05/15/10 16:20 Major Pathophysiologic Defects in Type 2 Diabetes Speaker Notes This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis. In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired. 1 Most patients with type 2 diabetes have insulin resistance. Pancreatic beta cells attempt to increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops. 1 By the time diabetes is diagnosed, beta-cell function has already decreased substantially and continues to decline over time. 1 Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production. 1 Likewise, with decreased secretion of insulin, less glucose is taken up by the muscle and adipose tissue. 2 References: 1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254. Purpose: To explain the 3 core pathophysiologic defects of type 2 diabetes. Takeaway: Insulin resistance, beta-cell dysfunction, and elevated hepatic glucose production each contribute to hyperglycemia in type 2 diabetes.
05/15/10 16:20 Slide 1-24 Stages of Type 2 Diabetes Epidemiological studies suggest that the onset of diabetes occurs 10 to 12 years before a clinical diagnosis is made. (Harris 1997) In the UKPDS study of type 2 diabetics, at least 50% of the patients had evidence of diabetic tissue damage when diabetes was first diagnosed. (UKPDS Study 16, 1995) In the earliest phase, when beta-cell function is not impaired, the ability of the beta-cells to hypersecrete insulin masks the impaired glucose tolerance, often for years. During the IGT phase, the FPG will be higher than the normal 110 mg/dL but lower than the 126 mg/dL that is indicative of diabetes. As beta-cell function continues to decline, mild postprandial hyperglycemia develops, reflecting the inability of the beta-cell to hypersecrete enough insulin to overcome insulin resistance. At the end of this prediabetic phase, the first phase of type 2 diabetes typically produces symptoms that lead to a diagnosis. During phase I, in the first 2 years after diagnosis of diabetes, beta-cell function decreases to between 70% and 40% of normal function. CORE
05/15/10 16:20 Most Patients With Type 2 Diabetes May Fail to Attain A1C Goal With Conventional Treatment Paradigm Speaker Notes This slide is a depiction of the conservative, stepwise approach to treating diabetes. The first step is diet and exercise (lifestyle modification), followed by oral monotherapy, up-titration of monotherapy to maximal doses, combination therapy, oral therapy plus basal insulin, and oral therapy plus multiple daily insulin injections. 1 This approach has been called “failure oriented,” with progression to the next step occurring after failure to maintain glycemic control becomes apparent. 2 A problem with the stepwise approach is that delays often occur between steps even when A1C levels are unacceptably high. 1,3 For example, data from the Kaiser Permanente Northwest database between 1994 and 2002 using an action threshold of A1C >8% showed that the mean time after reaching the A1C action point of >8% and moving to the next step in therapy for patients on metformin or sulfonylurea monotherapy was 14.5 and 20.5 months, respectively. 3 The authors analyzing the Kaiser data suggest that if, before starting insulin, a hypothetical patient were to progress from nonpharmacologic treatment through sulfonylurea or metformin monotherapy to combination oral therapy, he or she would accumulate nearly 5 A1C-years of excess glycemic burden >8% and about 10 A1C-years of burden >7%. 3 References: 1. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B, on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345–1355. 2. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7:625–631. 3. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535–1540. Purpose: To show a conceptual view of the stepwise approach to diabetes management. Takeaway: The stepwise approach to treatment, with changes in therapy only after treatment failure, may result in a prolonged glycemic burden.
05/15/10 16:20 Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy Speaker Notes The orange line depicts a conceptual view of the conventional stepwise treatment that was discussed earlier. Hypothetically, patients treated with this approach would have a considerable glycemic burden (time spent above A1C goals). 1,2 The green line depicts a conceptual view of an aggressive, A1C goal–oriented approach that would initiate changes in therapy earlier—that is, within several months of goals not being met. Hypothetically, patients treated with this approach might be able to achieve A1C results like those depicted in the straight green line. This approach also calls for an earlier use of combination therapy. Moreover, this approach is supported by the ADA/EASD consensus statement. The therapeutic sequence in this approach would be 2 : 1. Lifestyle change (diet and exercise) 2. Oral monotherapy 3. Oral combination therapy 4. Up-titration of oral therapy 5. Oral therapy plus basal insulin 6. Oral therapy plus multiple daily insulin injections This approach may increase the number of patients with type 2 diabetes who achieve and maintain glycemic goals, thus lowering the glycemic burden over time. 2 References: 1. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol . 2000;7:625–631. 2. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B, on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345–1355. Purpose: To show conceptually that early, aggressive intervention may reduce the glycemic burden of type 2 diabetes. Takeaway: A treat-to-goal therapeutic approach with aggressive treatment and a low threshold for action (A1C >7%) may reduce the glycemic burden of type 2 diabetes.
