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

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

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

4 DIABETES & RAMADAN

5 Counteregulatory hormones
FFA, Ketones Adipose

6 Hyperglycaemia &Ketoacidosis
Counteregulatory hormones Glucagon FFA, Ketones Adipose

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8 THE NEED FOR BALANCE

9 HYPERGLYCEMIA

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

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

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

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

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

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

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17 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%

18 Hypoglycemia Sever hypoglycemia was more frequent in patients:
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

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. Defining and Reporting Hypoglycemia in Diabetes. Diabetes Care 2005;28 59), 2. Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 2002;45:937–948 1. American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5): 2. Cryer PE. Diabetologia. 2002;45:937–948

20 Physiological defenses against falling plasma glucose concentrations
The physiological defenses against falling plasma glucose concentrations include: (a) decreased pancreatic islet β cell insulin secretion; (b) increased pancreatic islet α cell glucagon secretion; and, absent the latter, (c) increased adrenomedullary epinephrine secretion. The behavioral form of defense is the ingestion of food prompted by symptoms of hypoglycemia. All of these defenses are compromised in T1DM and advanced T2DM. This involves both peripheral (pancreatic islet) and CNS alterations. Both decrements in insulin and increments in glucagon are lost. The former is the result of β cell failure. The latter is plausibly attributed to loss of the decrement in intra-islet insulin that normally signals increased glucagon secretion. In the setting of absent insulin and glucagon responses, attenuated epinephrine responses cause the clinical syndrome of defective glucose counterregulation that is associated with a 25-fold or greater increased risk of severe hypoglycemia Attenuated sympathoadrenal, largely sympathetic neural (12), responses also cause the clinical syndrome of hypoglycemia unawareness that, by compromising the behavioral defense, is also associated with an increased risk of severe hypoglycemia. Thus, hypoglycemia is the result of the interplay of absolute or relative (to exogenous glucose delivery, endogenous glucose production, or insulin sensitivity) therapeutic insulin excess and compromised glucose counterregulation. Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J. Clin. Invest. 2006; 116:1470–1473 Adapted from: Cryer PE. J Clin Invest. 2006;116:1470–1473

21 Antecedent hypoglycemia Recurrent hypoglucemia
Hypoglycemia impairs defenses against recurrent hypoglycemia (Hypoglycemia-Associated Autonomic Failure) Antecedent hypoglycemia Sleep Antecedent exercise Reduced sympathoadrenal responses to hypoglycemia Reduced sympathetic neural responses Reduced epinephrine responses Defective glucose counter regulation Hypoglycemia unawareness Episodes of hypoglycemia, even asymptomatic episodes, impair defenses against subsequent hypoglycemia by causing hypoglycemia-associated autonomic failure (HAAF), the clinical syndromes of defective glucose counterregulation and hypoglycemia unawareness, and therefore a vicious cycle of recurrent hypoglycemia. The shift of the glycemic thresholds for sympathoadrenal responses to lower plasma glucose concentrations caused by recent antecedent hypoglycemia (or by sleep or prior exercise) could be the result of alterations in the peripheral afferent or efferent components of the autonomic nervous system or within the CNS. Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J. Clin. Invest. 2006;116:1470–1473 Recurrent hypoglucemia Cryer PE. J Clin Invest. 2006;116:1470–1473

22 Mechanisms by which hypoglycemia may affect cardiovascular events
Hypoglycemic events may trigger inflammation by inducing the release of C-reactive protein (CRP), IL-6, and vascular endothelial growth factor (VEGF). Hypoglycemia also induces increased platelet and neutrophil activation. The sympathoadrenal response during hypoglycemia increases adrenaline secretion and may induce arrhythmias and increase cardiac workload. Underlying endothelial dysfunction leading to decreased vasodilation may also contribute to cardiovascular risk. Desouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care. 2010; 33: Desouza CV, et al. Diabetes Care. 2010; 33:1389–394

23 Episodes suggestive of hypoglycemia
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 episodes defined 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 episodes defined 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

