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Management of Diabetes Mellitus during Ramadan

Management of Diabetes Mellitus during Ramadan. By. Professor Megahid M, Abuelmagd Diabetes and Endocrinology Unit Mansoura University. DIABETES & RAMADAN. Counteregulatory hormones. FFA, Ketones. Adipose. Hyperglycaemia &Ketoacidosis. Counteregulatory hormones Glucagon.

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Management of Diabetes Mellitus during Ramadan

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  1. Management of Diabetes Mellitus during Ramadan By Professor Megahid M, Abuelmagd Diabetes and Endocrinology Unit Mansoura University

  2. DIABETES&RAMADAN

  3. Counteregulatory hormones FFA, Ketones Adipose

  4. Hyperglycaemia &Ketoacidosis Counteregulatory hormones Glucagon FFA, Ketones Adipose

  5. THE NEED FOR BALANCE

  6. HYPERGLYCEMIA

  7. 70 Microvascularendpoint 60 50 Myocardialinfarction Adjusted incidence per 1000 person years (%) 40 30 20 10 0 8 5 6 7 9 10 11 Mean HbA1c (%) Diabetes-associated risks UKPDS 35. BMJ 2000; 321: 405-12

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

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

  10. Micro vascular complications Macro vascular complications Macro & Micro X 3.5 X 1.7 X 3.0 Cost of vascular complications

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

  12. Main risk associated withfasting in diabetic patients is: • Hypoglycemia

  13. Hypoglycemia 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%

  14. Hypoglycemia 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

  15. 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;45:937–948

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

  17. Hypoglycemia impairs defenses against recurrent hypoglycemia (Hypoglycemia-Associated Autonomic Failure) Antecedent hypoglycemia Sleep Antecedent exercise Reduced sympathoadrenalresponses to hypoglycemia Reduced sympatheticneural responses Reduced epinephrine responses Defective glucosecounter regulation Hypoglycemia unawareness Recurrent hypoglucemia Cryer PE. J Clin Invest. 2006;116:1470–1473

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

  19. Classification of hypoglycemia according to severity: European Committee for Medicinal Products for Human Use (CHMP) 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 .

  20. Risk Difference of Hypoglycemia with Different Glucose-lowering Agents for T2DM Drug 1 less harmful Drug 1 more harmful Pooled effect (95% CI) Studies (participated) Met vs Met + TZD 0.00 (-0.01 to 0.01) 3 (1557) SU vs repag 0.02 (-0.02 to 0.05) 5 (1495) Glyb vs other SU 0.03 (0.00 to 0.05) 6 (2238) SU vs Met 0.04 (0.0 to 0.09) 8 (2026) SU + TZD vs SU 0.08 (0.00 to 0.16) 3 (1028) SU vs TZD 0.09 (0.03 to 0.15) 5 (1921) SU + Met vs SU 0.11 (0.07 to 0.14) 8 (1948) SU + Met vs Met 0.14 (0.07 to 0.21) 9 (1987) 0 0.5 0.15 0.15 0.2 Weighted absolute risk difference CI=confidence interval; Glyb=glyburide; Met=metformin; repag=repaglinide; SU=sulfonylurea; TZD=thiazolidinediones. Bolen S, et al. Ann Intern Med. 2007;147:386–399

  21. Relative Risk of Hypoglycemia with Different Glucose-lowering Agents when added to Metformin Adapted from: Phung, et al. JAMA. 2010;303(14):1410–1418 Abbrevations: AGIs, α-glucosidase inhibitors; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin A1c; NA, not applicable; RR, relative risk; WMD, weighted mean difference. a ≥ 75% b = 50%-75%

  22. UKPDS – Treating to Targets Elevates the Risk of Hypoglycemia and Incidence can be High with SUs Cumulative Incidence of Hypoglycemia in T2DM over 6 Years Sulfonylurea (n=922) Insulin (n=689) Patients (%) Sulfonylurea Insulin Sulfonylurea Insulin Any hypoglycema Major hypoglycemia* HbA1c = 7.1% in all groups SUs=sulfonylureas; T2DM=type 2 diabetes melllitus; *Requiring medical assistance or hospital admission UK Prospective Diabetes Study Group. Diabetes.1995;44:1249–1258.

  23. Risk of Hypoglycemia with Different Sulfonylureas Relative Risk (%) Tolbutamide3.50 Chlorpropamide16.00 Glyburide16.00 Glimepiride0.86 Glipizide8.70 Severe hypoglycemia*n/1000 person years = Gliclazide0.85 *<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008;10:1128–1130.

  24. Health and economical consequences of hypoglycemia Hospitalization costs1 CV complications2 Weight gain by defensive eating3 Dizzy turn unconsciousness2 Hypoglycemia Seizures2 Car accident4 Increased risk of dementia5 Death6 Coma2 1. Jönsson L, et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006;9:193–198 2. Barnett AH. CMRO. 2010;26:1333–1342 3. Foley J & Jordan. J. Vasc Health Risk Manag. 2010;6:541–548 4. Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. CanJ Diabetes. 2003;27(2):128 –140. 5. Whitmer RA, et al. JAMA. 2009;301:15655–1572 6. Zammitt NN, et al. Diabetes Care. 2005;28:2948–2961 7. McEwan P, et al. Diabetes Obes Metab. 2010;12:431–436 Quality of Life7

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

  26. 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

  27. Vildagliptin improves Alpha and Beta Cell selectivity for both Hyper and Hypoglycemia

  28. Vildagliptin improves β-cell sensitivity to glucose Vildagliptin 50 mg once daily Placebo Glucose Sensitivity Basal Secretory Tone 75 260 70 240 65 Secretion at 7 mM glucose (pmol/min/m2) Glucose Sensitivity (pmol/min/m2/mM) 220 60 55 200 50 180 45 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) Time (weeks) Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109.

