3 Managing Diabetes and Metabolic syndrome Treatment Perspectives by Professor Dr Intekhab Alam Department of Medicine PGMI, Khyber Medical University Lady Reading Hospital, Peshawar.This slide module will:Discuss the importance of glycosylated haemoglobin A1c as a marker for blood glucose control in both type 1 and type 2 diabetes managementReview the Diabetes Control and Complications Trial, United Kingdom Prospective Diabetes Study, and other studies to identify the link between good glycaemic control and long-term clinical outcomesDemonstrate the need for aggressive therapy to achieve glycaemic control, thereby reducing the risk of microvascular and macrovascular complications
4 Dual defect of type 2 diabetes: treating a moving target InsulinResistanceType 2Diabetesb-cellDysfunctionHyperglycaemiaInsulin Actionb-cell FailureInsulinConcentrationInsulinResistanceDual defect of type 2 diabetes: treating a moving targetThe pathophysiology of type 2 diabetes is complex, and characterised by remorseless progression of the dual metabolic defects of insulin resistance and b-cell dysfunction.Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic.As insulin resistance progresses, however, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Eventually, insulin secretion from the b-cell begins to decline and the severity of the hyperglycaemia increases further.Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:EuglycaemiaNormalIGT ± ObesityDiagnosis of type 2 diabetesProgression of type 2 diabetesDeFronzo et al. Diabetes Care 1992;15:318-68
5 IGT is driving the worldwide diabetes pandemic 5045403530252015105IGTUndiagnosed type 2 diabetes% of populationDiagnosed type 2 diabetesIGT is driving the worldwide diabetes pandemicData from the USA suggest that type 2 diabetes is only the tip of the iceberg, in terms of the prevalence of glucose intolerance. Individuals with either undiagnosed type 2 diabetes or impaired glucose tolerance (IGT) are thought to be far more numerous than the type 2 diabetic population.This is especially so in older individuals (>65 years), of whom about two-fifths may have IGT or undiagnosed type 2 diabetes.Harris MI et al. Consultant 1997;37 (Suppl): S9.20-4445-5455-6465Age (years)Harris. Consultant. 1997;37 Suppl:S9
6 Type 2 Diabetes : Tip of the Iceberg Stage IIIDiabetesMacroangiopathyMicroangiopathyPostprandialPlasma glucose Glucose production Glucose transport Insulin secretory deficiencyStage IIImpaired glucosetoleranceStage INormal glucosetoleranceAtherogenesisHyperinsulinaemiaInsulin ResistanceTg HDL HypertensionLipogenesis ObesityWaist-hip ratioDiabetes Genes
7 “Genetics loads the gun But the environment pulls the trigger” Joslin, 1927
8 • • • • • • • • • ◄ Principles of Diabetes Care Life Style Hypertension•ExerciseDiet•HyperlipidaemiaIsulin Secretagogues•SulfonylureasMeglitinidesMicroalbuminuria••Insulin SensitizersMetformin•ThiazolidenedionesInsulin•◄Incretin mimetics••PramlintideGlycosidase Inhibitors
9 Treatment of the Metabolic Syndrome in Overweight or Obese Patients Weight loss induced by diet and increased physical activity is the cornerstone of therapyWeight loss induced by drug therapy can also improve specific features of the metabolic syndromeBariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndromeTreatment of the metabolic syndrome in overweight or obese patientsThe principal strategy for the treatment of the metabolic syndrome should be weight loss and increased physical activity. While there are no randomized clinical trials showing the effectiveness of these behavioral therapies for reducing cardiovascular disease, there are several randomized controlled trials showing that modest weight loss (around 5%) and increased physical activity may reduce the risk of type 2 diabetes by > 50% (Diabetes Prevention Program and Finnish Prevention Study.)References:Diabetes Prevention Program Research Group. Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):2.Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:
10 Treatment of Metabolic Syndrome in Patients with Diabetes 80-85% of diabetic subjects in North America and Europe have the metabolic syndromeHowever, most subjects with the metabolic syndrome do not have diabetesStatin 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).Treatment of metabolic syndrome in patients with diabetesThere is a great deal of data showing the effectiveness of blood pressure and lipid therapy in subjects with type 2 diabetes. Since 80-85% of diabetic subjects have the metabolic syndrome, this might be considered to be a good model for assessing whether traditional cardiovascular interventions might work in subjects with the metabolic syndrome. However, most subjects with the metabolic syndrome do not have type 2 diabetes.
