysing the physiological dysfunction complexity, the adverse effects induced by insulin and vildagliptin in human subjects with diabetes. Hence, the present study may helps to understand the progression of cardiovascular adverse effects of insulin and Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(ISC-2013), 403-407 (2014) Res. J. Recent. Sci. International Science Congress Association 404 vildagliptin in diabetic patients taking it as an oral anti diabetic medication by performing various cardiac marker assays. Material and MethodsA total number of 30 patients were selected from out patient of the diabetic clinic, in India after getting the approval from human ethical clearance. These patients diagnosed as having diabetes mellitus and were under treatment. The patients were selected by the following inclusion critera: under treatment or had diabetes mellitus diagnosed for atleast last one year or more, not having any other systemic diseases and willingness to participate in the study. In the present study thirty patients with type 2 diabetes subjected to oral hypoglycemic treatments were included. Subjects received insulin at a dose of 20 U, administered twice per day and vildagliptin 50 mg b.i.d. for 90 days in a randomized, double-blind, cross-over design. At the end of duration of treatment period, blood was collected from the patients and transferred to vacutainers filled with sodium fluoride and serum was separated by centrifugation at 3500rpm for 10min. Fasting blood glucose, Post prandial glucose, AST, CK-MB, LDH, HbA1c and Insulin levels were measured by semi auto analyzer using diagnostic kits. Heart rate, ECG, systolic and diastolic blood pressure was measured by using biomedical devices to analyse the effect of drug on cardiovascular system. Statistical comparison: All results are presented as means ± SEM. Statistical analysis among subjects was performed by one-way analysis of variance (ANOVA) followed by Dunnett’s T3 comparison post-hoc test. Differences were considered statistically significant if p 0.05. Results and Discussion Past studies have demonstrated such a strong bond between cardiovascular disease and diabetes, the American heart foundation HA has declared “diabetes is a cardiovascular disease”. Diabetes induces complex vascular changes, promoting accelerated atherosclerosis and hypercoagulability, as can be assessed indirectly by a number of markers. Conversely, certain classes of oral antidiabetic medications have been shown to cause hypoglycemia as well as adverse cardiovascular effects. As shown in figure-1 a significant increase in blood glucose and glycosylated hemoglobin and a significant decrease in serum insulin were observed in diabetic patients when compared to normal subjects. Administration of insulin + vildagliptin to diabetic patients significantly decreased the levels of blood glucose and Glycosylated Hb and at same time increased serum insulin9.The percentage of patients receiving vildagliptin in combination with insulin and experiencing one or more adverse event, severe adverse event or adverse event leading to discontinuation of the drug. The corresponding percentages for the placebo plus insulin group were 76.9%,24.4% and 6.4%, respectively10. Apart from hypoglycemia, the most common specific adverse event were edema hyperhidrosis, and dizziness11. Clinical and observational studies have reported that reducing HbA1c levels results in a lower incidence of cardiovascular complications in diabetic patients with a shorter time since diagnosis12,13, but not in diabetic patients with a longer time since diagnosis. Starting treatment for diabetes at an earlier stage is therefore thought to be important for decreasing the risk of cardiovascular events14. The glucose lowering effect (HbA1c reduction 0.9% from baseline of 7.7%)was in the range seen previously in studies of vildagliptin monotherapy and combination therapy in patients with a much shorter history of type 2 diabetes and normal renal function15. As expected, the magnitude of reduction in HbA1c and the between treatment difference was larger in patients with higher baseline