24 Weighted absolute risk difference Studies (participated)
Risk Difference of Hypoglycemia with Different Glucose-lowering Agents for T2DM Met vs Met + TZD Weighted absolute risk difference 0.2 0.15 0.5 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 harmful Drug 1 less harmful The risk of minor and major hypoglycemia was higher with combinations that included sulfonylureas compared with metformin or sulfonylurea monotherapy (absolute risk differences of 8% to 14% for short duration trials). Bolen et al. Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus. Ann Intern Med. 2007;147: CI=confidence interval; Glyb=glyburide; Met=metformin; repag=repaglinide; SU=sulfonylurea; TZD=thiazolidinediones. Bolen S, et al. Ann Intern Med. 2007;147:386–399

25 Relative Risk of Hypoglycemia with Different Glucose-lowering Agents when added to Metformin
HbA1c Goal Achieved Hypoglycemia Group vs. Placebo No. of Trials RR (95% CI) All drugs 10 2.56 (1.99 to 3.28)b 19 1.43 (0.89 to 2.30) Sulfonylureas 1 3.38 (2.02 to 5.83)a 3 2.63 (0.76 to 9.13)a Glinides 3.20 (1.47 to 7.58) 2 7.92 (1.45 to 43.21) Thiazolidinediones 1.69 (1.24 to 2.33) 2.04 (0.50 to 8.23) AGIs NA 0.60 (0.08 to 4.55) DPP-4 inhibitors 6 2.44 (1.78 to 3.33)b 8 0.67 (0.30 to 1.50) GLP-1 analogs 3.96 (2.37 to 6.79) 0.94 (0.42 to 2.12) The ADA guidelines emphasize the prevention of hypoglycemia as critical to the treatment strategy in type 2 DM.42 Therefore, considering a drug’s hypoglycemic rate is warranted when selecting a drug. Although mild hypoglycemia produces bothersome symptoms, excessive decrease in blood glucose is associated with complications, including coma, cardiac arrhythmias, or myocardial ischemia. Of the studies that reported hypoglycemia, patients receiving sulfonylureas or glinides experienced higher rates of hypoglycemia than placebo (RR range, ). This increased risk is likely related to the increase in insulin release, which may occur independent of the presence of a glucose load. The remaining drugs did not exhibit statistically significant differences in hypoglycemia risk compared with placebo. Phung et al. Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes. JAMA. 2010;303(14): 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%

26 Cumulative Incidence of Hypoglycemia in T2DM over 6 Years
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.

27 Risk of Hypoglycemia with Different Sulfonylureas
Gliclazide 0.85 Glipizide 8.70 Glimepiride 0.86 Tolbutamide 3.50 Chlorpropamide 16.00 Glyburide 16.00 Severe hypoglycemia* n/1000 person years = Relative Risk (%) Risk of Hypoglycemia with Different Sulfonylureas Incidence of hypoglycemia with SUs varies with different compounds.1 Reference 1.Tayek J. SUR receptor activity vs. incidence of hypoglycaemia and cardiovascular mortality with sulphonylurea therapy for diabetics. Diabetes Obes Metab. 2008; 10: 1128–1130. *<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008;10:1128–1130.

28 Health and economical consequences of hypoglycemia
CV complications2 Weight gain by defensive eating3 Coma2 Car accident4 Hospitalization costs1 Dizzy turn unconsciousness2 Seizures2 Death6 Increased risk of dementia5 Quality of Life7 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