11 >20% fall in total mortality OBESITY CO-MORBIDITYWEIGHT LOSSBENEFIT OF WEIGHT LOSSMortality10 kg>20% fall in total mortality>30% fall in diabetes-related deathsFall in obesity-related cancer deathsDiabetesFall in 50% fasting glucoseBlood pressureFall of 10 mmHg systolicFall of 20 mmHg diastolicBlood lipidsFall of 10 % total cholesterolFall of 15% LDLFall of 30% triglyceridesIncrease of 8% HDLBlood clotting indicesReduced red cell aggregabilityImproved fibrinolytic capacityPhysical complications5 – 10 kgImproved back and joint painImproved lung functionDecreased breathlessnessReduced frequency of sleep apnoeaOvarian function>5%Improved ovarian function
12 Goal for Glycemic Control HbA1C less than 7% (6.5%?)Fasting sugars less than 110Two-hour postprandial sugarsless than 140Blood pressure less than 130/80 (125/75 if renal impairment)
13 KEY CONCEPTS IN SETTING GLYCEMIC CONTROL Goals should be individualizedCertain populations(children, pregnant women,elderly) require special considerationsLess intensive glycemic goals for patients with frequent hypoglycemiaPostprandial goals may be targeted if A1C goals are not met despite reaching pre-prandial glucose goals
14 Principles of Diabetes Care Life StyleExerciseDietHow much?2½ hours weekly or 30 min a day for 5 days a wkModerate exertion like brisk walk, light exercise….Increase activity rather than stressing on exercise.
16 Principles of Diabetes Care Life StyleExerciseDietOutlineMaintain Ideal Body Weight.Maximum 25 (men) 24 (women)“Limit” total fat“Limit” free sugars
17 “From an excess of FAT diabetes begins & from an excess of FAT diabetics die.”
18 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.
19 2-hour plasma glucose (mmol/l) Fasting plasma glucose (mmol/l) Relative risk for death increases with 2-hour blood glucose irrespective of the FPG level2.52.01.51.00.50.0Hazard ratio³11.17.8–11.0Results from the DECODE study show that the relative risk for death increases with 2-hour blood glucose irrespective of fasting plasma glucose (FPG) levels.It can clearly be seen that within each FPG category, the hazard ratio for death increased with increasing 2-hour blood glucose. However, increasing FPG levels appear to have a minimal effect on the relative risk of death.This indicates that increases in 2-hour blood glucose levels are closely associated with the relative risk of mortality, irrespective of the FPG level.Fasting plasma glucose categories were defined as: normal <6.1 mmol/l (<110 mg/dl), impaired fasting glucose (IFG) 6.1–6.9 mmol/l (110–124 mg/dl) and fasting diabetes 7.0 mmol/l ( 126 mg/dl).Two-hour plasma glucose categories were defined as: normal <7.8 mmol/l (<140 mg/dl), impaired glucose tolerance (IGT) 7.8–11 mmol/l (140–198 mg/dl) and diabetes 11.1mmol/l ( 200 mg/dl).<7.82-hour plasma glucose (mmol/l)< –6.9 ³7.0Fasting plasma glucose (mmol/l)Adjusted for age, centre, genderDECODE Study Group. Lancet 1999;354:617–621
20 Knowledge from UKPDS and DECODE HyperglycaemiaTissue damageDiabetes complicationTotal load (HbA1c)Chronic glucose toxicityMicroangiopathyUKPDS1PostprandialpeaksAcute glucose toxicityMacroangiopathyDECODE2DECODE: Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe, HbA1c: haemoglobin A1c, UKPDS: UK Prospective Diabetes Study1. Stratton IM, et al. BMJ 2000;321:405–12.2. DECODE. Diabetes Care 2003;26:688–96.Knowledge from DECODE and UKPDSThe UK Prospective Diabetes Study (UKPDS) showed that interventions directed at lowering fasting plasma glucose (FPG) levels were far more effective at reducing the risk of micro- than macrovascular complications.1 In contrast, the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) demonstrated that the risk of CVD is more strongly associated with 2-hour postchallenge plasma glucose (2hPG) levels, than with FPG levels.2Both fasting and postprandial hyperglycaemia must be addressed to prevent diabetes complications. However, as the majority of diabetes patients die from CV causes, the current focus on pharmacological agents that target FPG levels may not offer optimal CV risk reduction.1. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35). BMJ 2000;321:405–12.2. DECODE Study Group, European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26:688–96.
