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Management of diabetes with risk factors getting to goal in glycemic control

Management of diabetes with risk factors getting to goal in glycemic control
Dr Mahir Khalil Jallo

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Management of diabetes with risk factors getting to goal in glycemic control  Dr Mahir Khalil Jallo Management of diabetes with risk factors getting to goal in glycemic control Dr Mahir Khalil Jallo Presentation Transcript

  • Management of Diabetes with Risk Factors: Getting to Goal in Glycemic Control Dr Mahir Khalil Jallo Associate Professor of Medicine Senior consultant – Diabetes & Endocrinology Gulf Medical University Hospital & Research Centre Member of AACE – ESE – EASD PRIMARY CARE S E M I N A R SHARJAH UAE 25 May 2012
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of Diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its Consequences.• Diabetes & Ramadan.
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its consequences.• Diabetes & Ramadan.
  • Key Messages• Diabetes is a huge and growing problem with high and escalating costs to the society.• Diabetes has reached epidemic proportions.• It is a complex multifactorial disease.• Management requires a complex multifactorial approach.
  • Diabetes and weight in the US
  • Prevalence of Type 2 Diabetes by Ethnicity Pima Indian Asian Indian Fiji Mauritius Hispanic US Black US White US Polynesian CookPolynesian Wallis Bantu China 0 10 20 30 40 50 60 Prevalence (%)
  • The Top 10s(number of people with diabetes)
  • The Top 10s (prevalence %)
  • The Global Burden 366 million people have diabetes in 2011 ..by 2030 this will have risen to 552 million The number of people with type 2 diabetes is increasing in every country 80% of people with diabetes live in low-and middle-income countries The greatest number of people with diabetes are between 40 to 59 years of age 183 million people (50%) with diabetes are undiagnosed Diabetes caused 4.6 million deaths in 2011 Diabetes caused at least USD 465 billion dollars in healthcare expenditures in 2011 .. 11% of total healthcare expenditures in adults (20-79 years) 78,000 children develop type 1 diabetes every year
  • Undiagnosed Diabetes
  • Deaths due to Diabetes• 4.6 million deaths due to diabetes in 2011• 8.2% of all- cause mortality• 48% in people under 60
  • The Benefits of Good Glucose Control in Type 2 DM
  • The UK Prospective Diabetes Study
  • UK Prospective Diabetes Study Does an intensive glucose controlpolicy reduce the risk of complications of diabetes?
  • Actual Therapy Conventional Policy Intensive Policy accept < 15 mmol/L aim for < 6 mmol/L 100 die t alone additional non-intens iveproportion of patient s 80 pharm acological therapy 60 intens ive 40 pharm acological therapy 20 die t alone 0 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 Ye ars from random isation
  • Aggregate Clinical Endpoints Relative Risk & 95% CI RR p 0.5 1 2Any diabetes related endpoint 0.88 0.029Diabetes related deaths 0.90 0.34All cause mortality 0.94 0.44Myocardial infarction 0.84 0.052Stroke 1.11 0.52Microvascular 0.75 0.0099 Favours Favours intensive conventional
  • Progression of RetinopathyTwo step change in Early Treatment Diabetic Retinopathy Study (ETDRS) sca Relative Risk & 99% CI RR p 0.5 1 2 0 - 3 years 1.03 0.78 0 - 6 years 0.83 0.017 0 - 9 years 0.83 0.012 0 - 12 years 0.79 0.015 Favours Favours intensive conventional
  • Microalbuminuria Urine albumin >50 mg/L Relative Risk & 99% CI RR p 0.5 1 2Baseline 0.89 0.24Three years 0.83 0.043Six years 0.88 0.13Nine years 0.76 0.00062Twelve years 0.67 0.000054Fifteen years 0.70 0.033 < Favours Favours intensive conventional
  • Glucose Control Study SummaryThe intensive glucose control policy maintained a lower HbA1cby mean 0.9 % over a median follow up of 10 years fromdiagnosis of type 2 diabetes with reduction in risk of: 12% for any diabetes related endpoint p=0.029. 25% for microvascular endpoints p=0.0099. 16% for myocardial infarction p=0.052. 24% for cataract extraction p=0.046. 21% for retinopathy at twelve years p=0.015. 33% for albuminuria at twelve years p=0.000054
  • ConclusionThe UKPDS has shown that intensiveblood glucose control reduces the risk ofdiabetic complications.. the greatest effectbeing on microvascular complications
  • Early control has lasting benefits 10 year follow-up analysis Treatment with Sulphonylureas and insulin
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its consequences.• Diabetes & Ramadan.
