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

The Diagnosis of Diabetes Mellitus PreDiabetes 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?

The Diagnosis of Diabetes Mellitus

Case Study (1): Laboratory White Cell Count: 17 x 109/L CRP: 120 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 Laboratory White Cell Count: 17 x 109/L CRP: 120 Glucose: 13mmol/L

Does this patient suffer from Diabetes Mellitus?

Case Studies (2): 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. How will you diagnose Diabetes Mellitus in this Patient?

History Fasting Glucose OGTT 1979 National Diabetes Data Group Glucose values = Symptoms ≥ 7.8 mmol/l ≥ 11.1 mmol/l {WHO} 1997 Expert Committee on the Diagnosis and Classification of DM Glucose values = Long term Complications ≥ 7.0 mmol/l 2003 Expert Commitee IFG = 5.6 -6.9 IGT = 7.8 – 11.1 2009 International Committee HbA1C Values = Complications HbA1C = 6.5%

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

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

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

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%).

Committee Report on the role 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

PreDiabetes

PreDiabetes What is PreDiabetes? Why is PreDiabetes Important? How do I treat PreDiabetes?

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%

Why is Prediabetes important?

Why is PreDiabetes Important? USA: Type 2 Diabetes Mellitus affects 7% of the population. 61% Increase in 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

Pathogenesis of Type 2 DM:

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 Type 2 diabetes mellitus (T2DM) develops because of a progressive decline in pancreatic -cell function and decreasing insulin sensitivity in peripheral tissues. The -cells may compensate for peripheral insulin resistance by increasing insulin output. Eventually the -cells fail to produce sufficient insulin, and hyperglycaemia and diabetes ensue. During insulin resistance, increased hepatic glucose production and reduced glucose uptake by skeletal muscle both contribute to hyperglycaemia. Insulin also fails to suppress lipolysis in adipose tissue, resulting in increased concentrations of circulating free fatty acids (FFAs). FFAs stimulate gluconeogenesis, triglyceride synthesis and glucose production in the liver, and further impair glucose utilisation by skeletal muscle. Excess circulating glucose and FFAs act on cells and tissues to inhibit insulin secretion and action. This is referred to as gluco-lipotoxicity. The progressive nature of T2DM requires a progressive treatment strategy. Reference Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995–1015. 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.

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 Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function as T2DM progresses. At the time of diagnosis, -cell function is already reduced by approximately 50% and continues to decline regardless of therapy. Severe -cell failure results in insulin deficiency and a subsequent requirement for insulin therapy. Reference Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5. ―10 ―8 ―6 ―4 ―2 2 4 6 Time (years) HOMA=homeostasis model assessment Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

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 (mg/dl) FBG Plasma glucose (mmol/l) 250 200 150 100 50 Relative -cell function (%) Insulin resistance Insulin level -cell failure Obesity IGT T2DM Uncontrolled hyperglycaemia Clinical features Risk for diabetes complications with uncontrolled hyperglycaemia T2DM is a progressive disease characterised by declining pancreatic -cell function leading to decreased insulin levels. -cell dysfunction begins some 10–12 years before diabetes is diagnosed. Typically, by the time of diagnosis, approximately 50% of -cell function has already been lost.1 When the secretion of insulin cannot keep pace with the underlying insulin resistance, impaired glucose tolerance (IGT) and T2DM develop. The natural progression of T2DM is prolonged; many key features such as insulin resistance and macrovascular changes occur before hyperglycaemia develops and before T2DM is diagnosed.2 Exposure to metabolic dysregulation substantially increases the risk of developing macrovascular (e.g. stroke, ischaemic heart disease and peripheral vascular disease) and microvascular (e.g. retinopathy, nephropathy and neuropathy) complications at a later date.2 References Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5. Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995–1015. 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.

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

How do I Manage PreDiabetes?

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

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

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

Weight Loss: Mean weight changes Weight changes for originally assigned treatment group since Diabetes Prevention Program (DPP) randomisation for (A) all participants, (B) those aged 25–44 years at randomisation, (C) 45–59 years, and (D) 60 years and older; and since enrolment in the present study for (E) all participants, (F) those aged 25–44 years, (G) 45–59 years, and (H) 60 years and older, including participants irrespective of whether they developed diabetes during follow-up. Webappendix p 2 shows numbers of those in every datapoint. 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

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

Cardiovascular Risk: Mean interval change in cardiovascular risk factors by category of glucose tolerance interval change and by treatment group. The mean interval changes with their five 95% confidence limits for SBP, DBP, triglycerides,HDLcholesterol, LDL cholesterol, and LDL-PPD are arranged from left to right in each panel by treatment group, according to whether there was improvement in glucose tolerance status (IGT to NGT), maintenance of improvement (NGT to NGT), no change (IGT to IGT), deterioration back to baseline status (NGT to IGT), or conversion to diabetes (DM) (IGT/NGT to diabetes). E, ILS group; f, MET group; ‚, placebo group. 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

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, acanthosis nigricans) History of CVD

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.

PREVENTION/DELAY OF 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.

PREVENTION/DELAY OF 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.

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.