29 Hypoglycemia and Weight Gain are intertwined
Agents capable of triggering hypoglycemic episodes can also promote weight gain, especially as part of an intensified regimen aimed at achieving normal or near-normal glycemic levels. The weight gain may be related in part to an increase in “defensive eating” to prevent a decline from normoglycemia to hypoglycemia. Foley J, et al. Weight neutrality with the DPP-4 inhibitor, vildagliptin: Mechanistic basis and clinical experience. Vascular Health and Risk Management. 2010;6:541–548. 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)
The model is based on the UKPDS 68 outcomes equations [12] and is designed to simulate a cohort of up to individuals over a period of 40 years. This model had been adapted to incorporate the impact of weight change upon HRQL, as assessed using the relationship between BMI and health-related utility. Each unit change in BMI was associated with a change in health-related utility [22]. Furthermore, health-related utility associated with hypoglycaemic events is incorporated into the model via statistical equations that relate the hypoglycaemia fear score (HFS) to changes in health-related utility conditioned upon the severity and frequency of hypoglycaemic events [23]. Each unit change of HFS is associated with a change in health-related utility as measured by the EQ-5D. Changes in glycaemic control, hypoglycaemia and BMI are important contributors to the prediction of QALYs. The results of this analysis demonstrate that the QALY decrement resulting from the adverse therapy effects, namely, weight gain and hypoglycaemia, associated with TZDs and SUs offsets the QALY benefit resulting from blood glucose reduction. In contrast, the QALY gain associated with the absence of such adverse effects seen with DPP-4 inhibitors augmented the QALY benefit derived from blood glucose reduction with this class of agents. The reference point relates to a 1% reduction in Glycosylated haemoglobin (HbA1c) with no associated changes in weight or hypoglycaemia, which was associated with a predicted QALY benefit of This figure illustrates the relative impact of weight change ±3 kg and hypoglycaemia changes ±30% on the QALY gained, beyond those already seen with the reference point. The graph illustrates that the QALY decrement associated with an increase in weight and hypoglycaemia by approximately 3 kg and 30% respectively, will offset the QALY gain associated with a 1% reduction in HbA1c. McEwan et al. Understanding the inter-relationship between improved glycaemic control, hypoglycaemia and weight change within a long-term economic model. Diabetes, Obesity and Metabolism. 2010;12:431– 436. 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
Glucose Sensitivity Basal Secretory Tone 75 260 70 240 65 Glucose Sensitivity (pmol/min/m2/mM) Secretion at 7 mM glucose (pmol/min/m2) 60 220 55 200 50 Effect of Vildagliptin on β-cell Sensitivity to Glucose This 52-week study was performed to explore the effects of vildagliptin 50 mg once daily on model-assessed β-cell function in a large population of drug-naïve patients with type 2 diabetes mellitus and mild hyperglycemia.1 β-cell function parameters derived by mathematical modeling were: fasting (basal) secretory tone (insulin secretion rate at 7 mM glucose) glucose sensitivity (slope of the β-cell response curve/glucose dose) rate sensitivity (marker of 1st-phase insulin response) potentiation factor ratio (between 4 hours and point 0). The effects of vildagliptin to increase basal secretory tone and glucose sensitivity were fully manifest by Week 24, which persisted until the end of treatment. Vildagliptin improves several measures of β-cell function (such as insulin secretory tone, glucose sensitivity, and rate sensitivity) but longer-term studies are necessary to determine possible effects on disease progression. Reference 1. Mari A, et al. Characterization of the influence of vildagliptin on model-assessed β-cell function in patients with type 2 diabetes and mild hyperglycemia. J Clin Endocrinol Metab. 2008; 93: 103–109. 45 180 −4 4 8 12 16 20 24 28 32 36 40 44 48 52 −4 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) Time (weeks) Vildagliptin 50 mg once daily Placebo Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109.

33 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 Effects of Vildagliptin Treatment on the Sensitivity of the α-cell to Glucose In this randomized, double-blind, crossover study assessing the effects of 4 weeks of vildagliptin (100 mg once daily), 30 drug-naïve patients with type 2 diabetes mellitus and mild hyperglycemia (HbA1c <7.5%) were screened for 4 weeks before being randomized to receive either vildagliptin or placebo for 4 weeks. This was followed by a 4-week washout period before patients received the alternate treatment for a further 4 weeks. On Day 28 of each treatment period, overnight-fasted patients received study medication followed by a standardized breakfast meal. Two hours later, a hyperinsulinemic, stepped glucose clamp was performed (45 minutes per step, target glucose levels = 7.5 nM, 5.0 nM and 2.5 nM). During the hyperglycemic and euglycemic steps, glucagon levels were significantly lower with vildagliptin 100 mg once daily than with placebo. During the hypoglycemic steps, glucagon levels increased from a significantly lower baseline to a slightly higher level with vildagliptin compared with placebo. The effect of vildagliptin to decrease glucagon in hyperglycemic states and increase glucagon in hypoglycemic states is consistent with the GLP-1 effect to enhance the glucose sensitivity of the α-cells to glucose. Vildagliptin may reduce the risk of hypoglycemia by this relative enhancement of glucagon secretion at low glucose levels. Reference Ahrén B, et al. Vildagliptin Enhances Islet Responsiveness to Both Hyper- and Hypoglycemia in Patients with Type 2 Diabetes. J Clin Endocrinol Metab. 2009;94(4):1236–1243 110 90 −30 30 60 90 120 165 210 255 285 Time (min) Placebo Vildagliptin 100 mg once daily Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243. Vildagliptin 100 mg once daily is NOT an approved dose. 33

