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Managing Diabetes and Metabolic syndrome 2008 Treatment Perspectives by Professor Dr Intekhab Alam D epartment of Medicine PGMI, Khyber Medical University.

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Presentation on theme: "Managing Diabetes and Metabolic syndrome 2008 Treatment Perspectives by Professor Dr Intekhab Alam D epartment of Medicine PGMI, Khyber Medical University."— Presentation transcript:




4 Managing Diabetes and Metabolic syndrome 2008 Treatment Perspectives by Professor Dr Intekhab Alam D epartment of Medicine PGMI, Khyber Medical University Lady Reading Hospital, Peshawar.

5 Insulin Resistance Type 2 Diabetes -cell Dysfunction Insulin Resistance Hyperglycaemia Insulin Concentration Insulin Action Euglycaemia -cell Failure Normal IGT ± Obesity Diagnosis of type 2 diabetes Progression of type 2 diabetes Dual defect of type 2 diabetes: treating a moving target DeFronzo et al. Diabetes Care 1992;15:318-68

6 Harris. Consultant. 1997;37 Suppl:S9 IGT Undiagnosed type 2 diabetes Diagnosed type 2 diabetes Age (years) % of population IGT is driving the worldwide diabetes pandemic

7 Type 2 Diabetes : Tip of the Iceberg Stage II Impaired glucose tolerance Stage III Diabetes Stage I Normal glucose tolerance Macroangiopathy Microangiopathy Atherogenesis Hyperinsulinaemia Insulin Resistance Postprandial Plasma glucose Glucose production Glucose transport Insulin secretory deficiency Lipogenesis Obesity Waist-hip ratio Tg HDL Hypertension Diabetes Genes

8 Genetics loads the gun But the environment pulls the trigger Joslin, 1927

9 Life Style Diet Exercise Principles of Diabetes Care Isulin Secretagogues Sulfonylureas Meglitinides Insulin Sensitizers Metformin Thiazolidenediones Incretin mimetics Hyperlipidaemia Hypertension Microalbuminuria Insulin Glycosidase Inhibitors Pramlintide

10 Treatment of the Metabolic Syndrome in Overweight or Obese Patients Weight loss induced by diet and increased physical activity is the cornerstone of therapy Weight loss induced by drug therapy can also improve specific features of the metabolic syndrome Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome

11 Treatment of Metabolic Syndrome in Patients with Diabetes 80-85% of diabetic subjects in North America and Europe have the metabolic syndrome However, most subjects with the metabolic syndrome do not have diabetes Statin therapy has been shown to be effective in diabetic subjects (4S, HPS, CARE, CARDS). Treatment of Hypertension is also crucially important in diabetic subjects (UKPDS, SYST- Euro, HOT).

12 OBESITY CO- MORBIDITYWEIGHT LOSSBENEFIT OF WEIGHT LOSS Mortality10 kg>20% fall in total mortality >30% fall in diabetes-related deaths Fall in obesity-related cancer deaths Diabetes10 kgFall in 50% fasting glucose Blood pressure10 kgFall of 10 mmHg systolic Fall of 20 mmHg diastolic Blood lipids10 kgFall of 10 % total cholesterol Fall of 15% LDL Fall of 30% triglycerides Increase of 8% HDL Blood clotting indices Reduced red cell aggregability Improved fibrinolytic capacity Physical complications 5 – 10 kgImproved back and joint pain Improved lung function Decreased breathlessness Reduced frequency of sleep apnoea Ovarian function>5%Improved ovarian function

13 Goal for Glycemic Control HbA1C less than 7% (6.5%?) Fasting sugars less than 110 Two-hour postprandial sugars less than 140 Blood pressure less than 130/80 (125/75 if renal impairment)

14 KEY CONCEPTS IN SETTING GLYCEMIC CONTROL Goals should be individualized Certain populations(children, pregnant women,elderly) require special considerations Less intensive glycemic goals for patients with frequent hypoglycemia Postprandial goals may be targeted if A1C goals are not met despite reaching pre-prandial glucose goals

15 Life Style Diet Exercise Principles of Diabetes Care How much ? 2½ hours weekly or 30 min a day for 5 days a wk Moderate exertion like brisk walk, light exercise…. Increase activity rather than stressing on exercise.

