Dr. W de Lange Division of Endocrinology Department of Internal Medicine

1. The Diagnosis of Diabetes Mellitus PreDiabetes Dr. W de Lange Division of Endocrinology Department of Internal Medicine University of the Free State

2. PreDiabetes The Diagnosis of Diabetes Mellitus The Current Guidelines (South-Africa) Case studies The History of the Diagnosis of Diabetes Mellitus HbA1C: The “NEW” Kid on the Block? • What is PreDiabetes? • Why is PreDiabetes Important? • How do I treat PreDiabetes?

3. The Diagnosis of Diabetes Mellitus

5. Case Study (1): 57 year old white male presents with: Gangrenous changes of the right foot due to vascular insufficiency. The patient is known with: • Hypertension (3 years) • Obesity Class 2 (BMI: 37) • Smoking (35 pack years) • Family history of ischemic heart disease

6. Does this patient suffer from Diabetes Mellitus?

7. Case Studies (2): How will you diagnose Diabetes Mellitus in this Patient? • 45 year old black woman presents with symptoms and signs suggestive of Diabetes Mellitus. • She has a random glucose value = 10. • She stays 300km from the hospital.

9. Correlation between FPG, 2hPG and HbA1C and the Prevalence of Retinopathy.

10. Advantages of A1C testing compared with FPG or 2hPG • Standardized (National Glycohemoglobin Standardization Program); • Better index of overall glycemic exposureand risk for long term complications; • Less biologic variability; • Less preanalytic instability; • No fasting or timed samples; • Relatively unaffected by acute changesin glucose levels & • Currently used in management.

11. Limitations of A1C testing • Abnormal Hemoglobin; • Conditions associated with Increased red cell turnover; • Ageing; • Race & • Rapidly evolving Diabetes Mellitus Type 1.

12. Conclusion: HbA1C is an old tool, but a new instrument in: • The identification of those at high risk for developing Diabetes Mellitus (HbA1C 5.7-6.4%)and • The diagnosis of Diabetes Mellitus (HbA1C ≥ 6.5%).

14. Nathan, DM et al. 2009. International Expert Committee Report on the role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care. 32(7):1327-34

15. PreDiabetes

16. PreDiabetes • What is PreDiabetes? • Why is PreDiabetes Important? • How do I treat PreDiabetes?

17. What is PreDiabetes? • American Diabetes Association (ADA): Fasting Glucose: 5.6-6.9mmol/L Glucose Tolerance Test: 7.8-11.0mmol/L HbA1C: 5.7-6.4%

18. Why is Prediabetes important?

19. Why is PreDiabetes Important? • USA: Type 2 Diabetes Mellitus affects 7% of the population. 61%Increasein Type 2 Diabetes Mellitus from 1990-2001. 1 500 000 new cases per year. • PreDiabetes is associated with increased incidence of Retinopathy, Neuropathy and Cardiovascular Disease (IGT). • 25% of Patients with PreDiabetes will convert to Diabetes Mellitus Type 2. • Conversion rate = 10% / year

20. Pathogenesis of Type 2 DM:

21. Type 2 diabetes mellitus (T2DM) requires progressive therapy • T2DM is a progressive disease characterised by increased insulin resistance and decreasing pancreatic β-cell function.1 • At diagnosis, patients may have already lost approximately 50% of β-cell function.2 • Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015. • Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

22. Decreasing -cell function as part of the progression of T2DM 100 Time of diagnosis ? 80 60 Normal -cell function by HOMA (%) Pancreatic function ~50% of normal 40 20 0 ―10 ―8 ―6 ―4 ―2 0 2 4 6 Time (years) HOMA=homeostasis model assessment Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

23. Both FBG and PPBG contribute to overall hyperglycaemia Onset of diabetes 350 300 250 200 150 100 50 19.4 16.7 13.9 11.1 8.3 5.5 2.8 PPBG Plasma glucose (mmol/l) Plasma glucose (mg/dl) FBG 250 200 150 100 50 0 Relative -cell function (%) Insulin resistance Insulin level -cell failure Uncontrolled hyperglycaemia Obesity IGT T2DM Clinical features Risk for diabetes complications with uncontrolled hyperglycaemia Years –10 –5 0 5 10 15 20 25 30 FBG=fasting blood glucose; IGT=impaired glucose tolerance;PPBG=postprandial blood glucose. Adapted from Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.

