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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
Incretins (GLP-1 and GIP)
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
Targets of controlin Diabetes Mellitus
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
What should be the target HbA1c?
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.