05/15/10 16:20 No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Speaker Notes No single-agent monotherapy has an MOA that addresses all key pathophysiologies of type 2 diabetes. Alpha-glucosidase inhibitors decrease intestinal absorption of glucose. 1,2 Meglitinides and sulfonylureas stimulate insulin secretion. 3–5 TZDs are insulin sensitizers that also lower hepatic glucose output. 6,7 Metformin, a biguanide, lowers hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity. 8 DPP-4 inhibitors improve insulin synthesis and release and lower hepatic glucose production, both through suppressing glucagon production and release, and by improving insulin synthesis and release. Each class of oral antihyperglycemic agent does not address at least 1 key pathophysiology of type 2 diabetes. Purpose: To examine the key pathophysiologies targeted by each class of oral antihyperglycemic agent. Takeaway: No one class targets all key pathophysiologies of type 2 diabetes. References: 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 4. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 5. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004. 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
*Patient should be educated to self-adjust the insulin dose (6,7). Advice insulin adjustment by 4IU, if fasting blood glucose exceeds 8 mmol/l. Advice insulin adjustment by 2IU, if fasting blood glucose is 6-8 mmol/l.
Recommended glycemic goals for nonpregnant adults (Table 10) are shown on three slides Slide 2 of 3 Glycemic goals should be individualized, based on a patient’s duration of diabetes, age, life expectancy, comorbid conditions, known cardiovascular disease (CVD) or advanced microvascular complications, unawareness of hypoglycemia, and other considerations Reference American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S21. Table 10.
APPROACH TO DIABETES
Approach to a newly diagnosed patients with Type 2 Diabetes Mellitus Dr Abhay sahoo MD,DM (Endocrinology, AIIMS) Asst. prof. Endocrinology IMS & SUM Hospital
Diabetes Mellitus• Diabetes Mellitus is derived from two terms: The Greek word Diabetes means• to Siphon i.e. pass through....• ....and the Latin word Mellitus means as sweet as honey....
Prevalence In 2010, prevalence has risen to 285 million, representing 6.6% of the world’s adult population. Predicted that by 2030 the number of people with diabetes will have risen to 438 million globally. Currently China has got the largest number of Diabetics. Type 2 DM is the commonest form of diabetes globally as well as in India. Constitutes more than 95% of the diabetic population in our country. *IDF Diabetes Atlas, 2010
Indian Diabetes Risk Score (IDRS) V Mohan , API 2010;20:93-96
Major Pathophysiologic Defects in Type 2 Diabetes Islet-cell dysfunction Glucagon (alpha cell) Pancreas Insulin Insulin resistance (beta cell) Hepatic glucose Glucose uptake in output muscle and fat Hyperglycemia Liver Muscle Liver Adipose tissueAdapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.Lippincott Williams & Wilkins; 2005:145–168.Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Insulin Resistance:An Underlying Cause of Type 2 Diabetes Aging Medications Obesity and inactivity Genetic abnormalities INSULIN RESISTANCE Type 2 PCOS diabetes Hypertension Atherosclerosis DyslipidemiaReaven GM. Physiol Rev. 1995;75:473-486Clauser, et al. Horm Res. 1992;38:5-12.
Progression of Type 2 DM Insulin resistance Insulin Secretion defect Hyperglycemia Type 2 DMStimulation of beta cells More loss of Beta cells More Insulin release Progression of Type 2 DM (Hyperinsulinemia) Complete loss of Beta cells Euglycemia Insulin requiring Type 2 DMExhaustion of Beta cells
Natural History of Type 2 Diabetes Postmeal glucose 35 30 IGT Diabetes 25 Fasting glucose Glucose 20 (mg/dL) 15 10 5 -15 -10 -5 0 5 10 15 20 25 120 100 Insulin resistance Relative function (%) 75 50 β cell 25 0 -15 -10 -5 0 5 10 15 20 25 Years of diabetesAdapted from: International Diabetes Center (Minneapolis, MN).
UKPDS: β-Cell Loss Over Time Almost 50% of the beta cell function is found to be destructed at the diagnosis of Type II DM* Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment(HOMA) data from UKPDS.† IGT=impaired glucose testing‡ The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and weredetermined by the HOMA model.Lebovitz HE. Diabetes Rev. 1999;7:139-153.
Complications at Diagnosis50% of newly presenting people with type 2 diabetes already have one or more complications at diagnosis Intermittent Retinopathy: 21% claudication: 3% Ischaemic skin Hypertension: 35% changes to feet: 6% Abnormal ECG: 18% Stroke or TIA: 1% Erectile dysfunction: 20% Plasma creatinine >120µmol/l: 3% Absent foot pulses: 13%UKPDS Group. Diabetologia 1991; 34:877–890.