24. PreDiabetes: • PreDiabetes is Associated with: • Obesity • Dyslipidemia: Tgl and / or HDL • Hypertension

25. How do I Manage PreDiabetes?

26. Rationale for preventing diabetes • Prevention of microvascular complications • Retinopathy • Nephropathy • Neuropathy • Amputations • Prevention of macrovascular complications • Coronary artery disease • Congestive heart failure • Stroke • Peripheral vascular disease • Changing the natural history of diabetes • Improving islet function • Simplified treatment and monitoring regimens • Decreasing polypharmacy Glenn Matfin et al. Advances in the treatment of Prediabetes. Ther Adv Endocrinol Metab (2010) 1(1) 514

27. Current treatment options: • Intensive Lifestyle Intervention • Drugs: Metformin Pioglitazone Rosiglitazone Acarbose Orlistat Ramipril • Surgery: Bariatric Surgery Jill P Crandall et al. The Prevention of Type 2 Diabetes. nature clinical practice ENDOCRINOLOGY & METABOLISM July 2008 Vol 4 no 7

28. Lifestyle Modification: Jill P Crandall et al. The Prevention of Type 2 Diabetes. nature clinical practice ENDOCRINOLOGY & METABOLISM July 2008 Vol 4 no 7

29. Weight Loss: Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009; 374: 1677–86

30. Medication: Jill P Crandall et al. The Prevention of Type 2 Diabetes. nature clinical practice ENDOCRINOLOGY & METABOLISM July 2008 Vol 4 no 7

31. Cardiovascular Risk: The Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group. Effect of Progression From Impaired Glucose Tolerance to Diabetes on Cardiovascular Risk Factors and Its Amelioration by Lifestyle and Metformin Intervention. Diabetes Care 32:726–732, 2009

32. Criteria for testing for diabetes in asymptomatic adult individuals: • Testing should be considered in all adults who are overweight (BMI 25kg/m2*) and have additional risk factors: 1. Physical inactivity • First-degree relative with diabetes • Members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacific Islander) • Women who delivered a baby weighing 9 lb or were diagnosed with GDM • Hypertension (140/90 mmHg or on therapy for hypertension) • HDL cholesterol level 35 mg/dl (0.90 mmol/l) and/or a triglyceride level 250mg/dl (2.82 mmol/l) • Women with polycystic ovary syndrome • A1C 5.7%, IGT, or IFG on previous testing • Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosisnigricans) • History of CVD

33. Criteria for testing for diabetes in asymptomatic adult individuals (Contd.): • In the absence of the above criteria, testing diabetes should begin at age 45 years • If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results and risk status.

34. PREVENTION/DELAYOF TYPE 2 DIABETES Patients with IGT, IFG, or an A1C of 5.7–6.4%: • Effective ongoing support program for weight loss of 5–10% of body weight and an increase in physical activity of at least 150 min/week of moderate activity such as walking. • Follow-up counseling appears to be important for success. • Based on potential cost savings of diabetes prevention, such counseling should be covered by third-party payers.

35. PREVENTION/DELAYOF TYPE 2 DIABETES • In addition to lifestyle counseling, metformin may be considered in those who are at very high risk for developing diabetes: Combined IFG and IGT plus other risk factors such as: A1C 6% Hypertension Low HDL cholesterol and/ or Elevated triglycerides Family history of diabetes in a first-degree relative Obesity Under 60 years of age • Monitoring for the development of diabetes in those with pre-diabetes should be performed every year.

36. Conclusion: • HbA1C: Old tool with a New application. • Diabetes Mellitus Type 2 is disease with severe morbidity and mortality. • T2DM can be prevented and reversed.