  • Managing Diabetes Blood pressure Cholesterol Micro albuminuria Glycaemia
  • OMINOUS OCTET Decreased Incretin Effect Decreased Insulin Secretion Increased LipolysisIslet–a cell ETIOLOGY OF T2DM Impaired Insulin Increased Lipolysis Secretion Hyperglycemia Increased Decreased Glucose HGP Uptake DEFN75-3/99 HYPERGLYCEMI Increased A Glucose ReabsorptionIncreasedGlucagonSecretion Increased HGP Decreased Glucose Uptake Neurotransmitter Dysfunction
  • Type 2 Diabetes Medication Choices Experience and Potency Efficacy as monotherapy: %Medication Route Year  in HgbA1cInsulin s.c. 1921 2.5Sulfonylureas Oral 1946 1.5Glinides Oral 1997 1.0-1.5Metformin Oral 1995 1.5a-glucosidase inhibitors Oral 1995 0.5-0.8TZDs Oral 1999 0.8-1.0GLP analogue s.c. 2005 0.6DPP-IV Inhibitors Oral 2006 0.5-0.8Amylin analogue s.c. 2005 0.6Colesevelam Oral 2008 0.5Bromocriptine mesylate Oral 2009 0.2-0.4
  • Mechanisms of Action of Pharmacologic Agents for DiabetesImproving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical ChallengesJames R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhDJAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14
  • Type 2 Diabetes Medication Choices and Potency • Higher baseline A1C levels predict greater drop in A1C • Shorter duration of diabetes predicts greater drop in A1C with any oral agent • All oral agents require presence of some endogenous b cell function.. as they work by either increasing insulin sensitivity or augmenting b cell insulin releaseSherifali et.al. Diabetes Care. 2010; 33: 1859-1864
  • ADA-EASD Position Statement: Management of Hyperglycemia in T2DM • Glycemic targets • HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) • Individualization is key:  Tighter targets (6.0 - 6.5%) – younger.. Healthier.  Looser targets (7.5 - 8.0%+) – older.. Comorbidities. hypoglycemia prone, etc. • Avoidance of hypoglycemiaPG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
  • ADA-EASD Position Statement: Management of Hyperglycemia in T2DM Achieve and Maintain near normoglycemia, A1c <7.0 Initiate Therapy with Lifestyle and Metformin Rapid addition of medications.. and transition to new regimens when targets are not achieved Early addition of insulin therapy in patients who do not met target goals Nathan, Diabetes Care 2008;31:1-11
  • Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print](Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
  • Diabetes Care, Diabetologia. 19 April 20T2DM Antihyperglycemic Therapy: General Recommendations ahead of print] [Epub
  • Diabetes Care, Diabetologia. 19 April 20T2DM Antihyperglycemic Therapy: General Recommendations ahead of print] [Epub
  • Diabetes Care, Diabetologia. 19 April 20T2DM Antihyperglycemic Therapy: General Recommendations ahead of print] [Epub
  • Diabetes Care, Diabetologia.19 April 2012 [Epub ahead of print]
  • Patient Preference: Efficacy sulfonylurea DPP4 inhibitor GLP1metformin TZD α- glucosidase inhibitors glinide
  • Patient Preference: Cost TZD DPP4metformin sulfonylurea inhibitor GLP1 α-glucosidase inhibitor
  • Patient Preference: Weight sulfonylurea DPP4 α-metformin inhibitor glucosidase GLP1 inhibitor TZD
  • Patient Preference: Hypoglycemia Avoidance DPP4 inhibitor GLP1 sulfonylureametformin TZD glinide α- glucosidase inhibitor
  • Factors to Consider when ChoosingPharmacological Agent(s) for Diabetes • Current A1C • Duration of diabetes • Potential Hypoglycemia • Body weight (BMI.. abdominal obesity) • Age of patient • Co-morbidities • Cost of medication • Convenience
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its consequences.• Diabetes & Ramadan.
  • Cardiovascular risks 140Age adjusted CVD death rate per non diabetic 120 diabetic 10,000 person years 100 80 60 40 20 0 none one only two only all three (from cholesterol, hypertension and smoking)
  • Level of established risk factors of CHD in type 2 diabetic compared with non-diabetic populations 80 Men 70 Women 60Difference (%) 50 40 30 20 10 0 -10
  • Survival of diabetic (1059) and non-diabetic (1378) subjects with and without prior MI in Finland 100 80 60 Non-diabetic no MI% Non-diabetic with MI 40 Diabetic no MI Diabetic with MI 20 0 1 2 3 4 5 6 7 8 years Haffner SM et al. NEJM 98;339:229-34
  • The Benefits of Tight Glucose Control in Type 2 DM Is the Lower always the Better ???
  • ACCORD..ADVANCE and VADT Trials • ACCORD - Action to Control Cardiovascular Risk in Diabetes • ADVANCE - Action in Diabetes to Prevent Vascular Disease • VADT - Veterans Administration Diabetes TrailACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.VADT Study Diabetes Obesity and Metabolism, 2008
  • ACCORD.. ADVANCE and VADT Trials Does Intensive Glucose Control Reduce Risk for Cardiovascular Disease in Type 2 Diabetes?ACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.VADT Study Diabetes Obesity and Metabolism, 2008
  • ACCORD, ADVANCE and VADT Study Design ACCORD ADVANCE VADTMajor Endpoints CV death, CV death, CV death, Non-fatal Non-fatal Non-fatal MI/Stroke MI/Stroke, MI/Stroke, CHF macrovacs event macrovacs eventStudy RCT RCT RCTdesign Glucose Glucose Glucose Intensive vs Intensive vs Intensive vs Standard Arm Standard Arm Standard Arm 2x2 2x2 2x1 BP control Perindopril All received BP +/-fenofibrate +indamide and Lipid Rx v placebo v placebo
  • ACCORD, ADVANCE and VADT Demographics ACCORD ADVANCE VADT# Participants 10,251 11,140 1,791population North America Europe /Asia USMale 62% 58% 97%Age group 40-79 >55 yrs >40yrsmean age 62.2 66 60.5Non-Hispanic White 27% Hispanic, 37% Asian 38% Hispanic,Ethnic Representation African Am African Am, Native Am
  • Outcomes ACCORD.. ADVANCE and VADT ACCORD* ADVANCE VADT A1C (%) 6.4 vs.7.5 † 6.4 vs. 7.0 † 6.9 vs. 8.4 † (Intensive vs. Std) Nonfatal MI (%) 3.6 vs 4.6% † 2.7 vs.2.8 6.3 vs. 6.1 (Intensive vs. Std) CV Death (%) 2.6 vs. 1.8 † 4.5 vs. 5.2 2.1 vs.1.7 (Intensive vs. Std) (1.35 Hazard Ratio) Microvascular - nephropathy ↓ 21% - retinopathy ↓ 5% NS Take home ↓ risk MIs, but Glucose control has no Glucose control ↑ risk death in impact on CV events, has no impact on intensive arm but ↓ Microvascular risk CV events*ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial halted intensive glucose group (2/6/08)† significant difference between intensive and standard group
  • Adverse Outcomes: ACCORD.. ADVANCE and VADTIntensive vs Std ACCORD* ADVANCE VADTSevere Hypoglycemia 3.0 vs 1.0 0.7 vs 0.4 -(% per yr)Hypoglycemia requiring 4.6 vs 1.5 1.8 vs 0.6 2.3 vs 1.1assistance (% per year)Weight Gain > 10Kg 27.8 % vs 14.1% 0.0 vs -1.0 -Wt gain (Kg) 3.5 0.7 6.8Intensive groupIncreased Mortality No No NoRosigliatzone?
