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Oral Agents in Management of Type 2 Diabetes

Oral Agents in Management of Type 2 Diabetes . Nemanja Stojanovi ć Consultant Endocrinologist Queen’s Hospital, Romford . We will talk about. T2DM in general… Metformin Sulphonylureas + PPG regulators α - Glucosidase Inhibitors Statistics Glitazones and meta- analysis

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Oral Agents in Management of Type 2 Diabetes

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  1. Oral Agents in Management ofType 2 Diabetes Nemanja Stojanović Consultant Endocrinologist Queen’s Hospital, Romford

  2. We will talk about • T2DM in general… • Metformin • Sulphonylureas + PPG regulators • α-Glucosidase Inhibitors • Statistics • Glitazones and meta- analysis • DPP-4 inhibitors and meta- analysis • GLP-1 analogues

  3. Definition • Fasting plasma glucose 7mmol/l- 2 occasions • 2 h plasma glucose or random glucose of 11.1 mmol/l

  4. BM’s

  5. Normal 24h profile

  6. T1DM: Relationship between HbA1c and Mean Glucose Dia Care2002: 25: 275-8

  7. “Drug therapies are replacing a lot of medicines as we used to know it…” George W Bush

  8. Treatment Diet, Exercise

  9. Medications:Metformin SulphonylureasPPGsAcarbose

  10. Metformin NH NH2 C NH2 Guanidine NH NH CH3 C NH2 N C NH CH3 Galega officinalis Metformin

  11. Metformin : Non- Glycaemic Effects • Abdominal obesity- stabilizes body weight; reduces weight gain and can facilitate weight loss • Reduces progression of IGT to type 2 diabetes • Dyslipidaemia: VLDL-TG, LDL-C, HDL-C • Procoagulant state: PAI-1,fibrinogen and platelet aggregation

  12. Metformin :contraindications • Cr> 150 umol/l • Hypoxic states- CCF/acute heart failure- sepsis- Severe COPD • Severe liver disease • Alcoholism • History of lactic acidosis • Radiological contrast

  13. Insulin Secretaguoges • SU • Repeglanide • Nateglinide • Glibenclamide

  14. Insulin Secretaguoges: Concerns • Hypoglycemia • Weight gain • Cardiovascular disease risk

  15. α-Glucosidase Inhibitors • Take within 15' of a major meal • Increase the dose gradually • SE/benefit dose 50mg tds

  16. α-Glucosidase Inhibitors: Side effects • Deranged LFT’s high doses • Ileus Japanese. • Contraindications:- IBD- Malabsorption- Bowel obstruction- Liver failure- Cr clearance<25 ml/min

  17. Thiazolidinediones Pharmacokinetics of TZD’s Pioglitazone Rosiglitazone

  18. Reduce HbA1c by 1-2% Peripheral vascular resistance : 4mmHg in 24-h mean systolic and diastolic blood pressure Lipids - Convert small, dense LDL particles to large, buoyant LDL particles - Increase plasma HDL cholesterol - Decrease plasma triglycerides if they are elevated (>200 mg/dl) Thiazolidinedions (Glitazones)

  19. Pioglitazone vs Rosiglitazone Dia Care 2005: 1547-54

  20. Rosiglitazone

  21. Before We Start • Rofecoxib • Muraglitazar • Rosiglitazone • Rofecoxib= Vioxx • SE Nissen

  22. Odds Ratio • Odds of an event occurring in a patient in the experimental group relative to that of a patient in the control group

  23. Confidence Interval and Odds Ratio • Odds ratio, for the result to be statistically significant, the 95% confidence interval should not overlap 1 (i.e. the odds ratios within the confidence interval should all be >1 or <1, the no difference point)

  24. Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471 • Analysed 42 out of 48 trials • 6 trials without CVS events ruled out of analysis • Trial duration ≥ 24 weeks • No time to event analysis • Mean age 57 years

  25. Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471 Caution about use… Limitations of the study acknowledged May increase CVS risk

