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Management of Diabetes Mellitus during Ramadan Management of Diabetes Mellitus during Ramadan By Professor Megahid M, Abuelmagd Diabetes and Endocrinology.

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Presentation on theme: "Management of Diabetes Mellitus during Ramadan Management of Diabetes Mellitus during Ramadan By Professor Megahid M, Abuelmagd Diabetes and Endocrinology."— Presentation transcript:

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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

4 DIABETES & RAMADAN

5 Adipose FFA, Ketones Counteregulat ory hormones

6 Adipose FFA, Ketones Counteregulat ory hormones Glucagon Hyperglycaemia &Ketoacidosis

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8 THE NEED FOR BALANCE

9 HYPERGLYCEMIA

10 Mean HbA 1c (%) Adjusted incidence per 1000 person years (%) Myocardial infarction Microvascular endpoint Diabetes-associated risks UKPDS 35. BMJ 2000; 321:

11 11 Pathophysiology Vascular Complications Hyperglycemia  Oxidative Stress Atheroma Formation Thrombus Formation Endothelial Dysfunction

12 12 Ramsey, pharmacoeconomics, 1999 Vascular Complications vascular complications among diabetics 3 years incidence (%)

13 13 Cost of vascular complications Micro vascular complications X 1.7 Macro vascular complications X 3.0 Macro & Micro X 3.5

14 14 Causes of death in diabetes % of deaths in diabetes mainly due to vascular complications

15  Hypoglycemia Main risk associated with fasting in diabetic patients is:

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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

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

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): Cryer PE. Diabetologia. 2002;45:937–948

20 Physiological defenses against falling plasma glucose concentrations Adapted from: Cryer PE. J Clin Invest. 2006;116:1470–1473

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;116:1470–1473

22 Mechanisms by which hypoglycemia may affect cardiovascular events Desouza CV, et al. Diabetes Care. 2010; 33:1389–394

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.

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;147:386–399 Met vs Met + TZD Weighted absolute risk difference (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

25 Relative Risk of Hypoglycemia with Different Glucose- lowering Agents when added to Metformin Abbrevations: AGIs, α-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 drugs (1.99 to 3.28) b (0.89 to 2.30) Sulfonylureas13.38 (2.02 to 5.83) a (0.76 to 9.13) a Glinides13.20 (1.47 to 7.58)27.92 (1.45 to 43.21) Thiazolidinedione s (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 (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):1410–1418

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;44:1249–1258. 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

27 Risk of Hypoglycemia with Different Sulfonylureas *<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008;10:1128–1130. Gliclazide 0.85 Glipizide 8.70 Glimepiride 0.86 Tolbutamide 3.50 Chlorpropamide Glyburide Severe hypoglycemia* n/1000 person years = Relative Risk (%)

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. Jönsson L, et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006;9:193– Barnett AH. CMRO. 2010;26:1333– Foley J & Jordan. J. Vasc Health Risk Manag. 2010;6:541– Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. CanJ Diabetes. 2003;27(2):128 – Whitmer RA, et al. JAMA. 2009;301:15655– Zammitt NN, et al. Diabetes Care. 2005;28:2948– McEwan P, et al. Diabetes Obes Metab. 2010;12:431–436

29 Hypoglycemia and Weight Gain are intertwined Foley J, et al. Vasc Health Risk Manag. 2010:6 541–548

30 Impact of changes in weight and rates of hypoglycaemia events on Quality-Adjusted Life Year (QALY) McEwan, et al. Diabetes Obes Metab. 2010;12:431–436

31 Vildagliptin improves Alpha and Beta Cell selectivity for both Hyper and Hypoglycemia

32 Vildagliptin improves β-cell sensitivity to glucose Vildagliptin 50 mg once daily Placebo Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109. Secretion at 7 mM glucose (pmol/min/m 2 ) − Time (weeks) Basal Secretory Tone − Time (weeks) Glucose Sensitivity (pmol/min/m 2 /mM) Glucose Sensitivity

33 Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243. Vildagliptin 100 mg once daily is NOT an approved dose. Effects of vildagliptin treatment on the sensitivity of the α-cell to glucose Time (min) − 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.