  • Hazard Ratios for the Primary Outcome and Death from Any Cause in Pre-specified Subgroups: ACCORD Study Prior CVD Age <65 A1c >8.1N Engl J Med 358;24, 2008
  • ACCORD.. ADVANCE and VADT Lessons Learned• Intensive glucose control does not reduce CVD mortality in T2DM.. and may increase risk, especially in patients with pre-existing CHD• Aggressive A1c targets (<6.5%) were associated with a 3-fold increased risk hypoglycemia
  • ACCORD, ADVANCE, and VADT Lessons Learned- Continued• Intensive control associated with reduced risk for nephropathy in ADVANCE.• To reach and maintain A1c targets of <6.5 required frequent adjustments of multiple anti- diabetic medications• Aggressive Targets (<6.5) are probably reasonable for healthy patients to reduce risk micro-vascular complications
  • Risks of Hypos ACCORD ADVANCEHbA1c, % 6.4 vs. 7.5* 6.5 vs. 7.3*Death from any cause,% 5.0 vs. 4.0* 8.9 vs. 9.6Death from cardiovascular event, 2.6 vs. 1.8* 4.5 vs. 5.2%Nonfatal MI, % 3.6 vs. 4.6* 2.7 vs. 2.8Major/severe hypoglycemia, % 10.5 vs. 3.5* 2.7 vs. 1.5*Weight gain, kg 3.5 vs. 0.4* 0.0 vs. -1.0* Summary of ACCORD & ADVANCE *p≤0.05
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its consequences.• Diabetes & Ramadan.
  • The Incretin System• The missing link in diabetes and metabolic syndrome?
  • Incretins• Messengers exist to stimulate insulin release and prepare vasculature for glucose/insulin combination• Glucagon-like peptede -1 (GLP-1)• Glucose-dependent insulinotropic polypeptide (GIP)
  • Insulin and Glucagon Regulate Normal Glucose Homeostasis Glucagon (a-cell) Fasting state Pancreas Fed state Insulin (b-cell) Glucose output Glucose uptake Muscle Blood glucose Blood glucose Liver Adipose tissuePorte D Jr, Kahn SE. Clin Invest Med. 1995;18:247-54. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds.Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145-68.
  • Role of Incretin System in Glucose Homeostasis Glucose- dependent Glucose insulin uptake by Ingestion (GLP-1 & GIP) peripheral of food tissue Pancreas Release of b-cells GI tract active incretins a-cells Normoglycaemia GLP-1 & GIP  Hepatic Glucose- glucose dependent production DPP-4  glucagon inactivates (GLP-1) GLP-1 & GIPAdapted from Drucker DJ. Cell Metab. 2006;3:153-65.
  • Food Promotes Insulin secretion Inhibits Inhibits background gastric emptying Glucagon secretion Increases Hypo-dependent Glucagon secretion GIP GLP-1 Vasodilatesperfusing beds Reduces appetite Inhibits gluconeogenesis
  • Food Promotes Inhibits Insulin secretion gluconeogenesis Inhibits background Glucagon secretion Increases Hypo-dependent Glucagon secretion GIP GLP-1 Vasodilatesperfusing beds Reduces DPP-IV appetite
  • The Incretin System and Glucose Homeostasis – Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins secreted from enteroendocrine cells postprandially that participate in regulation of glucose homeostasis1,2 – The incretins enhance glucose-dependent insulin secretion, suppress postprandial glucagon secretion from pancreatic a-cells, slow gastric emptying, reduce food intake and promote weight loss3 – The incretins are normally inactivated by dipeptidyl peptidase 4 (DPP-4)41. Mosjov S, et al. J Clin Invest. 1987;79:616-9.2. Kreymann B, et al. Lancet. 1987;2:1300-4.3. Drucker DJ. J Clin Invest. 2007;117(1):24-32.4. Kieffer TJ, et al. Endocrinology. 1995;136(8):3585-96.
  • GLP-1 and GIP are the Two Major Incretins GLP-1 GIP – Produced by K cells in the proximal – Produced by intestinal L cells1 gut6 – Stimulates glucose-dependent insulin – Stimulates glucose-dependent insulin release2-4 release2-4 – Suppresses hepatic glucose output by – Minimal effects on gastric emptying; inhibiting glucagon secretion in a no significant effects on satiety or body weight2-4 glucose-dependent manner2-4 – Potentially enhances b-cell – Inhibition of gastric emptying; proliferation and survival in islet cell reduction of food intake and body lines2-4 weight2-4 – In contrast to GLP-1, does not retain its – Enhances b-cell proliferation and insulinotropic activity in type 2 diabetics7 survival in animal models and – The contribution of endogenous GIP to isolated human islets2-4 the therapeutic efficacy of DPP-4 – Half-life 11.4 ± 1.0 minutes5 inhibitors uncertain4 – Half-life 7.3 ± 1.0 minutes81. Kieffer TJ, et al. Endocr Rev. 1999;20(6):876-913; 2. Drucker DJ. Cell Metab. 2006;3:153-65; 3. Dunning BE and Gerich JE.Endo Rev. 2007;28(3):253-83; 4. Drucker DJ. J Clin Invest. 2007;117(1):24-32; 5. Schjoldager BT, et al. Dig Dis Sci.1989;34(5):703-8; 6. Buchan AM, et al. Histochemistry. 1978;56(1):37-44; 7. Nauck MA, et al. J Clin Invest. 1993;91(1):301-7; 8.Deacon CF, et al. J Clin Endocrinol Metab. 2000;85(10):3575-81.
  • Sites of Action of GLP-1 Brain Neuroprotection Gastric emptying Heart Appetite Stomach Cardioprotection Cardiac output Glucose production Pancreas GI tract Insulin biosynthesis b-cell proliferation b-cell apoptosis Liver Insulin Insulin secretion sensitivity Glucagon secretion MuscleAdapted from Drucker DJ. Cell Metab. 2006;3:153-65.
  • The Incretin Effect in Type 2 Diabetes The incretins may be responsible for up to 70% of postprandial insulin secretion The incretin effect is severely reduced or absent in patients with type 2 diabetes The loss of GIP action is probably a consequence of diabetes GLP-1 secretion is also impaired, but its insulinotropic and glucagon- suppressive actions are preserved The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in diabetic patients Enhancement of incretin action may therefore represent a therapeutic solutionHolst JJ, et al. Mol Cell Endocrinol. 2009;297(1-2):127-36.
