Metformin Revisited A comprehensive review by Dr R

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

Diabetes Mellitus 1. Type 2 DM (NIDDM) 2. Not merely “ SUGAR DISORDER” 3. Multi system disease – A syndrome 4. Metabolic – endocrine – vascular – 5. Cardiac – cerebral – renal – ophthalmic From blood sugar to blood vessel Dr. Sarma@works

Prevention of Diabetes • 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 Dr. Sarma@works

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

Mandatory Examinations 1. H/o Smoking 1. Fasting and PP BG 2. H/o IHD 2. GHb A 1 c periodically 3. Family H/o DM 3. Microalbuminuria 4. H/o Hypoglycemia 4. Lipid profile 5. Exam for all pulses 5. ACR 6. B. P recording 6. ECG for LVH, IHD 7. Foot exam - Trophic 7. Echo for LV Dysfun. 8. Autonomic neuropathy 8. Stress test – ST Seg. 9. Fundus exam for DR Dr. Sarma@works

Diagnosis of Diabetes Mellitus Dr. Sarma@works

The questions ? 1. Does the patient have Diabetes Mellitus ? 2. If so, what is the type of DM ? Dr. Sarma@works

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

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

Diagnosis – Criteria § § § § 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 Dr. Sarma@works

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

Hyperglycemia Blood sugar rises above normal if 1. ↓ in insulin secretion (endogenous) 2. ↓ in insulin sensitivity (non-response) 3. ↑ increased hepatic production 4. ↓ decreased peripheral utilization 5. Excessive CHO consumption 6. A combination of any of the above Dr. Sarma@works

Hyperglycaemia Acute Chronic / Sustained Stress Hyperglycaemia Diabetes Mellitus Insulin 80 Glucagon GH 120 mg % Cortisol Catacholamines Differentiation: Hb. A 1 C / Fructosamine / Follow up Dr. Sarma@works

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. Hb. A 1 C - of use in DD of stress hyperglycemia 7. All diabetics need not be symptomatic One may present first time with complications Dr. Sarma@works

Diagnosis – New concept § § § § 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 Dr. Sarma@works

Metabolic Syndrome § NECP ATP III criteria – 3 or more below 1. Abdominal obesity –W. C (cm) > 88 ♀, 102 ♂ 2. ↑ in Triglycerides > 150 mg% 3. ↓ in HDL < 50 mg% for ♀, < 40 mg% for ♂ 4. Blood pressure > 130 / 85 mm Hg 5. IFG = FPG > 110 or IGT = PPBG > 140 mg% § WHO criteria (in addition to above) 1. ACR > 30 mg/g 2. Micro-Albuminuria > 20 μgs / min Dr. Sarma@works

Dr. Sarma@works

Treatment Strategies Dr. Sarma@works

Treatment Strategy Defect in insulin sensitivity 1. 2. 3. 4. Exercise - aerobic Weight reduction – Diet, drugs Thiazolidinediones - Glitazones Metformin Defect in insulin secretion 1. βcell stimulation - SU, Repaglinide 2. Insulin exogenous supplimentation Dr. Sarma@works

Treatment Strategy Increased hepatic glucose output 1. Metformin > Glitazones 2. Insulin supplimentation, SU Carbohydrate absorption (post-prandial hyperglycemia) 1. Acarbose Often the defects are multiple and hence the need for combination of the above strategies Dr. Sarma@works

Dr. Sarma@works

Prevention of Complications Dr. Sarma@works

How to prevention Complications of Diabetes ? 1. 2. 3. 4. 5. 6. 7. 8. Weight reduction Exercise Strict control hyperglycemia Improvement of lipid profile Smoking cessation Treatment of Hypertension Low dose aspirin therapy Early detection by evaluation Dr. Sarma@works

Metformin Dr. Sarma@works

History 1. 2. 3. 4. 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 1970 s- phenformin and buformin withdrawn because of lactic acidosis Dr. Sarma@works

Metformin Metabolic actions 1. Reduction of excessive Hepatic Glucose Output 2. Stimulation of insulin-mediated muscle glucose uptake -glycogen synthesis is increased 3. Inhibition of lipolysis and of FFA availability Dr. Sarma@works

Metformin Cellular actions 1. Increased insulin binding 2. Stimulation of insulin receptor tyrosine kinase activity 3. Enhanced glucose transport (GLUT 4) 4. Increased glycogen synthase 5. Doesn't cause hypoglycemia Dr. Sarma@works

Actions of Metformin Dr. Sarma@works

Metformin Additional actions 1. 2. 3. 4. 5. Favorable lipid effects Weight loss Increased fibrinolytic activity Decreased platelet aggregability Favorable effect on hypertension Dr. Sarma@works

Metformin Preferred choice in 1. Obese diabetics 2. Diabetics with hypertension 3. Diabetics with prominent Dyslipidaemia 4. Patients with IGT Dr. Sarma@works

