A comprehensive review by Dr. R.V. S. N. Sarma, M.D., M.Sc.,

1. Metformin Revisited A comprehensive review by Dr. R.V. S. N. Sarma, M.D., M.Sc., Dr.Sarma@works

2. Type 2 DM (NIDDM) Not merely “ SUGAR DISORDER” Multi system disease – A syndrome Metabolic – endocrine – vascular – Cardiac – cerebral – renal – ophthalmic From blood sugar to blood vessel Diabetes Mellitus Dr.Sarma@works

3. How we have grown ? Prevention holds the key – no users ? Diabetic care is Life long – Nutrition – Excercise – Education - DM How about NOW – or never ? 1,49, 806 studied – 1 kg  - 9%  DM Prevention of Diabetes Dr.Sarma@works

4. Should we wait ? and • Pay heavily on • ICUs, transplant units, amputation units • Laser therapy, physio therapy units • Or pay very little now • By preventing the epidemic rise in DM Clinical diabetes – ADA – Apr/June 2001 Dr.Sarma@works

5. H/o Smoking H/o IHD Family H/o DM H/o Hypoglycemia Exam for all pulses B.P recording Foot exam - Trophic Autonomic neuropathy Fundus exam for DR Mandatory Examinations • Fasting and PP BG • GHb A1c periodically • Microalbuminuria • Lipid profile • ACR • ECG for LVH, IHD • Echo for LV Dysfun. • Stress test – ST Seg. Dr.Sarma@works

6. Diagnosis of Diabetes Mellitus Dr.Sarma@works

7. The questions ? • Does the patient have Diabetes Mellitus ? • If so, what is the type of DM ? Dr.Sarma@works

8. Does the Patient have Diabetes ? + Unequivocal Hyperglycaemia on more than one occasion + No unequivocal Hyperglycaemia “POLYS” Loss of weight Asymptomatic Symptomatic Diabetes Abnormal GTT Normal Follow up Dr.Sarma@works

9. Diagnosis – O-GTT DM IGT Normal DM IFG Normal FPG 200 140 126 110 PPG 75g of oral glucose – 2 hrs. after Dr.Sarma@works

10. R B G > 200 mg % on 2 occasions or F B G > 126 mg % on 2 occasions or P P B G > 200 mg % on 2 occasions Never make a diagnosis on single test Never diagnose based on glycosuria Glucometer is not ideal for diagnosis Screening, Diagnosis and Monitoring Diagnosis – Criteria Dr.Sarma@works

11. Diabetes Mellitus in India 20 40 IDDM Type - 1 DM NIDDM Type - 2 DM ? IRDM Type - 1½ Dr.Sarma@works

12. Blood sugar rises above normal if ↓ in insulin secretion (endogenous) ↓ in insulin sensitivity (non-response) ↑ increased hepatic production ↓ decreased peripheral utilization Excessive CHO consumption A combination of any of the above Hyperglycemia Dr.Sarma@works

13. Hyperglycaemia Acute Chronic / Sustained Stress HyperglycaemiaDiabetes Mellitus Insulin 120 mg % 80 Glucagon Cortisol Catacholamines GH Differentiation: HbA1C / Fructosamine / Follow up Dr.Sarma@works

14. Diagnosis - Practical Points 1. Do not label one a diabetic by glycosuria alone For, one may have renal glycosuria 2. Benedict’s shows any reducing substance. Glucose oxidase test strips confirm glucosuria 3. Do not neglect urine test for acetone 4. Never base Dx on a single blood sugar test 5. O-GTT is the gold standard for diagnosis DM 6. HbA1C - of use in DD of stress hyperglycemia 7. All diabetics need not be symptomatic One may present first time with complications Dr.Sarma@works

15. Syndrome X Metabolic syndrome Insulin Resistance Syndrome Pre CHD + Pre Diabetic state It is very common in USA - > 24% above 20 years of age. Childhood overweight / obesity PCOD is common association Diagnosis – New concept Dr.Sarma@works