Early diagnostic criteria of DM• “Pre-diabetes” is a new term applied to hyperglycemia that does not meet the diagnostic criteria. • Impaired fasting glucose (IFG) = fasting plasma glucose of 100–125 mg/dl or • Impaired glucose tolerance (IGT) = OGTT 2-hr plasma glucose of 140–199 mg/dl• IFG and IGT are associated with a high risk for diabetes and cardiovascular disease.
Previously identified IGT and IFG• Previously Identified IFG or IGT Inmates with impaired glucose homeostasis are at increased risk of developing diabetes.• Approximately one third of patients with IFG or IGT will develop diabetes within five years.• Annual screening by fasting plasma glucose is recommended for these patients.
Need for an early and intensive approach to new onset of T2DM• At diagnosis of type 2 DM • 50% of patients already have complications • Upto 50% of β cell function has already been lost• Current management: • ⅔rd of patients do not achieve HbA1C • Majority require poly pharmacy to meet glycemic goals over time UKPDS Group. Diabetologia 1991:34:877-890. Saydah SH et al JAMA 2004; 291:335-342 Turner RC et al JAMA 1999; 281:2005-2012
ADA/EASD Revised Consensus Statement Tier 1 : Well-validated core therapies Lifestyle + Metformin Lifestyle + Metformin + + At diagnosis: Basal Insulin Intensive Insulin Lifestyle + Metformin Lifestyle + Metformin + Sulphonlyureasa Step 1 Step 2 Step 3 Tier 2 : Less well-validated core therapies Lifestyle + Metformin + Lifestyle + Metformin Pioglitazone + No hypglycemia Pioglitazone Oedema/CHF + Bone loss Sulphonylureas Lifestyle + Metformin + GLP-1 agonistb Lifestyle + MetforminDavid Nathan et al. No hypglycemia +Diabetes Care 2009; 32:193-203 Weight loss Basal insulin Nausea/Vomitting a A Sulphonylurea other than Glibenclamide or Chlorpropamide b Insufficient clinical use to be confident regarding safe
Most Patients With Type 2 Diabetes May Fail to Attain A1C Goal With Conventional Treatment ParadigmPublished Conceptual Approach OAD + multiple daily Diet and OAD OAD OAD OAD + insulin Mean A1C exercise monotherapy up-titration combination basal insulin injections of patients 10 A1C, 9 % 8 7 6 Duration of DiabetesOAD=oral antihyperglycemic drug.Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional TherapyPublished Conceptual Approach OAD + multiple daily Diet and OAD OAD OAD OAD + insulin exercise monotherapy up-titration combination basal insulin injections 10 A1C, 9 % 8 Mean A1C of patients 7 6 Duration of DiabetesAdapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
Initial treatment plan for new onset of DM• Many studies have demonstrated that diabetes can be delayed, and sometimes prevented in individuals at high risk for developing diabetes (those with IFG, IGT, or both)• Self-monitoring: HbA1C, FPG, PPG• Recognizing and treating severe hypoglycemic and hyperglycemic episodes• Identifying the diabetic complications• Lifestyle modifications: Improving food selection, increasing physical exercise, and smoking cessation.
Initial treatment plan for new onset of DM• Daily self-examination of the feet.• Regular screenings: fasting blood glucose, A1C, lipid levels, and kidney monitoring (BUN, creatinine, GFR)• Annual eye exams (funduscopic) done by an optometrist or ophthalmologist.
Ideal diabetic diet• Total Calorie content and their derivation from proximate principles of diet• Glycemic index• Fibre content• Consistency or physical form of food.
