Managing Diabetes and Metabolic syndrome 2008 Treatment Perspectives by Professor Dr Intekhab Alam Department of Medicine PGMI, Khyber Medical University Lady Reading Hospital, Peshawar. Dual defect of type 2 diabetes: treating a moving target Insulin Resistance Type 2 Diabetes Insulin Concentration b-cell Dysfunction b-cell Failure Insulin Resistance Euglycaemia Normal IGT ± Obesity Diagnosis of type 2 diabetes Progression of type 2 diabetes DeFronzo et al. Diabetes Care 1992;15:318-68 % of population IGT is driving the worldwide diabetes pandemic 50 45 40 35 30 25 20 15 10 5 0 20-44 IGT Undiagnosed type 2 diabetes Diagnosed type 2 diabetes 45-54 55-64 65 Age (years) Harris. Consultant. 1997;37 Suppl:S9 Type 2 Diabetes : Tip of the Iceberg Stage III Diabetes Stage II Impaired glucose tolerance Stage I Normal glucose tolerance Macroangiopathy Microangiopathy Postprandial Plasma glucose Glucose production Glucose transport Insulin secretory deficiency Lipogenesis Obesity Waist-hip ratio Atherogenesis Hyperinsulinaemia Insulin Resistance Tg HDL Hypertension Diabetes Genes “Genetics loads the gun But the environment pulls the trigger” Joslin, 1927 Principles of Diabetes Care Life Style Exercise • Diet • Hypertension Isulin Secretagogues Sulfonylureas • Hyperlipidaemia Meglitinides • • • • Insulin Sensitizers Microalbuminuria Metformin Thiazolidenediones Incretin mimetics Glycosidase Inhibitors ◄ • • Insulin Pramlintide 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 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, SYSTEuro, HOT). OBESITY COMORBIDITY WEIGHT LOSS BENEFIT OF WEIGHT LOSS Mortality 10 kg • >20% fall in total mortality • >30% fall in diabetes-related deaths • Fall in obesity-related cancer deaths Diabetes 10 kg • Fall in 50% fasting glucose Blood pressure 10 kg • Fall of 10 mmHg systolic • Fall of 20 mmHg diastolic Blood lipids 10 kg • Fall of 10 % total cholesterol • Fall of 15% LDL • Fall of 30% triglycerides • Increase of 8% HDL • Reduced red cell aggregability • Improved fibrinolytic capacity Blood clotting indices Physical complications Ovarian function 5 – 10 kg >5% • Improved back and joint pain • Improved lung function • Decreased breathlessness • Reduced frequency of sleep apnoea • Improved ovarian function 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) 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 Principles of Diabetes Care Life Style Diet Exercise 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. Exercise! Principles of Diabetes Care Life Style Exercise Diet Outline •Maintain Ideal Body Weight. Maximum 25 (men) 24 (women) •“Limit” total fat •“Limit” free sugars “From an excess of FAT diabetes begins & from an excess of FAT diabetics die.” Take Home Messages “if you love them don’t stuff them” Don’t allow your children to get obese. Eat less and remain healthy. Physical activity or exercise doesn’t 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. Relative risk for death increases with 2hour blood glucose irrespective of the FPG level 2.5 Hazard ratio 2.0 1.5 1.0 11.1 0.5 7.8–11.0 <7.8 0.0 <6.1 6.1–6.9 7.0 Fasting plasma glucose (mmol/l) Adjusted for age, centre, gender DECODE Study Group. Lancet 1999;354:617–621 Knowledge from UKPDS and DECODE UKPDS1 DECODE2 Hyperglycaemia Postprandial peaks Total load (HbA1c) Macroangiopathy Microangiopathy Acute glucose toxicity Chronic glucose toxicity Tissue damage Diabetes complication DECODE: Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe, HbA1c: haemoglobin A1c, UKPDS: UK Prospective Diabetes Study 1. Stratton IM, et al. BMJ 2000;321:405–12. 2. DECODE. Diabetes Care 2003;26:688–96. 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 Pharmacological Therapy Matching pathophysiology to pharmacology 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 Targeting Insulin Resistance: A Strategy for Improving Glycemic Control in Type 2 Diabetes 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 Rifkin’s Diabetes Mellitus. 5th ed. 1997:513-552. Consequences of Insulin Resistance Insulin resistance interferes with the insulin signal... Insulin Pancreas Liver …hepatic glucose output increases Fat FFA output increases Reaven. Physiol Rev 1995;75:473-483. Muscle ...and glucose uptake in fat and muscle decreases Insulin resistance exposes patients to..... Excessive calorific intake Obesity Insulin Resistance Inherited genetic susceptibility Hyperinsulinemia Dyslipidaemia Raised TG Raised LDL-C Lowered HDL-C Hypertension Atherosclerosis Reduced nitric oxide production Raised inflammatory markers Modified from Reaven G. In: LeRoith D, et al, eds. Diabetes Mellitus: A Fundamental and Clinical Text. 2000;Philadelphia, PA: LWW pp604-614. 