21 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 controlEmerging evidence that targeting postprandial glucose reduces adverse outcomes
22 Pharmacological Therapy Matching pathophysiology to pharmacology
23 Type 2 Diabetes Standard “Stepped” Approach to Treatment Step1: Education, Diet, Exercise & SMBGStep2: Oral Antidiabetic Agents (Monotherapay)Step3: Oral Antidiabetic Agents“Combination therapy”.Step4: Bedtime NPH or Glargine + Daytime OADStep5: BID Split / Mixed InsulinStep6: Multiple daily Injections
24 Targeting Insulin Resistance: A Strategy for Improving Glycemic Control in Type 2 Diabetes
25 Insulin Resistance: Definition Condition in which greater than normal amounts of insulin are required to produce a normal biological responseOlefsky JM. In: Ellenberg and Rifkin’s Diabetes Mellitus. 5th ed. 1997:
26 Consequences of Insulin Resistance Insulin resistance interferes with the insulin signal...InsulinPancreasInsulin resistance, a key factor in the pathogenesis of type 2 diabetes, is a condition in which the cells of various body tissues fail to respond efficiently to insulin. For example, muscle tissue fails to increase its uptake of blood glucose, and hepatic production of glucose is not inhibited as it normally would be by insulin. As insulin resistance develops, the beta-cells of the pancreas attempt to compensate by producing more insulin.Following the onset of beta-cell dysfunction, the pancreas is no longer able to compensate for insulin resistance by relative hypersecretion of insulin. As a consequence, control of blood glucose worsens, leading to impaired glucose tolerance, increased fasting and post-prandial glucose levels, and then to type 2 diabetes.LiverFatMuscle…hepatic glucose output increasesFFA output increases...and glucose uptake in fat and muscle decreasesReaven. Physiol Rev 1995;75:
27 Insulin resistance exposes patients to..... Excessive calorific intakeObesityInherited genetic susceptibilityInsulin ResistanceHyperinsulinemiaDyslipidaemiaHypertensionAtherosclerosisInsulin resistance can result from genetic and/or environmental influences which ultimately result in hyperinsulinaemia defined as raised levels of insulin in the blood.Insulin resistance has emerged as a potentially important risk factor for vascular disease. In separate investigations it has been associated with risk for coronary artery disease, atherosclerosis and stroke. Although the mechanism for this association is not totally understood but may involve hyperglycemia, dyslipidaemia, hypertension, hypercoaguability and endothelial dysfunction.Thus dyslipidaemia, hypertension and atherosclerosis are all associated with insulin resistance through different cellular mechanisms. The good news is that scientific and clinical research programs have proven that pioglitazone has a positive effect on diabetic dyslipidaemia, hypertension and markers of atherosclerosis in patients with type 2 diabetes through direct effects of the agent rather than through its ability to lower blood sugar.You may be asking yourselves what is the relevance of this and of the various published papers, well the remainder of this presentation will put all of that into context…hopefully.Raised TGRaised LDL-CLowered HDL-CReduced nitricoxide productionRaisedinflammatorymarkersModified from Reaven G. In: LeRoith D, et al, eds.Diabetes Mellitus: A Fundamental and Clinical Text. 2000;Philadelphia, PA: LWW pp.
28 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 diabetes8.5% of all adults have type 2 diabetes90% of diabetics are managed in primary care
29 One Approach to Selecting Medication for Type 2 Diabetics Check a fasting insulin C-peptide levelIf high or high-normal use an insulin sensitizer – biguanine or glitazone or a combination of the twoIf low or low-normal use an insulin secretagogueConsider changing patients who were put on insulin before the new oral diabetes medications to insulin sensitizers
30 • • • • • • • • • ◄ Principles of Diabetes Care Life Style Hypertension•ExerciseDiet•HyperlipidaemiaIsulin Secretagogues•SulfonylureasMeglitinidesMicroalbuminuria••Insulin SensitizersMetformin•ThiazolidenedionesInsulin•◄Incretin mimetics••PramlintideGlycosidase Inhibitors
33 First Line Drug for Type 2 Diabetes Biguanides (Metformin)Decreases hepatic glucose outputIncreases insulin sensitivityDecreases LDL and triglyceridesDecreases C-reactive proteinCauses weight loss or stabilizationNo risk of hypoglycemiaCauses nausea, cramps and diarrheaLactic acidosis rare (contraindications –CHF, renal impairment, age greater than 80)