16. NECP ATP III criteria – 3 or more below Abdominal obesity –W.C (cm) > 88 ♀, 102 ♂ ↑ in Triglycerides > 150 mg% ↓ in HDL < 50 mg% for ♀, < 40 mg% for ♂ Blood pressure > 130 / 85 mm Hg IFG = FPG > 110 or IGT = PPBG > 140 mg% WHO criteria (in addition to above) ACR > 30 mg/g Micro-Albuminuria > 20 μgs / min Metabolic Syndrome Dr.Sarma@works

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18. TreatmentStrategies Dr.Sarma@works

19. Defect in insulin sensitivity Exercise - aerobic Weight reduction – Diet, drugs Thiazolidinediones - Glitazones Metformin Defect in insulin secretion βcell stimulation - SU, Repaglinide Insulin exogenous supplimentation Treatment Strategy Dr.Sarma@works

20. Increased hepatic glucose output Metformin > Glitazones Insulin supplimentation, SU Carbohydrate absorption (post-prandial hyperglycemia) Acarbose Treatment Strategy Often the defects are multiple and hence the need for combination of the above strategies Dr.Sarma@works

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22. Prevention ofComplications Dr.Sarma@works

23. Weight reduction Exercise Strict control hyperglycemia Improvement of lipid profile Smoking cessation Treatment of Hypertension Low dose aspirin therapy Early detection by evaluation How to prevention Complications of Diabetes ? Dr.Sarma@works

24. Metformin Dr.Sarma@works

25. Biguanides- used in early medieval times- leguminosa Galega officinalis (goat's rue or French lilac) in Europe 1918-guanidine discovered as active glucose-lowering compound 3 biguanides available for medical use between 1957 & 1960- phenformin, metformin, buformin 1970s- phenformin and buformin withdrawn because of lactic acidosis History Dr.Sarma@works

26. Metformin Metabolic actions Reduction of excessive Hepatic Glucose Output Stimulation of insulin-mediated muscle glucose uptake -glycogen synthesis is increased Inhibition of lipolysis and of FFA availability Dr.Sarma@works

27. Metformin Cellular actions Increased insulin binding Stimulation of insulin receptor tyrosine kinase activity Enhanced glucose transport (GLUT 4) Increased glycogen synthase Doesn't cause hypoglycemia Dr.Sarma@works

28. Actions of Metformin Dr.Sarma@works

29. Favorable lipid effects Weight loss Increased fibrinolytic activity Decreased platelet aggregability Favorable effect on hypertension Metformin Additional actions Dr.Sarma@works

30. Obese diabetics Diabetics with hypertension Diabetics with prominent Dyslipidaemia Patients with IGT Metformin Preferred choice in Dr.Sarma@works

31. Metformin - Pharmacokinetics Dr.Sarma@works

32. Nausea, vomiting, distension Loss of appetite, diarrhoea Skin rashes, urticaria Increase in liver enzymes Rare – Lactic acidosis. Metformin - side effects Dr.Sarma@works

33. Metformin - contraindications • Patients with Type I diabetes • Patients with hepatic or renal impairment • Alcoholic liver disease • Chronic obstructive airway disease • Congestive heart failure, MI • Pregnancy and lactation • Peripheral vascular disease • Any condition associated with hypoxia • In patients > 70 yrs of age. • Care while using diuretics concomitantly Dr.Sarma@works

34. Metformin mono therapy in DM • Metformin in combination with • Glyburide • Pioglitazone • Insulin • Metformin in sec. OHA failure • Metformin I.G.T • Metformin in P.C.O.D • Metformin in Metabolic Syndrome • Metformin in obesity Dr.Sarma@works