34 Comparing with commonly used SUs

35 Incidence of hypoglycaemia b
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 Patients with 1 hypos (%) Number of severe hypoglycaemic events c Incidence (%) 1389 1383 n = No. of events 16.2 1.7 39 554 Mean HbA1c (%) 0.0 6.5 6.7 6.9 7.1 7.3 7.5 - 8 4 12 16 20 24 28 32 36 40 44 48 52 56 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) 1117 n = 1071 Change in body weight a * Glimepiride up to 6 mg once daily + metformin Vildagliptin 50 mg twice daily + metformin When metformin alone fails to maintain sufficient glycemic control, the addition of vildagliptin provides comparable efficacy to that of glimepiride after 52 weeks with no weight gain and a significant reduction in hypoglycemia compared with glimepiride: 10 fold lower incidence of hypoglycemia with vildagliptin vs glimepiride; vildagliptin significantly reduced body weight relative to glimepiride, between groups difference: 1.79 kg. BL=baseline; CI=confidence interval NI=non-inferiority; aPer protocol population ; bSafety population. cGrade 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.

36 2 years with no weight gain and low incidence of hypoglycemia
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 Patients with > 1 hypo (%) Number of hypo events Number of severe events a Discontinuations due to hypos N = 1553 1546 N = 1553 1546 N = 1553 1546 N = 1553 1546 18.2 No. of events Incidence (%) No. of events No. of events 59 Mean HbA1c 1 Change in body weight 3 Hypoglycemic events - After 2 years of treatment, 2.3% patients receiving vildagliptin had experienced at least one confirmed hypoglycaemic event, compared with 18.2% patients receiving glimepiride. In total, there were 59 events with vildagliptin compared with 838 events with glimepiride, a 14-fold difference. - None of the patients treated with vildagliptin experienced severe hypoglycemic events, while 15 patients in glimepiride group experienced severe hypoglycemic events. - Notably, none of the hypoglycaemic events with vildagliptin led to study drug discontinuation, whereas 13 events with glimepiride did. Efficacy Mean HbA1c: From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. Body weight: Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between group difference -1.5 kg; p<0.001]. Reference 1. Matthews DR et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diab Obes Metab 2010; 12: 780–789. 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) Glimepiride up to 6 mg qd +met Vildagliptin 50 mg bid + met * 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. 36

37 Very elderly patients pooled analysis

38 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 Add on therapy studies pool Monotherapy studies pool Add on therapy studies pool n = BL 62 8.3 25 8.5 n = BL 62 74.9 25 82.8 Change in Body Weight (kg) from baseline Change in HbA1c (%) from baseline * * * Very elderly patients analysis: change in HbA1c and body weight – at 24 weeks treatment, and hypoglycemic events - In the patient group ≥ 75 years, treatment with vildagliptin significantly reduced mean HbA1c by -0.9% from a baseline of 8.3% in the pooled monotherapy efficacy population (p<0.0001) and by -1.1% from a baseline of 8.5% in the pooled add-on therapy to metformin efficacy population (p=0.0004). - Vildagliptin did not induce weight gain in older or younger patients as either monotherapy or add-on therapy to metformin. In the patient group ≥ 75 years, modest mean weight reductions of -0.9 kg from a baseline of 75 kg (p=0.0277) in the pooled monotherapy efficacy population and of -0.2 kg from a baseline of 83 kg (p=0.6381) in the pooled add-to therapy to metformin efficacy population were seen. An analysis of hypoglycemia in the age groups showed that in patients ≥ 75 years, no confirmed-hypoglycemic events were reported with vildagliptin in monotherapy and add-on therapy to metformin, and that most notably no severe episodes were observed. Reference Schweizer A. et al. Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: A pooled analysis from a database of clinical trials. Diabetes, Obesity and Metabolism. 2011;13: 55–64. *<0.05 vs baseline (within group) Mono > 75 Add on > 75 Hypoglycemic events Monotherapy studies pool Add on therapy studies pool Any events 0.0 Severe events 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.