Metformin - Pharmacokinetics Bio-avalability (% of dose) 50% to 60% C max ( g/ml) 1. 0 to 1. 5 t max (in hours) 1. 9 to 3. 0 Plasma ½ life (t ½) 2. 0 to 5. 4 Renal clearance (ml/min) 400 to 600 Total clearance (ml/min) 1, 300 Dr. Sarma@works

Metformin - side effects 1. 2. 3. 4. 5. Nausea, vomiting, distension Loss of appetite, diarrhoea Skin rashes, urticaria Increase in liver enzymes Rare – Lactic acidosis. Dr. Sarma@works

Metformin - contraindications 1. Patients with Type I diabetes 2. 3. 4. 5. 6. 7. 8. 9. 10. 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

1. Metformin mono therapy in DM 2. Metformin in combination with 1. Glyburide 2. Pioglitazone 3. Insulin 3. Metformin in sec. OHA failure 4. Metformin I. G. T 5. Metformin in P. C. O. D 6. Metformin in Metabolic Syndrome 7. Metformin in obesity Dr. Sarma@works

Metformin mono therapy Dr. Sarma@works

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

Metformin - Efficacy NIDDM Pts 29 week therapy Significantly lowers Hb. A 1 c Dr. Sarma@works

Metformin – Efficacy in microvascular complications 1. 1704 obese type 2 diabetics with FPG > 6 mmol/lit after dietary trial 2. Randomised to metformin to maintain FPG <6 vs “conventional” Rx with diet 3. 10 year follow-up 1. 32% reduction in diabetes related endpoint 2. 42% reduction in diabetes related death 3. 36% reduction in all cause mortality UKPDS trial- Lancet 1998; 352: 837 -853 Dr. Sarma@works

Metformin combined therapy Dr. Sarma@works

Metformin with Glyburide Dr. Sarma@works

Metformin – Glyburide 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 2 diabetics Duration 20 weeks Therapy Placebo, glyburide 2. 5 mg, metformin 500 mg, glyburide/metformin 1. 25 +250/500 mg, once daily. Garber AJ et al. Diabetes Obes Metab 2002 May; 4(3): 201 -8 Dr. Sarma@works

Metformin – Glyburide glyburide/ metformin Placeb Metformin 1. 25/250 mg 2. 5/250 mg o Glyburide 0 -0. 21 * -0. 4 -0. 6 -0. 8 -1. 0 -1. 24 ** -1. 03 *** -1. 2 -1. 48 -1. 4 P<0. 001 -1. 6 P=0. 016 P<0. 001 -1. 53 * P<0. 001 * * P=0. 004 ** * *P<0. 001 * * * Garber AJ et al. Diabetes Obes Metab 2002 May; 4(3): 201 -8 Week 20 Dr. Sarma@works

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 pathophysiological defects of type 2 diabetes. Dr. Sarma@works

Metformin with Pioglitazone Dr. Sarma@works

Metformin – Pioglitazone Design Double blind Randomized placebo controlled clinical trial Duration 16 weeks Patients 328 patients with poorly controlled DM - Hb. Alc > 8. 0%, Rx. Metformin 30 days Later Pioglitazone 30 mg + Met (n=168) or Placebo + Metformin (n=160) Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395 -409 Dr. Sarma@works

Results Compared to placebo combination caused Fall in Hb. Alc (- 0. 83%)* Fall in FPG (-7. 7 mg/dl)* Fall in TG levels (-18. 2%) Rise in HDL +8. 7% Decrease in FPG levels occurred as early as 4 th weeks Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395 -409 * p<0. 05 Dr. Sarma@works

Metformin – Pioglitazone Open label extension of the study Metformin + 30/45 mg Pioglitazone 154 patients 72 weeks Fall in Hb. Alc: – 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

Metformin in Sec. OHA failure Dr. Sarma@works

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

Combination in Sec. OHA failure 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 Hb. A 1 c values (8. 13+/-0. 89 v/s 9. 05+/1. 30%, P=0. 003) Withdrawal of metformin therapy caused deterioration in Hb. A 1 c (P=0. 001) Tong PC et al. Diabetes Res Clin Pract 2002 Aug; 57(2): 93 -8 Dr. Sarma@works

Conclusion This study confirms that metformin plays an important role in the success of the combination therapy. The rational use of metformin and sulphonylurea together with insulin will help to improve metabolic control in Type 2 diabetes patients who have secondary drug failure. Tong PC et al. Diabetes Res Clin Pract 2002 Aug; 57(2): 93 -8 Dr. Sarma@works

Metformin in I. G. T. Dr. Sarma@works

IGT to Type 2 DM § Plasma glucose level at initial O-GTT, § Body mass index § Family history of DM, § Hypertension § Raised basal plasma insulin/ proinsulin § Lower post-load insulin/glucose ratio § Abnormal lipid profile § Abnormal serum creatinine Raman PG et al. Asian J Diabetol 2002 June-July; 4(4): 37 -42 Dr. Sarma@works

