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Slide 2 Slide 3 Management of Diabetes Mellitus during Ramadan Management of Diabetes Mellitus during Ramadan By Professor Megahid M, Abuelmagd Diabetes and Endocrinology Unit Mansoura University Professor Megahid M, Abuelmagd Diabetes and Endocrinology Unit Mansoura University Slide 4 DIABETES & RAMADAN Slide 5 Adipose FFA, Ketones Counteregulat ory hormones Slide 6 Adipose FFA, Ketones Counteregulat ory hormones Glucagon Hyperglycaemia &Ketoacidosis Slide 7 Slide 8 THE NEED FOR BALANCE Slide 9 HYPERGLYCEMIA Slide 10 10 0 10 20 30 40 50 6070567 8 91011 Mean HbA 1c (%) Adjusted incidence per 1000 person years (%) Myocardial infarction Microvascular endpoint Diabetes-associated risks UKPDS 35. BMJ 2000; 321: 405-12 Slide 11 11 Pathophysiology Vascular Complications Hyperglycemia Oxidative Stress Atheroma Formation Thrombus Formation Endothelial Dysfunction Slide 12 12 Ramsey, pharmacoeconomics, 1999 Vascular Complications vascular complications among diabetics 3 years incidence (%) Slide 13 13 Cost of vascular complications Micro vascular complications X 1.7 Macro vascular complications X 3.0 Macro & Micro X 3.5 Slide 14 14 Causes of death in diabetes % of deaths in diabetes mainly due to vascular complications Slide 15 Hypoglycemia Main risk associated with fasting in diabetic patients is: Slide 16 Slide 17 Decreased food intake is a well-known risk factor for the development of hypoglycemia. Results of the Diabetes Control and Complications Trial (DCCT) showed a threefold increase in the risk of severe hypoglycemia in patients who were in the intensively treated group and had an average HbA1c (A1C) value of 7.0% Hypoglycemia Slide 18 The incidence of severe hypoglycemia was probably underestimated in this study, since events requiring assistance from a third party without the need for hospitalization were not included. Sever hypoglycemia was more frequent in patients: in whom the dosage of oral hypoglycemic agents or insulin were changed. in those who reported a significant change in their lifestyle Hypoglycemia Slide 19 Hypoglycemia and clinical implications The ultimate goal of the glycemic management of diabetes is a lifetime of euglycemia without hypoglycemia (1) Hypoglycemia is recognized to be a major limitation in achieving good control (2) 1. American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249 2. Cryer PE. Diabetologia. 2002;45:937948 Slide 20 Physiological defenses against falling plasma glucose concentrations Adapted from: Cryer PE. J Clin Invest. 2006;116:14701473 Slide 21 Hypoglycemia impairs defenses against recurrent hypoglycemia (Hypoglycemia-Associated Autonomic Failure) Antecedent hypoglycemia Reduced sympathoadrenal responses to hypoglycemia Reduced sympathetic neural responses Hypoglycemia unawareness Defective glucose counter regulation Reduced epinephrine responses Antecedent exercise Sleep Recurrent hypoglucemia Cryer PE. J Clin Invest. 2006;116:14701473 Slide 22 Mechanisms by which hypoglycemia may affect cardiovascular events Desouza CV, et al. Diabetes Care. 2010; 33:1389394 Slide 23 Classification of hypoglycemia according to severity: European Committee for Medicinal Products for Human Use (CHMP) Episodes suggestive of hypoglycemia where blood glucose measurement were not available. Minor hypoglycemic episodesdefined as either a symptomatic episode with blood glucose level below 3 mmol/L [54mg/dl] and no need for external assistance, or an asymptomatic blood glucose measurement below 3 mmol/L, Major hypoglycemic episodesdefined as symptomatic episodes requiring external assistance due to severe impairment in consciousness or behaviour, with blood glucose level below 3 mmol/L and prompt recovery after glucose or glucagon administration, Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus. CPMP/EWP/1080/00 Rev. 1. Committee for Medicinal Products for Human Use (CHMP). 