16 Exercise!

17 Life Style Diet Exercise Principles of Diabetes Care Outline Maintain Ideal Body Weight. Maximum 25 (men) 24 (women) Limit total fat Limit free sugars

18 From an excess of FAT diabetes begins & from an excess of FAT diabetics die.

19 Take Home Messages if you love them dont stuff them Dont allow your children to get obese. Eat less and remain healthy. Physical activity or exercise doesnt play a great role in weight loss. It is possible to remain slim after overeating but it is not possible to get obese without overeating.

20 Relative risk for death increases with 2- hour blood glucose irrespective of the FPG level <6.16.1– –11.0 <7.8 Fasting plasma glucose (mmol/l) 2-hour plasma glucose (mmol/l) Hazard ratio Adjusted for age, centre, gender DECODE Study Group. Lancet 1999;354:617–621

21 Knowledge from UKPDS and DECODE Hyperglycaemia Tissue damage Diabetes complication Total load (HbA 1c ) Chronic glucose toxicity Microangiopathy UKPDS 1 Postprandial peaks Acute glucose toxicity Macroangiopathy DECODE 2 DECODE: Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe, HbA 1c : haemoglobin A 1c, UKPDS: UK Prospective Diabetes Study 1. Stratton IM, et al. BMJ 2000;321:405– DECODE. Diabetes Care 2003;26:688–96.

22 Postprandial Glucose Monitoring Take-home messages Epidemiological data supports relationship between postprandial glycemia and mortality including cardiovascular mortality. Outcomes trials show benefit of reducing HbA1c for microvascular and macrovascular disease with no threshold for glycemic control Emerging evidence that targeting postprandial glucose reduces adverse outcomes

23 Pharmacological Therapy Matching pathophysiology to pharmacology

24 Type 2 Diabetes Standard Stepped Approach to Treatment Step1: Education, Diet, Exercise & SMBG Step2: Oral Antidiabetic Agents (Monotherapay) Step3: Oral Antidiabetic Agents Combination therapy. Step4: Bedtime NPH or Glargine + Daytime OAD Step5: BID Split / Mixed Insulin Step6: Multiple daily Injections

25 Targeting Insulin Resistance: A Strategy for Improving Glycemic Control in Type 2 Diabetes

26 Insulin Resistance: Definition Condition in which greater than normal amounts of insulin are required to produce a normal biological response Olefsky JM. In: Ellenberg and Rifkins Diabetes Mellitus. 5th ed. 1997:

27 Consequences of Insulin Resistance Pancreas...and glucose uptake in fat and muscle decreases Insulin Insulin resistance interferes with the insulin signal... …hepatic glucose output increases LiverFat Muscle Reaven. Physiol Rev 1995;75: FFA output increases

28 Insulin resistance exposes patients to..... Modified from Reaven G. In: LeRoith D, et al, eds. Diabetes Mellitus: A Fundamental and Clinical Text. 2000;Philadelphia, PA: LWW pp Excessive calorific intake Obesity Insulin Resistance Inherited genetic susceptibility Hyperinsulinemia HypertensionAtherosclerosisDyslipidaemia Raised TG Raised LDL-C Lowered HDL-C Reduced nitric oxide production Raised inflammatory markers

29 Insulin Resistance and Type 2 Diabetes 40% of older people are insulin resistant mostly secondary to obesity and inactivity (important in prevention and treatment) 20% of the elderly have type 2 diabetes 8.5% of all adults have type 2 diabetes 90% of diabetics are managed in primary care

30 One Approach to Selecting Medication for Type 2 Diabetics Check a fasting insulin C-peptide level If high or high-normal use an insulin sensitizer – biguanine or glitazone or a combination of the two If low or low-normal use an insulin secretagogue Consider changing patients who were put on insulin before the new oral diabetes medications to insulin sensitizers