35. Metforminmono therapy Dr.Sarma@works

36. NIDDM Pts 29 week therapy Significantly lowers FPG Metformin - Efficacy Dr.Sarma@works

37. NIDDM Pts 29 week therapy Significantly lowers HbA1c Metformin - Efficacy Dr.Sarma@works

38. 1704 obese type 2 diabetics with FPG > 6 mmol/lit after dietary trial Randomised to metformin to maintain FPG <6 vs “conventional” Rx with diet 10 year follow-up Metformin – Efficacy in microvascular complications • 32% reduction in diabetes related endpoint • 42% reduction in diabetes related death • 36% reduction in all cause mortality UKPDS trial- Lancet 1998; 352: 837-853 Dr.Sarma@works

39. Metformincombined therapy Dr.Sarma@works

40. Metforminwith Glyburide Dr.Sarma@works

41. Objective To evaluate whether initial treatment with glyburide/metformin tablets is superior to monotherapy with each Design Randomized, parallel-group, placebo-controlled, multicentre Patients 806 treatment naïve type 2diabetics Duration 20 weeks Therapy Placebo, glyburide 2.5 mg, metformin 500 mg, glyburide/metformin 1.25 +250/500 mg, once daily. Metformin – Glyburide Garber AJ et al. Diabetes Obes Metab 2002 May;4(3):201-8 Dr.Sarma@works

42. Metformin – Glyburide glyburide/ metformin 1.25/250 mg glyburide/ metformin 2.5/250 mg Placebo Metformin Glyburide 0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 -0.21 * -1.03 *** -1.24 ** -1.48 -1.53 P<0.001 * P=0.016 * * P<0.001 * * * Week 20 P<0.001 * P=0.004 * * P<0.001 * * * Garber AJ et al. Diabetes Obes Metab 2002 May;4(3):201-8 Dr.Sarma@works

43. Metformin – Glyburide Conclusions Initial combination treatment with glyburide & metformin tablets produces greater improvements in glycaemic control than either glyburide or metformin alone. The superiority of initial therapy with glyburide + metformin tablets may arise from simultaneous treatment of both patho-physiological defects of type 2 diabetes. Dr.Sarma@works

44. Metforminwith Pioglitazone Dr.Sarma@works

45. Metformin – Pioglitazone Design Double blind Randomized placebo controlled clinical trial Duration 16 weeks Patients 328 patients with poorly controlled DM - HbAlc > 8.0%, Rx. Metformin  30 days Later Pioglitazone 30mg + Met (n=168) or Placebo + Metformin (n=160) Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409 Dr.Sarma@works

46. Results • Compared to placebo combination caused • Fall in HbAlc (- 0.83%)* • Fall in FPG (-7.7mg/dl)* • Fall in TG levels (-18.2%) • Rise in HDL +8.7% • Decrease in FPG levels occurred • as early as 4th weeks * p<0.05 Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409 Dr.Sarma@works

47. Metformin – Pioglitazone Open label extension of the study Metformin + 30/45 mg Pioglitazone 154 patients 72 weeks Fall in HbAlc: – 1.36% Fall in FPG: – 63.0 mg/dl Excellent tolerability No hepatotoxicity seen Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409 Dr.Sarma@works

48. Metformin in Sec. OHA failure Dr.Sarma@works

49. Design Randomised, open and parallel study Number Fifty-one subjects Patients Type 2 diabetes with secondary oral hypoglycaemic agent failure Therapy 1st phase 36 weeks- Combined therapy of sulphonylureas and nocturnal insulin, with or without metformin 2nd phase Metformin was withdrawn. Combination in Sec. OHA failure Tong PC et al. Diabetes Res Clin Pract 2002 Aug; 57(2):93-8 Dr.Sarma@works

50. Subjects on metformin - used less insulin to maintain glycaemic control (13.7+/-6.8 vs. 23.0+/-9.4 U/day, P=0.001) - lower HbA1c values (8.13+/-0.89 v/s 9.05+/-1.30%, P=0.003) Withdrawal of metformin therapy caused deterioration in HbA1c (P=0.001) Combination in Sec. OHA failure Tong PC et al. Diabetes Res Clin Pract 2002 Aug; 57(2):93-8 Dr.Sarma@works