HbA1c levels16. Thus, the Beta-cell dysfunction and other metabolic derangements attendant with severe renal impairment and longstanding type-2 diabetes requiring insulin therapy clearly did not mitigate the efficacy or the low hypoglycemic potential of vildagliptin17. Wide physiological distribution of the Vildagliptin suggests multiple mechanisms of metabolic control, both centrally and through peripheral neurohumoral pathways18. In figure-2 studies demonstrate increases in heart rate (HR) and decrease in blood pressure (BP) in insulin + Vildagliptin treated patients compared to normal control. In human studies, few chronotropic and hypotensive effects have been observed in vildalgliptin treated patients which are concordant with our present study. Thus, concomitant mechanisms associated with BP trends seem plausible and are consistent with other findings. Vildalgliptin increased cardiac output and reduced LV end diastolic pressure, in association with improved myocardial insulin sensitivity and myocardial glucose uptake with rapid pacing induced congestive heart failure19. Figure-4 shows hypoglycaemia due to the treatment of Vildagliptin alters ventricular repolarization with prolongation of the QT interval, indicating a possible mechanism which might explain the increased risk of sudden overnight deaths in young type 2 diabetic patients. QT dispersion is difficult to measure consistently with interobserver variability in QT- dispersion measurements rising as high as 30%, particularly if ECG morphology is abnormal. There is a clear relation between QT measurement error and ST-T amplitude and during hypoglycaemia, ECG morphology alters, with flattening of the ST segment. Thus, although we believe this observation may be worthy of further investigation. The findings of this study suggest that 90 days administration of Vildagliptin and insulin had increased effect on heart rate, showed some trends of reduced BP and elevation in cardiac enzyme elevation in humans20. Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(ISC-2013), 403-407 (2014) Res. J. Recent. Sci. International Science Congress Association 405 Activation of the sympathetic system has numerous implications, including surges of heart rate, blood pressure but also proinflammatory and procoagulant effects and increased marker enzyme levels in serum figure-3. This partially explains the increased cardiovascular adverse events noted with these DPP4i group of drugs21. Figure-1 Effect of insulin + vildalgliptin treatment on blood glucose level, HbA1C and Insulin levels in patients in taking the dose for 90 days. Results are expressed as mean ± S.E.M, n = 10. *P 0.001, statistically significant as compared with control rats and P 0.001 statistically significant as compared with diabetic patient group Figure-2 Effect of insulin + vildalgliptin treatment on blood pressure, pulse rate and heart glycogen levels in patients in taking the dose for 90 days. Results are expressed as mean ± S.E.M, n = 10. *P 0.001, statistically significant as compared with control rats and P 0.001 statistically significant as compared with diabetic patient group Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(ISC-2013), 403-407 (2014) Res. J. Recent. Sci. International Science Congress Association 406 Figure-3 Effect of insulin + vildalgliptin treatment on cardiac marker enzyme levels in patients in taking the dose for 90 days. Results are expressed as mean ± S.E.M, n = 10. *P 0.001, statistically significant as compared with control rats and P 0.001 statistically significant as compared with diabetic patient group Figure-4A Figure-4B Figure-4C This Electrocardiogram depicts the PQRST wave alteration after the treatment with combined therapy of insulin + vildalgliptin for the period of 90 days. Figure 4A – ECG signals of normal group, Figure 4B – ECG signals of Diabetes patient and Figure 4C- ECG signals of insulin + vildalgliptin treated group Research Journal of Recent Sciences ______________________________________________________________ ISSN 2277-2502Vol. 3(ISC-2013), 403-407 (2014) Res. J. Recent. Sci. International Science