31 Life Style Diet Exercise Principles of Diabetes Care Isulin Secretagogues Sulfonylureas Meglitinides Insulin Sensitizers Metformin Thiazolidenediones Incretin mimetics Hyperlipidaemia Hypertension Microalbuminuria Insulin Glycosidase Inhibitors Pramlintide


33 BIGUANIDES Metformin

34 First Line Drug for Type 2 Diabetes Biguanides (Metformin) Decreases hepatic glucose output Increases insulin sensitivity Decreases LDL and triglycerides Decreases C-reactive protein Causes weight loss or stabilization No risk of hypoglycemia Causes nausea, cramps and diarrhea Lactic acidosis rare (contraindications – CHF, renal impairment, age greater than 80)

35 UKPDS Traditional glycemic control (secretagogues) reduced microvascular complications Retinopathy-29% Nephropathy-33% Neuropathy-40% But not macrovascular complications MIs-16% Stroke+11% Deaths-6%

36 UKPDS 1998 Metformin decreased macrovascular complicatons (lower insulin levels) MI-39% Coronary Deaths-50% Diabetes Related Deaths-42% All Cause Mortality-36%

37 Risk reductions from intervention studies in type 2 diabetes Clinical Outcomes Diabetes-related deaths (%) All-cause mortality (%) All MI (%) Fatal MI (%) All stroke (%) Fatal stroke (%) Follow-up (years) UKPDS SU/Ins n= (+)11 (+) UKPDS Captopril Atenolol n= HOPE Ramipril n= HOT Felodipine Aspirin n= S Simva- statin n= UKPDS Metformin n=

38 Thiazolidinediones Pioglitazone Rosiglitazone

39 MECHANISM OF ACTION Peroxisome Proliferator Acivated Receptor-gamma (PPAR-γ) agonists. Expression of number of genes glucose transporter expression(GLUT 4) FFA hepatic gluconeogenesis differentiation of preadipocytes into adipocytes THIAZOLIDINEDIONES


41 PPAR Increases Glucose Disposal: Potential Site of Action

42 SITES OF ACTION OF ORAL ANTIDIABETIC AGENTS Delay Carbohydrate absorption Acarbose Reduce Hyperglycemia Stimulate Impaired Insulin secretion Sulfonylureas Reduce excessive Hepatic glucose output TZDs 20% Metformin 80% TZDs 80% Metformin 20% Reduce peripheral Insulin resistance

43 DURATION OF ACTION Hours SIDE EFFECTS Hepatotoxicity Weight gain Fluid retention Anemia CONTRAINDICATIONS Liver disease Heart Failure (NYHA class 3 &4) THIAZOLIDINEDIONES

44 Indications As an adjunct to diet & exercise to improve glycemic control in patients with type 2 diabetes. Indicated as monotherapy Also indicated for use in combination with a sulfonylurea, metformin or insulin.

45 Insulin Sensitizers Do More Than Just Lower Glucose Improve lipid (TZDs >> Metformin) –Decrease TG, Increase HDL, Increase LDL – bigger particle Lower CRP (TZD > Metformin) Lower PAI-1 (TZD & Metformin) Decrease intra abdominal fat (TZD) ? Protect beta cell (TZD) Prevent restenosis after stenting.

46 Fixed-Dose Monotherapy Study Change in HbA1c at Endpoint HbA1c at week 26 (% points) Change from baselineDifference from placebo Baseline mean HbA1c: 9.5% *p<0.05 vs baseline p<0.05 vs placebo adapted from: Aronoff S, et al., Diabetes Care 2000;23:

47 FPG at week 16 (mmol/L) Mean Change from baseline Baseline mean FPG placebo: 13.1 mmol/L, pioglitazone: 13.5mmol/L *p=0.05 vs baseline p=0.05 vs placebo +SU Kipnes MS, et al. Am J Med 2001;111: Pioglitazone + Sulphonylurea Study Mean Changes in FPG at Endpoint Placebo + SU (n=182) Plo 15mg + SU (n=179) Plo 30mg + SU (n=186)