  • Potential Strategies for Incretin- based Therapies– GLP-1 continuous infusion– Agents that mimic GLP-1 action (GLP-1 analogues)– Agents that prevent GLP-1 degradation (DPP-4 inhibitors)
  • Continuous Infusion of GLP-1 Decreases Fasting Glucose as well as HbA1c Compared to saline, patients treated with GLP-1 showed fasting and 8-hour mean plasma glucose that was decreased by 4.3 mmol/l and 5.5 mmol/l (P<0.0001), and HbA1c that was decreased by 1.3% (P=0.003) Patients assigned saline Patients assigned GLP-1 Week 0 Week 1 Week 6 25 25 Glucose concentration inGlucose concentration in 20 20 plasma (mmol/L) plasma (mmol/L) 15 15 10 10 5 5 0 0 0 2 4 6 8 0 2 4 6 8 Time (hr) Time (hr) 20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (N=10) or saline (N=10) for 6 weeks. The primary endpoints were HbA1c concentration, 8-h profile of glucose concentration in plasma and b-cell function. Adapted from Zander M, et al. Lancet. 2002;359(9309):824-30.
  • The GLP-1 Receptor Agonist Exenatide Improve Glycaemic Control Exenatide LAR offers the potential of 24-hour glycaemic control and weight reduction in type 2 diabetes Placebo Exenatide LAR Exenatide LAR (N=14) 0.8 mg (N=16) 2.0 mg (N=15) 13 10 *P<0.05 vs placeboMean (±SE) fasting plasma Mean D: Mean D: Mean (±SE) HbA1C (%) 12 glucose (mmol/l) 11 +1.0±0.7 9 +0.4±0.3% 10 8 9 8 -2.4±0.9* 7 -1.4±0.3%* 7 -2.2±0.5* -1.7±0.3%* 6 6 0 3 6 9 12 15 0 3 6 9 12 15 Time (weeks) Time (weeks) Patients receiving 2.0 mg exenatide LAR had significant reductions in body weight (-3.8 ± 1.4 kg) (P < 0.05) Randomised, placebo-controlled phase 2 study in which exenatide long-acting release (LAR) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes suboptimally controlled with metformin (60%) and/or diet and exercise (40%).Adapted from Kim D, et al. Diabetes Care. 2007;30:1487-93.
  • DPP-4 Inhibitors
  • DPP-4 Inhibitors Inhibit Breakdown of GLP-1 and GIP, Improving Incretin Activity Glucose- dependent Glucose insulin uptake by (GLP-1 & GIP) peripheral Ingestion tissue of food Pancreas  Blood glucose Release of GI tract a-cells in fasting and active incretins b-cells postprandial GLP-1 & GIP states DPP-4 inhibitors  Hepatic Glucose- glucose DPP-4 dependent inactivates production  glucagon GLP-1 & GIP (GLP-1)• When plasma glucose levels are high, GLP-1 and GIP provoke an increase in insulin release from b-cells• The action of GLP-1 on a-cells results in a decrease in glucagon secretionAdapted from Drucker DJ. Cell Metab. 2006;3:153-65.
  • DPP-4 Inhibitors Approved or Pending for Approval Compound Sitagliptin1 Vildagliptin2 Saxagliptin3 Linagliptin Alogliptin3 Sitagliptin + metformin4-6 Vildagliptin + metformin7-9 Saxagliptin + metformin XR1. Januvia, Summary of Product Characteristics, EMEA, 4 Nov 2008. 2. Jalra, Summary of Product Characteristics, EMEA,12 Jan 2009. 3. Ahrèn B. Expert Opin. Emerging Drugs. 2008;13(4):593-607. 4. Janumet, Summary of ProductCharacteristics, EMEA, 18 Feb 2009. 5. Efficib, Summary of Product Characteristics, EMEA, 18 Feb 2009. 6. Velmetia,Summary of Product Characteristics, EMEA, 18 Feb 2009. 7. Eucreas, Summary of Product Characteristics, EMEA, 18 Feb2009. 8. Icandra, Summary of Product Characteristics, EMEA, 4 Mar 2009. 9. Zomarist, Summary of Product Characteristics,EMEA, 12 Jan 2009. SU, sulphonylurea; MF, metformin; TZD, thiazolidinedione
  • Mechanism of action: Summary – Incretin hormones stimulate insulin release in a glucose-dependent manner1-3 – GLP-1 has a major contribution in suppressing postprandial glucagon secretion from pancreatic a- cells3-5 – The incretin hormone GLP-1 plays a major role in reducing postprandial glucose excursions3-5 – The incretin effect is diminished in type 2 diabetes61. Drucker DJ. Cell Metab. 2006;3:153-65; 2. Dunning BE and Gerich JE. Endo Rev. 2007;28(3):253-83; 3. Drucker DJ. J ClinInvest. 2007;117(1):24-32; 4. Mosjov S, et al. J Clin Invest. 1987;79:616-9; 5. Kreymann B, et al. Lancet. 1987;2:1300-4; 6. NauckM, et al. Diabetologia. 1986;29:46-52; 7. Ahrèn B. Expert Opin Emerging Drugs. 2008;13(4):593-607.
  • Clinical Profile of DPP-4 Inhibitors  Efficacy  Safety Profile
  • Efficacy
  • Sitagliptin Summary of Clinical Trials Baseline Change in Total Monotherapy/combination Duration HbA1c HbA1c number of (weeks) (%) (%) patients Reference Monotherapy 12 7.7 -0.39−0.56* 555 Curr Med Res Opin 2007;23:1329-39 Monotherapy 12 7.9 -0.38−0.77* 743 Int J Clin Pract 2007;61:171-180 Monotherapy 18 8.1 -0.48−0.60* 521 Diabetologia 2006;49:2564-71 Monotherapy 24 8.0 -0.79−0.94* 741 Diabetes Care 2006; 29:2632-7 Monotherapy 52 7.5 -0.67 1172 Diabet Obes Metab 2007;9:194-205 Metformin 18 7.7 -0.73 273 Diabet Obes Metab 2008;10:959-69 Metformin 24 8.0 -0.65* 701 Diabetes Care 2006;29:2638-43 Metformin 24 8.8 -1−2.1 1091 Diabetes Care 2007;30:1979-87 Metformin 52 7.5 -0.67 1172 Diabet Obes Metab 2007;9:194-205 Metformin 104 8.6 -1.4−1.7 587 Diabetologa 2008;51(Suppl 1):S36 Thiazolidinedione 24 8.1 -0.70* 353 Clin Ther 2006;28:1556-68 Sulphonylurea 24 8.3 -0.74* 441 Diabet Obes Metab 2007;9:733-45 Metformin + sulphonylurea 24 8.3 -0.89* 222 Diabet Obes Metab 2007;9:733-45 Metformin + thiazolidinedione 18 8.8 -0.9 277 Diabetologa 2008;51(Suppl 1):S365*Placebo-adjusted change. Note that the studies are different and therefore not comparable; doses of compounds are not shown and may varyin different studies. Change in HbA1c shows change from baseline except when asterisk is shown. Ahrèn B. Expert Opin Emerging Drugs 2008; 13(4): 593-607.