Congress Association 407 Conclusion The patients who are taking the combined therapy of insulin and vildalgliptin are more prone to cardiovascular dysfunction. Larger subsequent studies should clarify the effect of Vildagliptin on trends in other organ markers to explore the potential of overall risk of using this drug for diabetes type II patient. References 1.Schweizer A., Dejager S., Foley J.E. and Kothny W., Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies, Vasc Health Risk Manag.,7, 49–572011)2.Brierley E.J., Broughton D.L., James O.F., Alberti K.G., Reduced awareness of hypoglycaemia in the elderly despite an intact counter-regulatory response, QJM, 88, 439–441995)3.Gawlowski T., Stratmann B., Stork I., Engelbrecht B., Brodehl A., Niehaus K., Körfer R., Tschoepe D. and Milting H., Heat shock protein 27 modification is increased in the human diabetic failing heart, Horm Metab Res., 41, 594–5992009)4.Burgess M.L., McCrea J.C. and Hedrick H.L., Age-associated changes in cardiac matrix and integrins,Mech Ageing Dev.,122, 1739–17562001)5.Mariappan N., Elks C.M., Sriramula S., Guggilam A., Liu Z., Borkhsenious O. and Francis J. NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes, Cardiovasc Res.,85, 473–483 (2010) 6.Russell N.E., Higgins M.F., Amaruso M., Foley M., McAuliffe F.M., Troponin T. and pro-B-type natriuretic Peptide in fetuses of type 1 diabetic mothers, Diabetes Care., 32, 2050–2055 (2009) 7. Feng B., Chen S., George B., Feng Q. and Chakrabarti S., miR133a regulates cardiomyocyte hypertrophy in diabetes, Diabetes Metab Res Rev., 26, 40–492010) 8.Horsdal H.T., Søndergaard F., Johnsen S.P. and Rungby J., Antidiabetic treatments and risk of hospitalisation with myocardial infarction: a nationwide case–control study, Pharmacoepidemiol Drug Saf., 20, 331–337 (2011) 9.Corley B.T., Davenport C., Delaney L., Hatunic M. and Smith D., Hypoglycaemia-induced myocardial infarction as a result of sulphonylurea misuse, Diabet Med., 28, 876–879(2011)10.Zoungas S., Patel A., Chalmers J., de Galan B.E., Li Q., Billot L., Woodward M., Ninomiya T., Neal B., MacMahon S. et al. Severe hypoglycemia and risks of vascular events and death, N Engl J Med., 363, 1410–1418 (2010) 11.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet., 352, 837–8531998) 12.Adler A.I., Stratton I.M., Neil H.A., Yudkin J.S., Matthews D.R., Cull C.A., Wright A.D., Turner R.C., Holman R.R., Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study, BMJ, 321, 405–412 2000) 13.Dluhy R.G., McMahon G.T. Intensive glycemic control in the ACCORD and ADVANCE trials, N Engl J Med., 358, 2630–2633 (2008) 14.Fadini G.P., Boscaro E. and Albiero M., et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor 1alpha, Diabetes Care.,33, 1607–16092010) 15. Schweizer A., Dejager S., Foley J.E., Couturier A., Ligueros-Saylan M. and Kothny W., Assessing the cardio- cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population, Diabetes Obes Metab.,12, 485–494 (2010) 16.Betteridge D.J. and Verges B., Long-term effects on lipids and lipoproteins of pioglitazone versus gliclazide addition to metformin and pioglitazone versus metformin addition to sulphonylurea in the treatment of type 2 diabetes, Int J Obes Relat Metab Disord., 12, 2477–24812005) 17.Van Poppel P.C., Netea M.G., Smits P. and Tack C.J., Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes, Diabetes Care., 12, 2072– 2077 (2011) 18.Sokos G.G., Nikolaidis L.A., Mankad S., Elahi D., Shannon R.P., Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure, J Card Fail.,12, 694–9 (2006) 19.Ireland R.H., Robinson R.T.C.E., Heller S.R., Marques J.L.B. and Harris N.D., Measurement of high resolution ECG QT interval during controlled hypoglycaemia, Physiol Meas., 21, 295–303 (2000) 20.Johansen O.E., Neubacher D., von Eynatten M., Patel S. and Woerle H.J., Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme, Cardiovasc Diabetol., 11, 2012) 21.Horsdal H.T., Søndergaard F., Johnsen S.P. and Rungby J., Antidiabetic treatments and risk of hospitalisation with myocardial infarction: a nationwide case–control study, Pharmacoepidemiol Drug Saf., 20, 331–337 (2011)