48 Pioglitazone + Metformin Study Mean Changes in FPG at Endpoint FPG at week 16 (mmol/L) Mean Change from baseline Baseline mean FPG:placebo 14.4 mmol/L, pioglitazone 14.0 mmol/L *p<0.05 vs baseline p<0.05 vs placebo + Met Einhorn D, et al. Clin Ther 2000;22: Placebo + Met (n=157) Plo 30mg + Met (n=167)

49 Pioglitazone: Favorable effects on serum lipids

50 Study Objective To evaluate the impact of pioglitazone and rosiglitazone on lipid profiles and glycemic control in patients with type 2 diabetes pioglitazone rosiglitazone

51 Mean Change in Triglyceride Mean change in TG (mg/dL) Pioglitazone vs. Rosiglitazone: P < P <0.001 vs. baseline -23% P = vs. baseline -6% PioglitazoneRosiglitazone

52 Mean Change in Total Cholesterol Mean change in TC (mg/dL) PioglitazoneRosiglitazone Pioglitazone vs. Rosiglitazone: P < % P <0.001 vs. baseline 4.8 2% P = vs. baseline

53 Mean Change in HDL-C Mean change in HDL-C (mg/dL) PioglitazoneRosiglitazone Pioglitazone vs. Rosiglitazone: P = % P <0.001 vs. baseline % P = vs. baseline

54 Mean Change in LDL-C Mean change in LDL-C (mg/dL) PioglitazoneRosiglitazone Pioglitazone vs. Rosiglitazone: P < % P = vs. baseline 3.6 3% P = vs. baseline

55 Conclusions Blood lipid levels changed more favorably with pioglitazone than with rosiglitazone Changes in HbA 1c and weight gain were equivalent pioglitazone rosiglitazone

56 Pioglitazone. A new armament against Type 2 DM An insulin sensitizer that reduces insulin resistance Provides excellent glycemic control Less risk of Hypoglycemia Improves lipid profile Reduces the risk of CVD. Indicated as mono therapy as well as in combination with Metformin, Sulfonylureas & Insulin

57 Non Glycemic Goals: Treat All Cardiovascular Risks Factors Aggressively Smoking Hypertension –BP less than 130/80 Lipids –LDL Cholesterol < 100 mg/dl LDL less than 70 mg/dl in high risk cases –HDL cholesterol > 40 mg/dl –Triglycerides < 150 mg/dl Aspirin

58 Case History 30 y.o. woman with a history of gestational diabetes with her first pregnancy at age 21 presents with frequent urination, thirst, weight loss and a random glucose of 250. She has an IUD in place. Her BMI is 33. BP is 140/80. Is this enough information to diagnose diabetes? What other tests would you order?

59 Test Results HbA1C 9.2 Alb/Cr Cr 0.6 LFTs WNL CBC WNL TSH 2.3 Fasting Insulin C-peptide 3.5 HCGNeg

60 What will you do now? Educate your patient about diabetes and set goals together for her care Diabetic diet counseling and a weight loss program Educate her in use of a glucometer. Devise exercise program for physical fitness.

61 Anything else? Refer to ophthalmologist Do microfilament check for neuropathy See frequently to reinforce diet, exercise, home glucose monitering Start Metformin. Treat BP with ACEI if remains over 130/80

62 Eight Months Later Despite modest weight loss and compliance with her medications your patient still has a HbA1C of 8.0. Her blood pressue is 120/75 and her Alb/Cr is LFTs remain normal. What would you do now?

63 Second Oral Medication Add a Glitazone or Sulfonylurea

64 Summary Type 2 diabetes affects many organs Type 2 diabetes changes over time Diabetes treatment changes over time Medications can now be selected to work where the problem is Combinations of medications, because they work at different sites, in the body usually work better than monotherapy


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