Metformin in I G T Design Objective Patients Therapy Duration Randomized double blind To evaluate effect of metformin on glucose metabolism & rate of conversion to DM 70 patients with IGT Placebo (n = 37) or metformin (n= 33) 250 mg three times daily 12 months Li CL et al. Diabet Med 1999 Jun; 16(6): 477 -81 Dr. Sarma@works

Metformin in PCOD Dr. Sarma@works

What is PCOD ? 1. 2. 3. 4. Poly Cystic Ovarian Disease Common form of female infertility Poor conception rates Pregnancy loss rates are high (30 -50%) during the 1 st trimester Dr. Sarma@works

Metformin in PCOD Objective Assess pregnancy outcome pts with polycystic ovary syndrome (PCOS) Design Case series, Outpatient. Patients Anovulatory patients (n = 48) with a diagnosis of PCOD enrolled over 15 m. Rx. Metformin started at 500 mg b. i. d. for 6 weeks and increased to 500 mg t. i. d. if no ovulation occurred. Clomiphene citrate 50 mg added if no ovulatory response after 6 wks. Heard MJ et al. Fertil Steril 2002 Apr; 77(4): 669 -73 Dr. Sarma@works

Metformin - Effective in PCOD 1. 40% patients resumed spontaneous menses with metformin alone 2. 31% required CC (50 mg) in conjunction with metformin therapy 3. 67% of combination therapy had evidence of ovulation 4. Overall 42% conceived with a median time of 3 m for conception Heard MJ et al. Fertil Steril 2002 Apr; 77(4): 669 -73 Dr. Sarma@works

Metformin in PCODEarly Pregnancy loss 1. Retrospective study 2. Women with PCOD who became pregnant 3. Duration of enrollment- 4. 5 yr , OPD setting 4. Sixty-five women received metformin during pregnancy (metformin group) and 31 women did not (control group). Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb; 87(2): 524 -9 Dr. Sarma@works

Metformin prevents early Preg. loss Early Preg. Loss Rate 41. 9 % 50 60 40 P < 0. 001 P < 0. 002 30 20 10 58. 3 % 50 40 30 In prior h/o Miscarriage 20 8. 8 % 10 0 Metformin Placebo 0 11. 1 % Metformin Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb; 87(2): 524 -9 Placebo Dr. Sarma@works

Conclusion Metformin administration during pregnancy reduces 1 st trimester pregnancy losses in women with Polycystic ovary syndrome. Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb; 87(2): 524 -9 Dr. Sarma@works

Metformin in Insulin resistance Dr. Sarma@works

Metabolic syndrome 1. Exercise 2. Weight reduction 3. Diet modification 4. Control of blood pressure 5. IFG or IGT may be treated with Metformin 250 to 500 mg b. i. d Dr. Sarma@works

Insulin Sensitizers 1. Exercise 2. Weight reduction 3. Metformin 4. Glitazones Dr. Sarma@works

Metformin in Obesity Dr. Sarma@works

Metformin in obesity • In childhood over weight and obesity • Its action of interfering with glucose absorption in the intestine • Anorexio-genic action • No effect on normal blood sugar; non hypoglycemic (only anti hyperglycemic) Dr. Sarma@works

Metformin XL vs Plain Design Double blind randomized Patients Type 2 DM on Metformin 500 mg BID for 8 weeks with FPG 200 mg/dl and Hb. A 1 c 8. 5 % Therapy Plain metformin 500 mg BID (n=69) Metformin XL* 1000 mg OD (n=72) Duration 24 weeks Physician’s Desk Reference 2002 Pg. 1083 Dr. Sarma@works

Advantages of Metfromin SR Convenience ONCE DAILY dosing simplifies treatment regimen Reduces number of tablets to be consumed To be taken conveniently at - DINNER Compliance Adverse effects such as Nausea / Vomiting (due to gastritis) and diarrhea - less likely with SR Preparation Better tolerated than plain metformin Control Comparable to that of plain metformin b. i. d / t. i. d Dr. Sarma@works

Metformin SR with evening meal Evening dosing takes advantage of slow GI transit while patients are sleeping This allows tablet to move slower through GI tract than when patients are awake Dr. Sarma@works

D I E Dr. Sarma@works

WHO recommendation -Diet CARBOHYDRATES : 50 -60% - mainly from complex carbohydrates FATS : 30% - saturated 10% - poly-unsaturated 10% - mono-unsaturated 10% - cholesterol < 300 mg/day PROTEINS : 12 -20% SODIUM : < 6 g/day - hypertensive diabetic, < 3 g/day Dr. Sarma@works

Managing Diabetes Follow a Healthy Meal Plan Eat Least Eat Moderately Sugar, Fat, Alcohol, Salt Protein Foods Eat More Carbohydrate Foods Eat Most Vegetables Dr. Sarma@works

EXERCISE Benefits • • • Reduces weight Improves cardiovascular function Increases fitness Increases physical working capacity Improves sense of well-being /quality of life Dr. Sarma@works

Let us together win the war against Diabetes Dr. Sarma@works

Dr. Sarma@works