  • Vildagliptin Summary of Clinical Trials Baseline Change in Total Monotherapy/com Duration HbA1c HbA1c number of bination (weeks) (%) (%) patients Reference Monotherapy 4 7.2 -0.38* 37 J Clin Endocrinol Metab 2004;89:2078-84 Monotherapy 12 8.0 -0.6* 98 Horm Metab Res 2006;387:423-38 Monotherapy 24 8.4 -0.5−0.9* 354 Diabets Res Clin Pract 2007;76:132-8 Monotherapy 24 8.4 -0.8−0.9 632 Horm Metab Res 2007;39:218-23 Monotherapy 24 8.7 -1.1 786 Diabetes Care 2007;30:217-23 Monotherapy 52 6.6 -0.30 131 Diabetes Obes Metab 2008;10:1114-24 Metformin 24 8.4 -0.7-1.1* 544 Diabetes Care 2007;30:890-5 Metformin 24 8.4 -0.9 576 Diabet Obes Metab 2008;10:82-90 Metformin 52 7.8 -1.1* 107 Diabetes Care 2004;27:2874-80 Metformin 52 7.3 -0.44 2789 Diabetes Obes Metab 2009;11:157-66 Thiazolidinedione 24 8.7 -0.8−1.1* 463 Diabet Obes Metab 2007;9:166-74 Sulphonylurea 24 8.5 -0.6−0.7* 515 Diabetes Obes Metab 2008;10:1047-56*Placebo-adjusted change. Note that the studies are different and therefore not comparable; doses of compounds are not shown and mayvary in different studies. Change in HbA1c shows change from baseline except when asterisk is shown. Ahrèn B. Expert Opin Emerging Drugs 2008; 13(4): 593-607.
  • Saxagliptin Summary of Clinical Trials Baseline Change in Total Monotherapy/comb Duration HbA1c HbA1c number of ination (weeks) (%) (%) patients Reference Monotherapy 12 7.9 -0.45−0.63* 338 Diabet Obes Metab 2008;10:376 Poster presented at 68th ADA, June Monotherapy 24 7.9 -0.54−0.43 401 2008, San Francisco, CA, USA. Poster presented at AADE. August 6 Metformin 24 8.0 -0.83−0.72* 733 - 9, 2008 Washington, DC, USA. Poster presented at EASD. Thiazolidinedione 24 8.3 -0.66−0.94 565 September 7-11, 2008 Rome, Italy. Poster presented at EASD. Sulphonylurea 24 8.4 -0.54−0.64 768 September 7-11, 2008 Rome, Italy Initial combination Poster presented at ICE 2008, Rio de 24 9.5 -2.53−2.49 1306 Janeiro, Brazil. with metformin*Placebo-adjusted change. Note that the studies are different and therefore not comparable; doses of compounds are not shown and may varyin different studies. Change in HbA1c shows change from baseline except when asterisk is shown.
  • Saxagliptin Phase 2 Dose-ranging StudySignificant Reduction from Baseline in HbA1c in All Treatment Arms for Saxagliptin vs Placebo* Mean baseline HbA1c (%) 8.0 7.7 7.9 8.0 7.9 7.8 0 -0.2 - Adjusted mean change -0.4 - in HbA1c (%) -0.6 - -0.8 - * * * -1.0 - * * -1.2 - *P<0.007 vs placebo -1.4 - Placebo 2.5 mg 5 mg 10 mg 20 mg 40 mg (N=67) (N=55) (N=47) (N=63) (N=54) (N=52) Saxagliptin dose 12-week, multicentre, randomised, parallel-group, double-blind, placebo-controlled trial conducted at 152 out-patient US study centres in 338 (low-dose cohort) and 85 (high-dose cohort) drug-naive patients with type 2 diabetes and inadequate glycaemlc control (baseline HbA1c ≥6.8 and ≤9.7%). Following a 2-week washout, patients received saxagliptin 2.5, 5, 10, 20 or 40 g once daily, or placebo, for 12 weeks. The test for log-linear trend across the treatment groups (the primary endpoint) did not demonstrate a statistically significant dose-response relationship after 12 weeks of treatment. Adapted from Rosenstock J, et al. Diabetes, Obesity and Metab. 2008;10:376-386.
  • Efficacy Both drugs added to baseline metformin therapy Vildagliptin Sitagliptin 0.4 Mean 0.4 Mean baseline baselineMean change from baseline HbA1C (%) 0.2 HbA1c:8.3% 0.2 HbA1c: 8.1% 0.0 0.0 -0.2 -1.1% -0.2 0.67% -0.4 (p<0.001) -0.4 p<0.001 -0.6 -0.6 -0.8 -0.8 -1.0 -1.0 -1.2 -1.2 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time (weeks of treatment)
  • Efficacy Both drugs added to baseline metformin therapy Vildagliptin Saxagliptin 0.4 Mean 0.4 Mean baseline baselineMean change from baseline HbA1C (%) 0.2 HbA1c:8.3% 0.2 HbA1c: 8.2% 0.0 0.0 -7.2% -0.2 -1.1% -0.2 P<0.0001 -0.4 (p<0.001) -0.4 -0.6 -0.6 -0.8 -0.8 -1.0 -1.0 -1.2 -1.2 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time (weeks of treatment)
  • Explaining the differences?• Unlikely mediated through insulin – Insulin levels are lower in vildagliptin than sitagliptin – No comparisons with Saxa available• Also
  • DPP-4s and Glucagon Meal 20 Vildagliptin 100 mg (n=16) 10 Placebo (n=16) 0Delta Glucagon (ng/L) −10 −20 * −30 * −40 * * −50 * * * * * −60 17:00 20:00 23:00 02:00 05:00 08:00 Time
  • Effect on Glucagon • 1x head to head comparison of Sita and Vilda • Vilda maintains better 24-hour control glucose control with very similar insulin, but much better Glucagon controlVildagliptin Sitagliptin
  • Safety Profile
  • Risk of hypos with agents 14 fold reduction 6.5 fold reductionFerrannini E, et al Diabetes, Obesity and Metabolism Nauck MA, et al. Diabetes Obes Metab. 2007;9(2):194-205.2009;11:157–166.