  26. Interim analysis at 3.9 yrs Non- inferiority Study !! 4447 patients 40- 75 years A1c 7.1-9% BMI> 25 2220 Rosi + Met or SU 2227 Met + SU Primary Outcomes - Myocardial infarction - Congestive heart failure Stroke TIA Unstable angina Unplanned CVS revascularization Amputation of extremities Death from CVS cause RECORD Trial

  27. RECORD Study : Problems • Expected event rate 11% p.a. • Actual event rate 2% p.a. • Expected study dropout rate 2% p.a. • Actual study dropout rate 3% p.a. • As a result the study is underpowered

  28. RECORD: Conclusion • Rosiglitazone association with an increased risk of heart failure acknowledged • As the study was underpowered, it is nit possible to determine whether the drug was associated with anincrease in the risk of myocardial infarction

  29. Pioglitazone

  30. PROactive • 5238 patients • HbA1c above 6.5% • At least one of the following • Previous MI • Previous CVA • PTCA • ACS> 3months prior to the study entry • History of intermittent claudication Lancet; 366: 1279-89

  31. Primary Endpoints - Composite of all cause mortality, MI, CVA, unstable angina, PTCA, Revascularisation procedures, amputations Secondary Endpoints Time to death of any of the disease endpoints - MI CVA Unstable angina etc PROactive Lancet; 366: 1279-89

  32. PROactive • NNT 49 over 3 years to prevent an event • 21 first MI would be saved in 1000 patients started on pioglitazone • Heart failure was increased in pioglitazone group( Odds ratio 1.38), but LVF mortality was equal

  33. Pioglitazone Meta-analysis • 16390 Patients • Pioglitazone n= 8554; Control n= 7836 • Primary Endpoint: Composite of Death, Non-fatal MI and Non-fatal CVA • Secondary Endpoint Heart Failure

  34. Primary endpoint Pioglitazone 4.4% vs Control 5.5% p=0.05 HR= 0.82; CI 0.72- 0.94 Time to event apparent after 1 year Heart Failure: Pioglitazone 2.3% vs Control 1.8% p=0.02 HR 1.4 No difference in fatal HF!!! Pioglitazone did well…

  35. The PERISCOPE Trial • 547 patients randomised: pioglitazone vs glimepiride • Age 35- 85 • HbA1C 6-9% • Angiographic Coronary a stenosis 20-50% • Target vessel stenosis had to be less than 50% throughout 4cm segment JAMA 2008; 299: 1561- 73

  36. The PERISCOPE Trial JAMA 2008; 299: 1561- 73

  37. ACCORD Trial • Intensive glycaemic management • Target HbA1c 6.4% • Stopped a month ago… • Increased mortality in active treatment group • Analysis is awaited

  38. New Kids on the Block DPP-4 inhibitors GLP-1 mimetics

  39. Of Men and Mice • Dipeptidyl Peptidase – 4 (DPP-4) degrades • Glucose-dependent Insulinotropic Peptide (GIP):improves glycaemic control in mice - Glucagon Like Peptide 1 ( GLP-1): improves glycaemic control in mice and men

  40. DDP-4 Knock Out Mice • Improved glucose tolerance • Elevated GLP-1 and GIP levels • Resistance to diet induced obesity and hyperglycaemia

  41. DDP-4 Knock Out Mice • Increased pain threshold • Reduced stress like responses • Reduced number of CD4 cells in spleen • Immune and inflammatory responses increased in experimental arthritis

  42. DPP-4 other Biological Activities • Loss of DPP-4 in tumours: > aggressive behaviour • Implicated in control of immune and lymphocyte function • Cell migration

  43. Sitagliptin Studies

  44. Vildagliptin Studies

  45. Sitagliptin In addition to TZD OR Metformin OR SU ± Metformin Dose 100mg OD Vildagliptin In combination with - TZD OR Metformin SU: 50mg OD Indications 50 mg BD

  46. Exenatide • GLP-1 analogue • 5-10 ug BD • Injection • Licensed with SU/Metformin or in combination • Induces ~2kg weight loss

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