34 Comparing with commonly used SUs

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 (%) n = No. of events 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 <0.001; adjusted mean change from BL to Week 52, between-treatment difference and P value were from an ANCOVA model containing terms for treatment, baseline and pooled centre. Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166. Mean HbA1c (%) NI: 97.5% CI (0.02, 0.16) −0.4% −0.5% Time (weeks) Adjusted mean change in body weight (kg) from BL (BL mean ~88.8kg) 1117n =1071 Change in body weight a *

36 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 *p < BL=baseline; EP = week 104 endpoint; Met= metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789. Vildagliptin was as effective as glimepiride when added to metformin at 2 years with no weight gain and low incidence of hypoglycemia No. of events Incidence (%) 18.2 Patients with > 1 hypo (%)Discontinuations due to hyposNumber of severe events a Number of hypo events N = Glimepiride up to 6 mg qd +met Vildagliptin 50 mg bid + met No. of events N = N = 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

37 Very elderly patients pooled analysis

38 Monotherapy studies pool Add on therapy studies pool n = BL Change in HbA1c (%) from baseline Mono > 75 Add on > 75 *<0.05 vs baseline (within group) * Body Weight: At 24 weeks treatment n = BL * * Monotherapy studies pool Add on therapy studies pool Change in Body Weight (kg) from baseline Very elderly patients pooled analysis: Vildagliptin add on metfrmin shows NO hypoglycemic event HbA1c Reduction: At 24 weeks treatment Hypoglycemic eventsMonotherapy studies poolAdd on therapy studies pool Any events0.0 Severe events0.0  OR No hypoglycemic events, including severe events was reported in elderly patients with monotherapy and add-on therapy Schweizer A. et al, Diabetes, Obesity and Metabolism 13: 55–64, Pooled analysis at 24 weeks; 50 mg bid

39 Even When Add-on to Insulin

40 Fewer hypoglycemic events in vildagliptin add-on to insulin compared with insulin alone Add-on Treatment to Insulin Duration: 24 weeks Add-on to insulin: vilda vs PBO PBO + insulin Vilda 50 mg twice daily + insulin PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148– No. of EventsNo. of Severe Events No. of Severe Events * ** No. of Events

41 The Question Now: Is Vildagliptin A Safe Drug To Be Used With Diabetic Patients During Rmadan

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43 VECTOR: Aim and objectives Vildagliptin Experience Compared To gliclazide Observed during Ramadan Main aim  To determine the incidence of hypoglycaemic events in Muslim patients with T2D fasting during Ramadan, who are treated with dual therapy of metformin plus vildagliptin or metformin plus sulphonylurea (SU) Primary objectives  The incidence of hypoglycaemic events defined as:  Any reported symptoms by the patient and/or any blood glucose measurement of less than 3.9 mmol/L (also defined as mild or Grade 1 hypoglycaemia)  The need for third party assistance (also defined as severe or Grade 2 hypoglycaemia); Secondary objectives  The change in weight;  The change in HbA1c levels; and  The treatment adherence during Ramadan. M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374

44 Metformin Gliclazide 80 mg* per daily n 36 Ramadan Metformin Vildagliptin 50 mg bid daily n23 Study Design  Observational,  Non-interventional  Two-cohort study  Conducted in the UK.  HbA1c 8.5% up to 1 month prior to fasting 6 weeks post Ramadan 6weeks pre Ramadan *Different formulations were used for gliclazide therefore the following conversion factor was used: 80 mg standard formulation 30 mg modified release formulation Data collection M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374

45 Vildagliptin: Significantly lowered HbA1c compared to SU Hassanein M, et al. Curr Med Res Opin 2011; 27: 1367–1374 *mean between-group difference 0.5% BL=baseline; HbA1c=haemoglobin A1c Hypoglycaemic eventsVildagliptinSulfonylurea Any events034 (in 15 pts) Severe events Change in HbA1c (%) from baseline Vildagliptin 50 mg twice daily (n=23) Sulfonylurea (n=36) Duration: ≤16 week observational study Add-on to metformin: vildagliptin vs gliclazide BL= p= 0.02*

46 VECTOR Study: Results P= Hypoglycaemia Vildagliptin arm - no Hypo SU arm - 34 Hypo including 1 severe HE M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374 No. of Hypos

47 VECTOR Study: Results  Adherence  Vildagliptin arm : 0.2 missed doses (p=0.0204)  SU arm : 7.6 missed doses  Weight  Body weight remained unchanged in both groups M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374

48 Consistency of Data Devendra et al. Int J Clin Pract. 2009;63(10):1446–1450

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50 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

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):1446–1450 *P=0.8217; **P= * n= 26 BL Hypoglycemic events ** n= 26 BL

52 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

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