  • Vildagliptin: similar efficacy to glimepiride when added to metformin at 52 weeks (interim analysis) – no weight gain and low incidence of hypoglycemia Add-on treatment to metformin (~1.9 g mean daily) Number of Severe events Patients with hypoglycemic (grade 2 and ≥1 hypos (%) 7.5 Events suspected grade 2) n= 1389 1383 1389 1383 1389 1383 7.3 554 600 12 Mean HbA1c (%) 20 10 16.2 NI: 97.5% 500 10 7.1 16 Incidence (%) No. of events No. of events CI (0.02, 0.16) 400 8 12 6.9 300 6 –0.5% 8 200 4 6.7 –0.4% 4 100 2 1.7 39 0 6.5 0 0 0 –8 –4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Time (weeks) 91.0 90.5 Body weight (kg) 90.0 Vildagliptin 50 mg twice daily + metformin 89.5 Glimepiride up to 6 mg once daily + metformin −1.8 kg 89.0 difference Duration: 52 weeks 88.5 Add-on to metformin: vildagliptin vs glimepiride 88.0 87.5 –8 –2 12 22 32 42 52Safety population Time (weeks)CI=confidence interval; hypo=hypoglycemia; NI=non-inferiorityFerrannini E et al. Diabetes Obes Metab 2009;11:157–66Data on file, Novartis Pharmaceuticals
  • Vildagliptin plus metformin: similar efficacy to glimepiride plus metformin – with lower incidence of hypoglycemia after 104 weeks Duration: 104 weeks Hypoglycemiaa Add-on to metformin: vildagliptin vs glimepiride Patients with ≥1 hypos (%) Number of hypo events Number of severe eventsb Discontinuations due to hypos n= 1553 1546 n= 1553 1546 n= 1553 1546 n= 1553 1546 20 900 838 16 15 14 13 18.2 18 800 14 12 16 700 12 10 14 600 Incidence (%) No. of events No. of events No. of events 12 10 8- 500 14- 8 10 8 fold 400 fold 6 8 6 6 300 4 4 4 200 2.3 59 2 2 2 100 0 0 0 0 0 0 Vildagliptin 50 mg bid + metformin Glimepiride up to 6 mg qd + metformin Mean HbA1cc • Adjusted mean change in HbA1c was comparable between vildagliptin and glimepiride treatment: ‒ 0.1% for both • Primary objective of non-inferiority was met: ‒ 97.5% CI= (-0.00, 0.17); non-inferiority margin 0.3%aSafety population; bAny episode requiring the assistance of another party; cPer protocol populationMatthews DR et al. Diabetes Obes Metab 2010;12:780–9
  • Vildagliptin plus metformin: similar efficacy to glimepiride plusmetformin, with no weight gain after 104 weeksDuration: 104 weeks Change in body weight1Add-on to metformin:vildagliptin vs glimepiride Change from BL to EP (BL mean ~89 kg) N = 1.5 1539 1520 1.2 1.0 Adjusted mean change -1.5 kg in body weight (kg) 0.5 difference P <0.001 0.0 -0.3 Vildagliptin 50 mg bid + metformin -0.5 Glimepiride up to 6 mg qd + metformin Mean HbA1c2  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%1Intent-to-treat population 2Per protocol population.BL=baseline; EP=week 104 end point; HbA1c=haemoglobin A1c.Matthews DR, et al. Diabetes Obes Metab. 2010; 12: 780–789.
  • Saxagliptin Phase 2 Dose-ranging Study: Safety and Tolerability Adverse Events* in Double-blind Treatment Period in Low- dose Cohort Placebo SAXA 2.5 mg SAXA 5 mg SAXA 10 mg SAXA 20 mg SAXA 40 mg N 67 55 47 63 54 52 AE*, N (%) 53 (79.1) 44 (80.0) 36 (76.6) 49 (78.8) 47 (87.0) 39 (75.0) Serious AE 1 (1.5) 1 (1.8) 0 1 (1.6) 1 (1.9) 0 Discontinuations due to AEs 1 (1.5) 0 1 (2.1) 1 (1.6) 1 (1.9) 2 (3.8) Headache 6 (9.0) 8 (14.5) 4 (8.5) 10 (15.9) 6 (11.1) 5 (9.6) URI 4 (6.0) 6 (10.9) 3 (6.4) 6 (9.5) 6 (11.1) 0 UTI 5 (7.5) 6 (10.9) 2 (4.3) 4 (6.3) 5 (9.3) 2 (3.8) Nasopharyngitis 5 (7.5) 0 2 (4.3) 5 (7.9) 3 (5.6) 6 (11.5) Arthralgia 2 (3.0) 6 (10.9) 3 (6.4) 3 (4.8) 5 (9.3) 2 (3.8) Nausea 5 (7.5) 1 (1.8) 2 (4.3) 2 (3.2) 2 (3.7) 5 (9.6) Cough 3 (4.5) 4 (7.3) 3 (6.4) 1 (1.6) 3 (5.6) 3 (5.8) Confirmed hypoglycaemia 0 0 0 0 0 0 *Hypoglycaemia events excluded.12-week, multicentre, randomised, parallel-group, double-blind, placebo-controlled trial conducted at 152 out-patient US study centresin 338 (low-dose cohort) and 85 (high-dose cohort) drug-naive patients with type 2 diabetes and inadequate glycaemic control.Following a 2-week washout, patients received saxagliptin 2.5, 5, 10, 20 or 40 g once daily, or placebo, for 12 weeks.SAXA, saxagliptin; AE, adverse event; URI, upper respiratory tract infection; UTI, urinary tract infection.Rosenstock J, et al. Diabetes, Obesity and Metab. 2008;10:376-86.