20 January 2010. Slide 24 Risk Difference of Hypoglycemia with Different Glucose-lowering Agents for T2DM CI=confidence interval; Glyb=glyburide; Met=metformin; repag=repaglinide; SU=sulfonylurea; TZD=thiazolidinediones. Bolen S, et al. Ann Intern Med. 2007;147:386399 Met vs Met + TZD Weighted absolute risk difference 0.20.15 0.50 3 (1557) 5 (1495) 6 (2238) 8 (2026) 3 (1028) 5 (1921) 8 (1948) 9 (1987) Studies (participated) 0.00 (-0.01 to 0.01) 0.02 (-0.02 to 0.05) 0.03 (0.00 to 0.05) 0.04 (0.0 to 0.09) 0.08 (0.00 to 0.16) 0.09 (0.03 to 0.15) 0.11 (0.07 to 0.14) 0.14 (0.07 to 0.21) Pooled effect (95% CI) SU vs repag Glyb vs other SU SU vs Met SU + TZD vs SU SU vs TZD SU + Met vs SU SU + Met vs Met Drug 1 more harmfulDrug 1 less harmful Slide 25 Relative Risk of Hypoglycemia with Different Glucose- lowering Agents when added to Metformin Abbrevations: AGIs, -glucosidase inhibitors; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HbA 1c, glycated hemoglobin A 1c ; NA, not applicable; RR, relative risk; WMD, weighted mean difference. a 75% b = 50%-75% HbA 1c Goal AchievedHypoglycemia Group vs. Placebo No. of TrialsRR (95% CI) No. of TrialsRR (95% CI) All drugs102.56 (1.99 to 3.28) b 191.43 (0.89 to 2.30) Sulfonylureas13.38 (2.02 to 5.83) a 32.63 (0.76 to 9.13) a Glinides13.20 (1.47 to 7.58)27.92 (1.45 to 43.21) Thiazolidinedione s 11.69 (1.24 to 2.33)22.04 (0.50 to 8.23) AGIs0NA20.60 (0.08 to 4.55) DPP-4 inhibitors62.44 (1.78 to 3.33) b 80.67 (0.30 to 1.50) GLP-1 analogs13.96 (2.37 to 6.79)20.94 (0.42 to 2.12) Adapted from: Phung, et al. JAMA. 2010;303(14):14101418 Slide 26 UKPDS Treating to Targets Elevates the Risk of Hypoglycemia and Incidence can be High with SUs SUs=sulfonylureas; T2DM=type 2 diabetes melllitus; *Requiring medical assistance or hospital admission UK Prospective Diabetes Study Group. Diabetes.1995;44:12491258. Cumulative Incidence of Hypoglycemia in T2DM over 6 Years Sulfonylurea (n=922) Insulin (n=689) SulfonylureaInsulinSulfonylureaInsulin Patients (%) Any hypoglycemaMajor hypoglycemia* HbA1c = 7.1% in all groups Slide 27 Risk of Hypoglycemia with Different Sulfonylureas * Slide 28 Health and economical consequences of hypoglycemia Hypoglycemia CV complications 2 Weight gain by defensive eating 3 Coma 2 Car accident 4 Hospitalization costs 1 Dizzy turn unconsciousness 2 Seizures 2 Death 6 Increased risk of dementia 5 Quality of Life 7 1. Jnsson L, et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006;9:193198 2. Barnett AH. CMRO. 2010;26:13331342 3. Foley J & Jordan. J. Vasc Health Risk Manag. 2010;6:541548 4. Canadian Diabetes Associations Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. CanJ Diabetes. 2003;27(2):128 140. 5. Whitmer RA, et al. JAMA. 2009;301:156551572 6. Zammitt NN, et al. Diabetes Care. 2005;28:29482961 7. McEwan P, et al. Diabetes Obes Metab. 2010;12:431436 Slide 29 Hypoglycemia and Weight Gain are intertwined Foley J, et al. Vasc Health Risk Manag. 2010:6 541548 Slide 30 Impact of changes in weight and rates of hypoglycaemia events on Quality-Adjusted Life Year (QALY) McEwan, et al. Diabetes Obes Metab. 