34 UKPDS - 1998 Traditional glycemic control (secretagogues) reduced microvascular complicationsRetinopathy -29%Nephropathy -33%Neuropathy -40%But not macrovascular complicationsMI’s -16%Stroke +11%Deaths -6%
36 Risk reductions from intervention studies in type 2 diabetes Clinical OutcomesDiabetes-related deaths (%)All-cause mortality (%)All MI (%)Fatal MI (%)All stroke (%)Fatal stroke (%)Follow-up (years)UKPDSMetforminn=75342363950412510.7UKPDSSU/Insn=386710616(+)11(+)1710.7UKPDSCaptoprilAtenololn=11483218212844588.4HOTFelodipineAspirinn=1501674351-303.84SSimva- statinn=202364355-625.4HOPERamipriln=3577372422-334.5Risk reductions from intervention studies in type 2 diabetesThe magnitudes of the outcome benefits in the study of metformin in overweight patients compare well with the results of other major clinical trials, which recruited substantial proportions of diabetic subjects and addressed the prognostic effects of controlling blood pressure or lipids.A total of 1148 hypertensive patients enrolled in the UKPDS were randomised to tight blood pressure control with the antihypertensive agents atenolol (n=358) or captopril (n=400), or to less tight blood pressure control (n=390).The Hypertension Optimal Treatment (HOT) study randomised patients to three target blood pressures (< 90 mmHg, < 85 mmHg or < 80 mmHg), achieved using a calcium channel blocker, felodipine, plus additional antihypertensive therapy as needed.The Heart Outcomes Prevention Evaluation (HOPE) study evaluated the effects of an angiotensin converting enzyme inhibitor, ramipril, in patients at high cardiovascular risk, i.e. patients with atherosclerosis or diabetes with at least one additional cardiovascular risk factor.The Scandinavian Simvastatin Survival Study (4S) showed that aggressive lipid- lowering therapy significantly reduced the incidence of major cardiovascular events.In summary, type 2 diabetic patients have multiple risk factors, which if corrected are likely to lead to reduced morbidity and mortality. The evidence base points towards the need for multiple interventions to minimise cardiovascular risk and premature mortality.
38 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
39 THE PPAR FAMILY OF NUCLEAR RECEPTORS FIBRATESTHIOZOLIDINEDIONESFATTY ACIDSLIGANDPPAR αPPAR δPPAR γRECEPTOREFFECTLIPOPROTEIN EXPRESSIONPEROXISOME PROLIFERATIONLIPID SYNTHESISCARBOHYDRATE METABOLISM
40 PPARg Increases Glucose Disposal: Potential Site of Action Slide IV.4PPARg Increases Glucose Disposal: Potential Site of ActionPPARg Increases Glucose Disposal: Potential Site of Action*Through their activation of PPARg, the thiazolidinediones improve insulin-stimulated glucose disposal.Impaired glucose transport in adipose tissue and skeletal muscle is an important defect in patients with type 2 diabetes. Under normal circumstances, this process is initiated when insulin binds to surface receptors on fat and muscle cells and transmits a signal (signal transduction) across the cell membrane. GLUT4, which is the only one of several glucose transporters known to be insulin-sensitive, is translocated to the cell membrane where it facilitates the movement of glucose across the membrane into the cell. After insulin leaves its receptor, GLUT4 reenters the cell and returns to its storage vesicle.In patients with insulin resistance, the insulin signal is not propagated. Activation of PPARg by the thiazolidinediones enhances insulin signal transduction, increases the recruitment of GLUT4 to the cell membrane, and increases glucose uptake and transport into the cell.*An animated version of this slide is located in the folder “Animated Slides.”
41 SITES OF ACTION OF ORAL ANTIDIABETIC AGENTS DelayCarbohydrate absorptionAcarboseReduce excessiveHepatic glucose outputStimulate ImpairedInsulin secretionReduceHyperglycemiaTZD’s 20%Metformin 80%SulfonylureasTZD’s80%Metformin20%Reduce peripheralInsulin resistance
42 THIAZOLIDINEDIONES DURATION OF ACTION 24-30 Hours SIDE EFFECTS HepatotoxicityWeight gainFluid retentionAnemiaCONTRAINDICATIONSLiver diseaseHeart Failure (NYHA class 3 &4)
43 IndicationsAs an adjunct to diet & exercise to improve glycemic control in patients with type 2 diabetes.Indicated as monotherapyAlso indicated for use in combination with a sulfonylurea, metformin or insulin.
44 Insulin Sensitizers Do More Than Just Lower Glucose Improve lipid (TZDs >> Metformin)Decrease TG, Increase HDL, Increase LDL – bigger particleLower CRP (TZD > Metformin)Lower PAI-1 (TZD & Metformin)Decrease intra abdominal fat (TZD)? Protect beta cell (TZD)Prevent restenosis after stenting.