  • Saxagliptin Add-on to Metformin: Safety and Tolerability Most Common (≥5%) AEs During 24-Week Treatment Period Placebo + MET All SAXA + MET (N=179) (N=564) Total patients with AEs* (%) 116 (64.8) 413 (74.3) Adverse event, N (%) Nasopharyngitis 14 (7.8) 49 (8.7) Headache 13 (7.3) 45 (8.0) Diarrhoea 20 (11.2) 40 (7.1) URI 9 (5.0) 37 (6.6) Influenza 13 (7.3) 34 (6.0) UTI 8 (4.5) 29 (5.1) Back pain 12 (6.7) 24 (4.3) Pain in extremity 10 (5.6) 17 (3.0)*Hypoglycaemia events based upon the saxagliptin predefined list of hypoglycaemia events are excluded. Incidence of hypoglycaemia was 5.7% for all saxagliptin+metformin groups vs 5.0% for placebo+metformin Mean change from baseline in body weight at week 24 was -1.4 kg, -0.9 kg and -0.5 kg for saxagliptin 2.5, 5 and 10 mg groups, respectively, vs -0.9 kg for placebo + METSAXA, saxagliptin; MET, metformin; URI, upper respiratory tract infection; UTI, urinary tract infection.Ravichandran S, et al. Saxagliptin added to metformin improves glycemic control in T2DM patients. Poster presented at AADE.August 6-9, 2008 Washington, DC, USA.
  • Guidelines for Use of DPP-4Inhibitors in Clinical Practice
  • DPP-4 inhibitors• Dependent on presence of endogenous GLP-1• Excellent for use in early diabetes as add-on to metformin• May have additional cardiovascular benefits by reducing Glucagon & Improving perfusion
  • Guidelines on Clinical Use of DPP-4 Inhibitors Summary of Recommendations by Various Organisations Organisation Recommendations/Considerations ESC/EASD1 • No specific recommendations ADA/EASD2 • Not as first- second-tier agents, although may be appropriate choices in selected patients • According to the ACE/AACE roadmap, DPP-4 inhibitors can be considered as initial ACE/AACE3 therapy when initial HbA1c is between 6% and 7% or as combination therapies when initial HbA1c is between 7-9 • DPP-4 inhibitors have shown significant benefits in reducing post-meal plasma glucose IDF4 excursions and lowering HbA1c • Consider as second-line therapy instead of a sulphonylurea when blood glucose control remains or becomes inadequate with metformin or if metformin not tolerated • If a trial of metformin in combination with a sulfonylurea does not adequately control blood NICE (UK)5 glucose (HbA1c ≤7.5%) and human insulin is unacceptable or inappropriate • May be preferable in certain patient populations (e.g. problems with weight gain or thiazolidinedione therapy1. Rydén L, et al. Eur Heart J. 2007;28(1):88-136.2. Nathan DM, et al. Diabetes Care. 2009;32(1):193-203.3. American Association of Clinical Endocrinologists. Available at: http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf. Accessed on 12 Feb 2009.4. International Diabetes Foundation. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan 2009.5. National Institute for Clinical Excellence (UK). http://www.nice.org.uk/nicemedia/pdf/T2DDraftGudeline.pdf. Accessed 26 Jan 2009.
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its consequences.• Diabetes & Ramadan.
  • Hypoglycaemia“The major limiting factor to achievingintensive glycaemic control for people with type 2 diabetes” Briscoe VJ, et al. Clin Diab 2006;24:115-121.
  • What is a hypo?• Any blood sugar that is lower than usual• Relative reduction in glucose to the tissues• Historically at a value of around 4mmol/l• Patients can experience symptoms at 11mmol if they usually run at 15mmol
  • Definition of hypoglycaemia• Plasma glucose <3.9mmol/l based on activation of counter-regulatory responses• In clinical trials threshold ranges between 3- 3.9 mmol/l• Others “classify” into “mild” and “severe” Result: difficult to pinpoint exact incidence! Briscoe VJ, Davis SN. Clin Diabetes 2006;24:115-21.
  • Hypoglycaemia in type 2 diabetes• Hypoglycaemia symptoms are common in type 2 diabetes (38% of patients)1• Associated with: – Reduced quality of life – Reduced treatment satisfaction – Reduced therapy adherence – More common at HbA1c < 7% 1. Diabetes, Obesity and Metabolism 2008 Jun;10 Suppl 1:25-32.
  • Clinical consequences of hypoglycaemia• Hospital admissions: – In a prospective study1 of well-controlled elderly T2D patients, 25% of hospital admissions for diabetes were for severe hypos• Increased mortality: – 9% in a study2 of severe SU-associated hypoglycaemia• Road accidents caused by hypos3: – 45 serious events per month 1. Diab Nutr Metab 2004;17(1):23-26. 2. Horm Metab Res Suppl 1985;15:105-111. 3. BMJ 2006;332:812.
  • Hypoglycaemia• Hypoglycaemia event triggers – Parasympathetic stimulation – Adrenaline release (comparable with Acute MI) – Electrophysiology changes (dysrythmias) – Increased peripheral systolic BP – Reduced central diastolic BP
  • Hypoglycaemias• Acutely hypoglycaemias may cause – Irritability – Impaired judgement – Confusion – Convulsions• All due to reduced cerebral perfusion
  • Longer term damage• Most likely mediated through damage to the Glycocalyx• Literally “sugar coating”• On lining of platelets and endothelium• Reduces friction of blood flow• Barrier for loss of fluid and protein through vessel wall.