2010;12:431436 Slide 31 Vildagliptin improves Alpha and Beta Cell selectivity for both Hyper and Hypoglycemia Slide 32 Vildagliptin improves -cell sensitivity to glucose Vildagliptin 50 mg once daily Placebo Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103109. Secretion at 7 mM glucose (pmol/min/m 2 ) 180 200 220 240 260 40481216202428323640444852 Time (weeks) Basal Secretory Tone 45 50 55 60 65 70 75 40481216202428323640444852 Time (weeks) Glucose Sensitivity (pmol/min/m 2 /mM) Glucose Sensitivity Slide 33 Ahrn B, et al. J Clin Endocrinol Metab. 2009;94(4):12361243. Vildagliptin 100 mg once daily is NOT an approved dose. Effects of vildagliptin treatment on the sensitivity of the -cell to glucose Time (min) 300306090120165210255285 90 110 130 150 170 Dose Meal Glucagon (mg/L) 7.5 mM5.0 mM2.5 mM Placebo Vildagliptin 100 mg once daily During the hypoglycemic steps, glucagon levels increased from a significantly lower baseline to a slightly higher level with vildagliptin compared with placebo. Slide 34 Comparing with commonly used SUs Slide 35 In patients uncontrolled with metformin monotherapy vildagliptin is as effective as glimepiride over 1 year with low incidence of hypoglycaemia and no weight gain Glimepiride up to 6 mg once daily + metformin Vildagliptin 50 mg twice daily + metformin Number of hypoglycaemic events Patients with 1 hypos (%) Number of severe hypoglycaemic events c Incidence (%) 13891383138913831389 1383 n = No. of events 16.2 1.739 554 Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride Mean HbA1c reduction a Incidence of hypoglycaemia b BL=baseline; CI=confidence interval NI=non-inferiority; a Per protocol population ; b Safety population. c Grade 2 or suspected grade 2 events. * P No. of events Duration: 104 weeks, add-on to metformin: vildagliptin vs glimepiride Hypoglycaemia 2 1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p1 hypo (%)Discontinuations due to hyposNumber of severe events a Number of hypo events 15531546 N = Glimepiride up to 6 mg qd +met Vildagliptin 50 mg bid + met No. of events 59 15531546 N = 15531546 N = 15531546 N = Mean HbA1c 1 Adjusted mean change in HbA1c was comparable between vildagliptin and glimepiride treatment: 0.1% (0.0%) for both Primary objective of non-inferiority was met: 97.5% CI= (-0.00, 0.17); upper limit 0.3% Adjusted mean change in body weight (kg) 1539n =1520 * Change in body weight 3 Change from BL to EP (BL Mean ~89kg) Between-treatment Difference Slide 37 Very elderly patients pooled analysis Slide 38 Monotherapy studies pool Add on therapy studies pool n = BL 62 8.3 25 8.5 Change in HbA1c (%) from baseline Mono > 75 Add on > 75 * Study Design Gliclazide 160 mg bd n 26 Ramadan N= 52 Vildagliptin 50 mg bid daily n26 Methods HbA1c was > 8.5% despite treatment with metformin 2 g daily before Ramadan All patients received education about how to identify and manage hypoglycemia during Ramadan. 2 weeks 10 days after Ramadan Recording of hypoglycemia and weight gain Metformin 2 g Slide 51 Vildagliptin Gliclazide Glycated haemoglobin (%) Vildagliptin therapy and hypoglycaemia in Muslim T2DM during Ramadan Analysis of covariance models with treatment group, gender and ethnicity as factors. a Age, duration of diabetes, HbA 1c, weight and prefasting value, b age, duration of diabetes, weight and prefasting value, or c age, duration of diabetes, HbA 1c and prefasting value as covariates. SD, standard deviation; SEM, standard error mean. Devendra et al. Int J Clin Pract. 2009;63(10):14461450 *P=0.8217; **P=0.0168 * n= 26 BL 8.988.95 Hypoglycemic events ** n= 26 BL 0.420.27 Slide 52 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Slide 53