45 Fixed-Dose Monotherapy Study Change in HbA1c at Endpoint HbA1c at week 26 (% points)Change from baselineDifference from placeboBaseline mean HbA1c: 9.5%*p<0.05 vs baseline†p<0.05 vs placeboadapted from: Aronoff S, et al., Diabetes Care 2000;23:
46 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)Mean Change from baselineBaseline mean FPG placebo: 13.1 mmol/L, pioglitazone: 13.5mmol/L *p=0.05 vs baseline †p=0.05 vs placebo +SUKipnes MS, et al. Am J Med 2001;111:10-17.
47 Pioglitazone + Metformin Study Mean Changes in FPG at Endpoint FPG at week 16 (mmol/L)Placebo + Met (n=157)Plo 30mg + Met (n=167)Mean Change from baselineBaseline mean FPG:placebo 14.4 mmol/L, pioglitazone 14.0 mmol/L *p<0.05 vs baseline †p<0.05 vs placebo + MetEinhorn D, et al. Clin Ther 2000;22:
48 Pioglitazone: Favorable effects on serum lipids
49 Study ObjectiveTo evaluate the impact of pioglitazone and rosiglitazone on lipid profiles and glycemic control in patients with type 2 diabetespioglitazonerosiglitazone
50 Mean Change in Triglyceride PioglitazoneRosiglitazone-13.3P = vs. baseline-6%-10Mean change in TG (mg/dL)-20-55.2P <0.001 vs. baseline-23%-30-40-50Pioglitazone vs. Rosiglitazone: P <0.001-60
51 Mean Change in Total Cholesterol PioglitazoneRosiglitazone64.82%P = vs. baseline4Mean change in TC (mg/dL)2-2-8.5-4%P <0.001 vs. baseline-4-6-8Pioglitazone vs. Rosiglitazone: P <0.001-10
52 Mean change in HDL-C (mg/dL) Pioglitazone vs. Rosiglitazone: P = 0.064 3.02.76%P <0.001 vs. baseline2.5Mean change in HDL-C (mg/dL)2.0Pioglitazone vs. Rosiglitazone: P = 0.0641.51.00.5-0.1-0.3%P = vs. baseline0.0-0.5
53 Mean Change in LDL-C 3% -4% Pioglitazone Rosiglitazone 63.63%P = vs. baseline4Mean change in LDL-C (mg/dL)2-5.1-4%P = vs. baseline-2-4Pioglitazone vs. Rosiglitazone: P <0.001-6
54 ConclusionsBlood lipid levels changed more favorably with pioglitazone than with rosiglitazoneChanges in HbA1c and weight gain were equivalentpioglitazonerosiglitazone
55 A new armament against Type 2 DM Pioglitazone.A new armament against Type 2 DMAn insulin sensitizer that reduces insulinresistanceProvides excellent glycemic controlLess risk of HypoglycemiaImproves lipid profileReduces the risk of CVD.Indicated as mono therapy as well as incombination with Metformin, Sulfonylureas &Insulin
56 Non Glycemic Goals: Treat All Cardiovascular Risks Factors Aggressively SmokingHypertensionBP less than 130/80LipidsLDL Cholesterol < 100 mg/dlLDL less than 70 mg/dl in “high risk” casesHDL cholesterol > 40 mg/dlTriglycerides < 150 mg/dlAspirin
57 Case History 30 y.o. woman with a history of gestational diabetes with her first pregnancy at age 21presents with frequent urination, thirst, weightloss and a random glucose of She has anIUD in place. Her BMI is 33. BP is 140/80.Is this enough information to diagnose diabetes?What other tests would you order?
59 What will you do now?Educate your patient about diabetes and set goals together for her careDiabetic diet counseling and a weight loss programEducate her in use of a glucometer.Devise exercise program for physical fitness.
60 Anything else? Refer to ophthalmologist Do microfilament check for neuropathySee frequently to reinforce diet, exercise, home glucose moniteringStart Metformin.Treat BP with ACEI if remains over 130/80
61 Eight Months LaterDespite modest weight loss and compliance with her medications your patient still has a HbA1C of Her blood pressue is 120/75 and her Alb/Cr is LFT’s remain normal.What would you do now?
62 Second Oral Medication Add aGlitazone orSulfonylurea
63 Summary Type 2 diabetes affects many organs Type 2 diabetes changes over timeDiabetes treatment changes over timeMedications can now be selected to work where the problem isCombinations of medications, because they work at different sites, in the body usually work better than monotherapy