  • Hypoglycaemia• Recurrent hypoglycaemia associated with increased risk of – Falls – Dementia – Increased sudden cardiac death – Myocardial infarction – Heart failure – Stroke (both large and small vessel)
  • Frequency of Recurrent hypos• Hypoglycaemia = 7% of patients/year• Severe hypoglycaemia = 0.35/patient/year• Risk is the same with insulin and SU• Risk of all hypos is similar between type 1 and type 2 diabetes• Elderly patients at greatest risk
  • The consequences of hypoglycaemia Hospitalisation Coma3 costs4 Death2,3 Cardiovascular complications3 Increased risk Weight gain Hypoglycaemia of dementia1 by defensive eating Reduced Loss of quality of consciousness3 life7 Increased risk Increased risk of car accident6 of seizures31Whitmer RA, et al. JAMA. 2009; 301: 1565–1572; 2Bonds DE, et al. Br Med J. 2010; 340: b4909;3BarnettAH. Curr Med Res Opin. 2010; 26: 1333–1342; 4Jönsson L, et al. Value Health. 2006; 9: 193–198;5Foley JE, Jordan J. Vasc Health Risk Manag. 2010; 6: 541–548; 6Begg IS, et al. Can J Diabetes. 2003; 27: 128–140; 7McEwan P, et al. Diabetes ObesMetab. 2010; 12: 431–436.
  • Hypoglycemia as a cause for cardiovascular events - Mechanisms Desouza CV, et al. Diabetes Care. 2010; 33:1389–394
  • Potential mechanisms of hypoglycaemia-induced mortality• Cardiac arrhythmias due to abnormal cardiac repolarization in high-risk patients (IHD, cardiac autonomic neuropathy)• Increased thrombotic tendency/decreased thrombolysis• Cardiovascular changes induced by catecholamines – Increased heart rate – Silent myocardial ischaemia – Angina and myocardial infarction
  • Effect of experimental hypoglycaemia on QT interval A B QTc= 456 ms QTc= 610 ms HR= 66 bpm HR= 61 bpm 5.0mM 2.5mM International Diabetes Monitor 2009; 21(6): 234-241.
  • Why are they missed• Patients are not asked!• Symptoms are misdiagnosed• Patients are ill-informed• Therefore patients do not report symptoms• Even after Severe hypoglycaemia patients often don’t report it
  • Objectives:• Epidemiology of Diabetes in UAE.• Recent ADA-EASD Position Statement: Management of Hyperglycemia in T2DM.• Cardiovascular Risks of diabetes.• Role of DPP4 Inhibitor in Diabetic Care.• Hypoglycemia and its consequences.• Diabetes & Ramadan.
  • Hypoglycaemia During Ramadan
  • (4.7 fold)(7.5 fold)
  • Hypoglycemia in Sulphonylurea -Treated Subjects with Type 2 Diabetes Undergoing Ramadan Fasting: A Five-Country Observational Study Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242
  • Results• Symptomatic hypoglycemia was 40% in occupied Palestine and 10% in Saudi Arabia• Over all symptomatic hypoglycemic events were recorded in 271 subjects (19.7%)• Headache represent 14.5%, sweating 10.2%, tremors 8.5% and palpitation 7%. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242
  • Incidence of symptomatic hypoglycemia during Ramadan by countriesCountries N of PatientsOccupied Palestine 40%Malaysia 24%United Arab Emirates 18%India 13%Saudi Arabia 10% Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242
  • Hypoglycaemias in Ramadan• 52 patients preparing for Ramadan• Currently poorly controlled (HbA1c >8.5%)• Minimum Metformin 2g/day• Randomised to receive – Gliclazide 160mg bd – Vildagliptin 50mg bd• All given educational program Devendra et al 2009
  • Results• Hypos were more common in gliclazide group 61.5 vs 7.7% (p < 0.001)• One Severe hypo in gliclazide arm• HbA1c – Similar reductions Int J Clin Pract, 2009
  • • Main aim – To determine the incidence of hypoglycaemic events in 100 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.
  • VECTOR: Results - Hypoglycaemic events (HE)Mean between-group difference in patients who experienced at least one HE was –41·7% (p = 0·0002)
  • VECTOR: HbA1c The between group difference was −0·6% (p = 0·0262) (7·7% to 7·2%) (7·2% vs 7·3%)
  • :AdherenceOnly 1 patient in the Vildagliptin group missed at least one dose, compared with 10 patients in the SU group. p = 0·0204
  • VECTOR study Vildagliptin in Fasting Ramadan T2DM pts Hypoglycemia in SU group = 41.7 % No hypoglycemia in Vildagliptin groupMedian total dose after Ramadan adjustment, mg/dayVildagliptin = 100 ; Gliclazide = 80**Different formulations of gliclazide were used: conversion factor used: 80mgstandard formulation = 30mg modified release formulation Mohamed Hassanein etal, Vildagliptin in Muslim patients fasting during RamadanCurrent Medical Research & Opinion Volume 27, Number 7 July 2011
  • Cardiovascular endpointsStudy Author Year DPP-4 SU CV events on DPP-4 SUNauck et al 2007 Sita Glipizide n.r. n.r.Seck et al 2010 Sita Glipizide n.r. n.r.Ferrannini et al 2009 Vilda Glimepiride 12/1389 22/1383Matthews et al 2010 Vilda Glimepiride n.r. n.r.Filosof & Gautler 2010 Vilda Gliclazide 7/501 12/494
  • Cardiovascular endpointsStudy Author Year DPP-4 SU CV events on DPP-4 SUNauck et al 2007 Sita Glipizide n.r. n.r.Seck et al 2010 Sita Glipizide n.r. n.r.Ferrannini et al 2009 Vilda Glimepiride 12/1389 22/1383Matthews et al 2010 Vilda Glimepiride n.r. n.r.Filosof & Gautler 2010 Vilda Gliclazide 7/501 12/494 19/1902 36/1877Relative Risk 0.53 (95% CI 0.30-0.91) p=0.029 by χ2 test (Nauck et al, EASD 2010)
  • Take Home Message• The DPP-4 inhibitors appear to have great potential for the treatment of type 2 diabetes.• They do not lower glucose to a greater extent than existing therapies .. but they offer many potential advantages:1. The ability to achieve sustainable reductions in HbA1c.2. Well-tolerated agent .3. Low risk of hypoglycemia.. Safe during Ramadan.4. No weight gain5. Can be administered as a once-daily oral dose.• Choose the right patient.