39 Even When Add-on to Insulin

40 Fewer hypoglycemic events in vildagliptin add-on to insulin compared with insulin alone
Duration: 24 weeks Add-on to insulin: vilda vs PBO Add-on Treatment to Insulin No. of Events No. of Severe Events * 185 200 10 160 ** 113 8 6 120 No. of Severe Events No. of Events 6 80 4 40 2 Vildagliptin Add-on to Insulin: Significant Reduction in HbA1c and Fewer Hypoglycemic Events This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg twice daily (n=144) or placebo (n=152) in patients with type 2 diabetes mellitus (T2DM) treated with insulin (>30 U/day) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 Mean daily insulin dose was similar in both the vildagliptin 50 mg twice-daily (81 U) and placebo (82 U) treatment groups. Overall, vildagliptin 50 mg twice daily as add-on to insulin significantly reduced HbA1c levels compared with both baseline and placebo at 24 weeks. The placebo-adjusted mean change in HbA1c from baseline to end point was −0.3% (P=0.01). In patients aged ≥65 years, there was a significant decrease of −0.7% in mean HbA1c levels compared with baseline (P <0.001). The placebo-adjusted mean change in HbA1c from baseline to end point was −0.6% (P=0.001). Significantly fewer patients who received vildagliptin 50 mg twice daily as add-on to insulin treatment experienced hypoglycemic events (22.9% of patients reported 113 events; P <0.01) compared with placebo (29.6% of patients reported 185 events). There were no severe hypoglycemic events in the vildagliptin group compared with six events in the placebo group. One hypothesis for these favorable effects is that dipeptidyl peptidase-4 (DPP-4) inhibitors can restore pancreatic α-cell function, improving glucose sensing and response to changes in plasma glucose levels. Additionally, through DPP-4 inhibition, vildagliptin extends glucagon-like peptide-1 activity to increase glucagon levels and enhance the stimulatory effect of low glucose levels on the α-cell.1 These results demonstrate that vildagliptin as add-on to insulin produces significant decreases in HbA1c levels in the general population of patients with T2DM and in elderly patients with T2DM. Furthermore, despite lowering HbA1c levels, vildagliptin as add-on to insulin treatment reduces the incidence of hypoglycemic events and may protect patients from severe hypoglycemia. Reference 1. Fonseca V, et al. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007; 50: 1148–1155. 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: 1148–1155. 40

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

42

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 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 Vildagliptin 50 mg bid daily n23 Patients aged 18 years and diagnosed with T2DM 12 months prior to fasting were enrolled, providing they had received vildagliptin or SU add-on to metformin for weeks prior to fasting, were planning to fast for 10 days and had HbA1c 8.5% up to 1 month prior to fasting. Metformin Gliclazide 80 mg* per daily n 36 6weeks pre Ramadan Ramadan 6 weeks post 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

45 Change in HbA1c (%) from baseline
Vildagliptin: Significantly lowered HbA1c compared to SU Duration: ≤16 week observational study Add-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 34 (in 15 pts) Severe events 1 *mean between-group difference 0.5% BL=baseline; HbA1c=haemoglobin A1c Hassanein M, et al. Curr Med Res Opin 2011; 27: 1367–1374

46 VECTOR Study: Results 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

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

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

50 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 Patient received gliclazide 160 mg twice daily (n = 26) or vildagliptin 50 mg twice daily (n = 26) in addition to metformin. Hypoglycemic events, HbA1c and weight were recorded 2 weeks before and 10 days after the Ramadan fast. All patients received education about how to identify and manage hypoglycemia during Ramadan. N= 52 Metformin 2 g Gliclazide 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

51 Glycated haemoglobin (%)
Vildagliptin therapy and hypoglycaemia in Muslim T2DM during Ramadan Glycated haemoglobin (%) Hypoglycemic events * n= 26 BL 8.98 8.95 ** n= 26 BL 0.42 0.27 *P=0.8217; **P=0.0168 Vildagliptin Gliclazide Analysis of covariance models with treatment group, gender and ethnicity as factors. aAge, duration of diabetes, HbA1c, weight and prefasting value, bage, duration of diabetes, weight and prefasting value, or cage, duration of diabetes, HbA1c and prefasting value as covariates. SD, standard deviation; SEM, standard error mean. Devendra et al. Int J Clin Pract. 2009;63(10):1446–1450

52 Ultimately, more intensive insulin regimens may be required (see Figure 3.)
Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥ %). Consider beginning with insulin if patient presents with severe hyperglycemia (≥ mg/dl [≥ mmol/l]; HbA1c ≥ %) with or without catabolic features (weight loss, ketosis, etc). Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] 52

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