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 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 Principles of Diabetes Care Life Style Exercise • Diet • Hypertension Isulin Secretagogues Sulfonylureas • Hyperlipidaemia Meglitinides • • • • Insulin Sensitizers Microalbuminuria Metformin Thiazolidenediones Incretin mimetics Glycosidase Inhibitors ◄ • • Insulin Pramlintide Insulin sensitizers BIGUANIDES THIAZOLIDINEDIONES. BIGUANIDES Metformin 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) UKPDS - 1998 Traditional glycemic control (secretagogues) reduced microvascular complications • Retinopathy -29% • Nephropathy -33% • Neuropathy -40% But not macrovascular complications • MI’s -16% • Stroke +11% • Deaths -6% UKPDS 1998 Metformin decreased macrovascular complicatons (lower insulin levels) • MI -39% • Coronary Deaths -50% • Diabetes Related Deaths -42% • All Cause Mortality -36% Risk reductions from intervention studies in type 2 diabetes Clinical Outcomes HOT 4S UKPDS UKPDS UKPDS Metformin SU/Ins Captopril Felodipine SimvaAtenolol Aspirin statin n=1501 n=202 n=753 n=3867 n=1148 Diabetes-related deaths (%) 42 HOPE Ramipril n=3577 10 32 67 36 37 All-cause mortality (%) 36 6 18 43 43 24 All MI (%) 39 16 21 51 55 22 Fatal MI (%) 50 6 28 - - - All stroke (%) 41 (+)11 44 30 62 33 Fatal stroke (%) 25 (+)17 58 - - - 10.7 10.7 8.4 3.8 5.4 4.5 Follow-up (years) Thiazolidinediones Pioglitazone Rosiglitazone THIAZOLIDINEDIONES 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 THE PPAR FAMILY OF NUCLEAR RECEPTORS LIGAND RECEPTOR FIBRATES PPAR α THIOZOLIDINEDIONES PPAR γ FATTY ACIDS PPAR δ EFFECT LIPOPROTEIN EXPRESSION PEROXISOME LIPID SYNTHESIS PROLIFERATION CARBOHYDRATE METABOLISM PPARg Increases Glucose Disposal: Potential Site of Action SITES OF ACTION OF ORAL ANTIDIABETIC AGENTS Delay Carbohydrate absorption Acarbose Stimulate Impaired Insulin secretion Reduce excessive Hepatic glucose output TZD’s 20% Metformin 80% TZD’s 80% Reduce Hyperglycemia Sulfonylureas Metformin 20% Reduce peripheral Insulin resistance THIAZOLIDINEDIONES DURATION OF ACTION 24-30 Hours SIDE EFFECTS Hepatotoxicity Weight gain Fluid retention Anemia CONTRAINDICATIONS Liver disease Heart Failure (NYHA class 3 &4) 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. 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. Fixed-Dose Monotherapy Study Change in HbA1c at Endpoint HbA1c at week 26 (% points) 1 1 0.6 Placebo (n=25) 7.5mg (n=27) 15mg (n=26) 30mg (n=26) 45mg (n=21) 0.5 0.5 0 0 0 -0.5 -0.5 -1 -0.6 -0.8 * * -1 -1.5 -1.5 -2 -2 -1.9 * -2.5 Change from baseline Baseline mean HbA1c: 9.5% *p<0.05 vs baseline †p<0.05 vs placebo -0.6 -1.4 -1.3 + + -2.5 -3 -2.6 Difference from placebo+ adapted from: Aronoff S, et al., Diabetes Care 2000;23:1605-1611. Pioglitazone + Sulphonylurea Study Mean Changes in FPG at Endpoint FPG at week 16 (mmol/L) Placebo + SU (n=182) Plo 15mg + SU (n=179) Plo 30mg + SU (n=186) 1 0.5 0.3 0 -0.5 -1 -1.5 -2 -1.8 -2.5 -3 -2.9 -3.5 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;111:10-17. Pioglitazone + Metformin Study Mean Changes in FPG at Endpoint FPG at week 16 (mmol/L) Placebo + Met (n=157) Plo 30mg + Met (n=167) 1 0.5 0 -0.5 -0.3 -1 -1.5 -2 -2.5 -2.4 -3 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;22:1395-1409. Pioglitazone: Favorable effects on serum lipids Study Objective To evaluate the impact of pioglitazone and rosiglitazone on lipid profiles and glycemic control in patients with type 2 diabetes pioglitazone rosiglitazone Mean Change in Triglyceride Pioglitazone 0 Rosiglitazone -6% -10 Mean change -20 in TG (mg/dL) -30 -13.3 -23% P = 0.041 vs. baseline -40 -50 -60 -55.2 P <0.001 vs. baseline Pioglitazone vs. Rosiglitazone: P <0.001 Mean Change in Total Cholesterol Pioglitazone 6 4 Mean 2 change 0 in TC (mg/dL) -2 -4 -6 -8 -10 Rosiglitazone 4.8 2% P = 0.011 vs. baseline -4% -8.5 P <0.001 vs. baseline Pioglitazone vs. Rosiglitazone: P <0.001 Mean Change in HDL-C Pioglitazone 3.0 Rosiglitazone 2.7 2.5 Mean 2.0 change in HDL-C 1.5 (mg/dL) 1.0 6% 0.5 Pioglitazone vs. Rosiglitazone: P = 0.064 -0.3% 0.0 -0.5 P <0.001 vs. baseline -0.1 P = 0.924 vs. baseline Mean Change in LDL-C Pioglitazone Rosiglitazone 6 3.6 4 Mean 2 change in LDL-C 0 (mg/dL) -2 3% P = 0.030 vs. baseline -4% -4 -6 -5.1 P = 0.002 vs. baseline Pioglitazone vs. Rosiglitazone: P <0.001 Conclusions pioglitazone rosiglitazone • Blood lipid levels changed more favorably with pioglitazone than with rosiglitazone • Changes in HbA1c and weight gain were equivalent 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 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 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? Test Results • • • • • • • HbA1C Alb/Cr Cr LFT’s CBC TSH Fasting Insulin C-peptide b-HCG 9.2 0.010 0.6 WNL WNL 2.3 3.5 Neg 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. 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 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 0.012. LFT’s remain normal. What would you do now? Second Oral Medication Add a • Glitazone or • Sulfonylurea 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