  29. Effects of vildagliptin treatment on the sensitivity of the α-cell to glucose During the hypoglycemic steps, glucagon levels increased from a significantly lower baseline to a slightly higher level with vildagliptin compared with placebo. 170 Meal 7.5 mM 5.0 mM 2.5 mM Dose 150 Glucagon (mg/L) 130 110 90 −30 0 30 60 90 120 165 210 255 285 Vildagliptin 100 mg once daily Time (min) Placebo Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243. Vildagliptin 100 mg once daily is NOT an approved dose.

  30. Comparing with commonly used SUs

  31. In patients uncontrolled with metformin monotherapy vildagliptin is as effective as glimepiride over 1 year with low incidence of hypoglycaemia and no weight gain Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride Incidence of hypoglycaemia b Mean HbA1c reduction a Number of hypoglycaemic events Number of severe hypoglycaemic events c Patients with1 hypos (%) 7.5 1383 n = 1389 1383 1389 1383 1389 7.3 554 NI: 97.5% CI (0.02, 0.16) 7.1 16.2 Mean HbA1c (%) 6.9 −0.4% 6.7 Incidence (%) No. of events −0.5% No. of events 6.5 0.0 - 8 - 4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 1.7 39 Time (weeks) Change in body weight a (BL mean ~88.8kg) n = 1117 1071 BL=baseline; CI=confidence intervalNI=non-inferiority; aPer protocol population ; bSafety population.cGrade 2 or suspected grade 2 events. Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin *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. Adjusted mean change in body weight (kg) from BL Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166. *

  32. Vildagliptin 50 mg bid + met Glimepiride up to 6 mg qd +met Vildagliptin was as effective as glimepiride when added to metformin at 2 years with no weight gain and low incidence of hypoglycemia Duration: 104 weeks, add-on to metformin: vildagliptin vs glimepiride Hypoglycaemia 2 Number of hypo events Patients with > 1 hypo (%) Number of severe events a Discontinuations due to hypos N = N = 1553 1546 N = N = 1553 1546 1553 1546 1553 1546 18.2 No. of events Incidence (%) No. of events No. of events 59 Change in body weight 3 Mean HbA1c 1 Change from BL to EP(BL Mean ~89kg) Between-treatment Difference 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% n = 1539 1520 Adjusted mean change in body weight (kg) * 1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p <0.001. BL=baseline; EP = week 104 endpoint; Met= metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789.

  33. Very elderly patients pooled analysis

  34. Add on > 75 Mono > 75 Very elderly patients pooled analysis: Vildagliptin add on metfrmin shows NO hypoglycemic event Pooled analysis at 24 weeks; 50 mg bid HbA1c Reduction: At 24 weeks treatment Body Weight: At 24 weeks treatment Monotherapy studies pool Monotherapy studies pool Add on therapy studies pool Add on therapy studies pool Change in Body Weight (kg) from baseline Change in HbA1c (%) from baseline * * * *<0.05 vs baseline (within group) • 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, 2011.

  35. Even When Add-on to Insulin

  36. Fewer hypoglycemic events in vildagliptin add-on to insulin compared with insulin alone Vilda 50 mg twice daily+ insulin PBO + insulin Add-on Treatment to Insulin Duration: 24 weeksAdd-on to insulin: vilda vs PBO No. of Events No. of Severe Events * 185 200 10 160 ** 113 8 6 120 No. of Severe Events 6 No. of Events 80 4 40 2 0 0 0 PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.

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

  38. 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

  39. Study Design • Observational, • Non-interventional • Two-cohort study • Conducted in the UK. • HbA1c 8.5% up to 1 month prior to fasting -----Data collection Metformin 2000 + Vildagliptin 50 mg bid daily n23 Metformin 2000 + Gliclazide 80 mg* per daily n 36 6 weeks post Ramadan 6weeks pre Ramadan Ramadan *Different formulations were used for gliclazide therefore the following conversion factor was used: 80 mg standard formulation 30 mg modified release formulation. M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374

  40. Vildagliptin: Significantly lowered HbA1c compared to SU Duration: ≤16 week observational studyAdd-on to metformin: vildagliptin vs gliclazide BL= 7.6 7.2 0.1 + 0.1 0.0 p= 0.02* Change in HbA1c (%) from baseline -0.2 Vildagliptin 50 mg twice daily (n=23)Sulfonylurea (n=36) -0.4 -0.4 Hypoglycaemic events Vildagliptin Sulfonylurea Any events 0 34 (in 15 pts) Severe events 0 1 *mean between-group difference 0.5% BL=baseline; HbA1c=haemoglobin A1c Hassanein M, et al. Curr Med Res Opin 2011; 27: 1367–1374

  41. VECTOR Study: Results P=0.0002 Hypoglycaemia • Vildagliptin arm - no Hypo • SU arm - 34 Hypo including 1 severe HE No. of Hypos M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374

  42. 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

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

  44. Devendra et al. Int J Clin Pract. 2009;63(10):1446–1450

  45. 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. Vildagliptin 50 mg bid daily n26 Study Design Study Design N= 52 Metformin 2 g Gliclazide 160 mg bd n 26 10 days after Ramadan 2 weeks Ramadan Recording of hypoglycemia and weight gain Devendra et al. Int J Clin Pract. 2009;63(10):1446–1450

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