Medical Nutritional therapyDietary composition should be : Carbohydrate : 50- 60 % Protein : 15-20% Fats : 15-25% Saturated fats : <10 % PUFA : up to 10%
Exercise• Exercise improves the metabolism of a diabetic patient by several mechanism.• Increase the number of Insulin receptor as well as the Sensitivity• Increase in uptake of glucose
Currently Available agents for the treatment of Type 2 Diabetes
Incretins (GLP-1 and GIP)• GLP-1(Glucogen like peptide 1) are secreted from L cells• GIP ( Glucose dependant insulinotrpic polypeptide ) are secreted from K cells• Rapidly metabolized by Dipeptidyl peptidase 4 (DPP4) • Half life of GLP-1 is 2 mins • GIP- 5 mins
Dipeptidyl-Peptidase 4 Inhibitors• Agent in Class: Vildagliptin Sitagliptin, Saxagliptin• Mechanism of action: • slows the inactivation of incretin hormones (glucagon- like peptide 1 and glucose-dependent insulinotropic polypeptide) • Increases glucose-stimulated insulin secretion • Causes glucose-stimulated glucagon suppression • primarily lowers postprandial glucose levels but has also been shown to reduce fasting plasma glucose AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008
No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Alpha- Meglitinides3 SUs4,5 TZDs6,7 Metformin8 DPP-4 Glucosidase Inhibitors Inhibitors1,2 Insulin Major Pathophysiologies deficiency Insulin resistance Excess hepatic glucose output Intestinal glucose absorption 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
Potential advantages of early combination therapy• Earlier achievement of therapeutic goals• Potential reduction in risk of side effects if you combine drugs at lower doses versus up-titration of single dose• Opportunity to combine oral anti diabetic drugs with complementary modes of action• Potential to delay disease progression
Guidelines for Starting InsulinInsulin therapy is indicated if the followingmeasures fail to achieve glycaemic targets: • Maximum tolerated dose of Oral Hypoglycaemic Agents (OHA) • Failure to reach glycemic targets • Remediable factors considered (e.g. food and exercise plan, inter current problems)
Guidelines for Starting Insulin•If more than 30-36 IU of insulin necessary toobtain good metabolic control, consider stoppinginsulin secretagogues and continue on same totaldose of insulin + metformin or actos•Divide the dose into 2 daily injections: 2/3 before breakfast 1/3 at bedtime
Stages of Diabetic Nephropathy• Stage I – Hyperfiltration - increased blood flow through the kidney, early renal hypertrophy• Stage II – Glomerular lesions without clinically evident disease• Stage III – Incipient nephropathy with microalbuminuria - alb/cr ratio .03 - .3 or albumin 20-200 mcg/min on timed specimen• Stage IV – Overt diabetic nephropathy with proteinuria >500 mg/24 hr & creatinine clearance <70 ml/min• Stage V – End stage renal disease (ESRD) – creatinine clearance <15 ml/min – creatinine = 6mg/dl•
Stages of Diabetic Nephropathy 180 160 140 II III 120 I 100GFR IV 80 60 40 20 0 V 0 5 10 15 20 25 30 Duration of Diabetes
Prevention of Diabetic Nephropathy• Optimal Glycemic Control• Intensive Blood Pressure control (>130/80 mm Hg)• Use of ACE –I• Reduce Salt Intake• Reduce Alcohol Intake
Prevention for Diabetic Retinopathy• Optimal Blood Preesure Control• Optimal Glycemic Control• Control Lipid Profile• Use of Aspirin• Regular Screening Must
Neuropathy• Develops within 10 years after onset of diabetes in 40-50% of patients with diabetes• Some type 2 patients already have neuropathy at diagnosis• Increased risk of foot ulcers and amputation• 45% of lower extremity amputations occur in patients with diabetes
Prevention for Diabetic Neuropathy• Intensive Glycemic control• Lifestyle Modification – Quit Smoking – Reduce Alchol Intake• Foot Care: – Wear Non Weight bearing Comfortable Shoes – Keep feet Clean & Dry – Wash feet daily with Warm Water – Do not go barefeet – Trim your toenails straight across – Wear fresh socks every day
Indians are Different• Earlier onset of diabetes as compared to Caucasians• Considerably thinner (particularly in the limbs) but more centrally obese than the Caucasian• Despite being lean, Indians are more insulin resistant and hyperinsulinaemic.• Obese and physical inactivity• High procoagulant tendency• Genetic predisposition Indian J Med Res 129, May 2009, pp 485-499
Primary Prevention of CVD in People with Diabetes Mellitus A Scientific Statement from ADA & AACE• A1c goal for patients in general is <6.5%• A1c goal for the individual patients is an A1c as close to normal (<6%) as possible without causing hypoglycemia
Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE and VA Diabetes Trials A Position Statement of the ADA and a Scientific Statement of the ACC & AHA• Lower A1c goal if can be achieved without significant hypoglycemia: – Short duration of diabetes – Long life expectancy – No significant CVD Skyler et al, J Am Coll Cardiol 2009;53:298-304
Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE and VA Diabetes Trials A Position Statement of the ADA and a Scientific Statement of the ACC & AHA• Less stringent A1c goal: – History of severe hypoglycemia – Limited life expectancy – Advanced micro- or macrovascular complications or extensive comorbid conditions – Long-standing diabetes which is difficult to control Skyler et al, J Am Coll Cardiol 2009;53:298-304
Glycemic Recommendations for type-2 DMGoals should be individualized based on• Duration of diabetes• Age/life expectancy• Comorbid conditions• Known CVD or advanced microvascular complications• Hypoglycemia unawareness• Individual patient considerations• Hypoglycemia unawareness• Individual patient considerations ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.
Current Practice• Emphasize achieving current standards of care in the diabetic patient – A1c Goal of ~ 7% – BP Goal of 130/80 – LDL Goal of 100 mg/dl (70 mg/dl in patients with established CVD) – Assist in behavior controls of diet, exercise, tobacco cessation – Emphasis should be on translation research and implementing programs to assist patients in reaching current goals.