Hyperglycemia and Diabetic Microvascular Complications (DMC)

Transcription

1 Hyperglycemia and Diabetic Microvascular Complications (DMC) Lois Jovanovic, MD CEO & Chief Scientific Officer Sansum Diabetes Research Institute Santa Barbara, California 1

2 Hyperglycemia and DMC: Outline 2 Overview of DMC Impact Risk factors Glycemic control and DMC Risk reduction benefits Evidence Diabetes Control and Complications Trial (DCCT) United Kingdom Prospective Diabetes Study (UKPDS) Recommended targets Limitations Targeting postprandial glucose (PPG) control Roundtable discussion

3 3 Overview of DMC

4 DMC in the United States Nervous system damage occurs in 60% to 70% of people with diabetes Each year, between 12,000 and 24,000 people lose their sight as a result of diabetic retinopathy Diabetes is the leading cause of end-stage renal disease (ESRD) 4 American Diabetes Association (ADA). Available at:

5 Impact of Diabetic Neuropathy More hospitalizations are due to neuropathy than all other diabetic complications combined Diabetic neuropathy is the most common peripheral neuropathy in developed nations Diabetic neuropathy contributes to 50%-70% of all nontraumatic amputations in the United States About 82,000 nontraumatic lower-limb amputations were performed in people with diabetes in Vinik AI. South Med J. 2002;95: ADA. Available at:

6 Impact of Diabetic Retinopathy Frequently present at diagnosis of type 2 diabetes Progresses, resulting in: Microaneurysms Retinal hemorrhages Blindness May include diabetic macular edema (DME) US cost of blindness due to diabetes $500 million 6 ADA. Diabetes 4-1-1: Facts, Figures and Statistics at a Glance. Alexandria, Virginia: ADA; Ciulla T, Amador A, Zinman B. Diabetes Care. 2003;26(9): Porta M, Bandello F. Diabetologia. 2002;45:

7 Impact of Diabetic Nephropathy Diabetic nephropathy occurs in 20%-40% of patients with diabetes It is the leading single cause of end-stage renal disease (ESRD) Approximately 25% of people with type 1 diabetes and 5%-10% with type 2 diabetes develop ESRD The total estimated costs for treatment of patients with ESRD in the US was $15.6 billion in ADA. Diabetes Care. 2004;27(suppl 1):S79-S83. ADA. Diabetes Care. 2005;28(suppl 1):S4-S36. International Diabetes Federation. Available at:

8 Risk Factors for DMC Modifiable Neuropathy Hyperglycemia Blood pressure Hyperlipidemia Weight Smoking Alcohol intake Hypertension Retinopathy Nephropathy Hyperglycemia Blood pressure Hyperlipidemia Weight Hyperglycemia Blood pressure Hyperlipidemia Weight 8 ADA. Diabetes Care. 2005;28(suppl 1):S4-S36; Fong DS, et al. Diabetes Care. 2003;26(suppl 1):S99-S102; ADA. Diabetes Care. 2004;27(suppl 1):S79-S83; Shaw JE, Zimmet PZ. Diabetes Rev. 1999;7: ; Duby JJ, et al. Am J Health-Syst Pharm. 2004;61:

9 9 Glycemic Control and DMC

10 Intensive Glycemic Control Reduces DMC Risk 10 Maintenance of near-normal glucose levels* in patients with type 1 diabetes: Reduces retinopathy development and progression Reduces kidney damage Reduces nerve damage Other studies have shown similar benefits of intensive glycemic control in patients with type 2 diabetes *Mean A1C = 7.3%. DCCT/EDIC Research Group. JAMA. 2002;287:

11 DMC Risk Reduction per 1% Decrease in A1C Study Retinopathy Nephropathy Neuropathy DCCT 27%-38% 22%-28% 29%-35% Kumamoto 28% 50% NCV* UKPDS 19% 26% 18% * NCV = Nerve Conduction Velocity. 11 Davidson JA. Endocr Pract. 2002;8(suppl 1):S13-S14.

12 DCCT: Objective and Study Design 12 Objective: Determine whether maintaining blood glucose levels near normal range decreases severity and frequency of DMC in type 1 diabetes patients Study design N = 1,441 type 1 diabetes patients Randomized, controlled trial Mean duration: 6.5 years Primary and secondary prevention cohorts Conventional and intensive therapy regimens Regular assessment of retinopathy, nephropathy, and neuropathy The DCCT Research Group. N Engl J Med. 1993;329:

13 DCCT: Eligibility and Exclusion Criteria PRIMARY SECONDARY PREVENTION INTERVENTION AGE Y Y DURATION 1-5 Y 1-15 Y RETINOPATHY NONE MIN. TO MOD. ALBUMINURIA <40 mg/ 24 h 200 mg/ 24 h EXCLUSION CRITERIA: hypertension, hypercholesterolemia, severe diabetic complications or medical conditions 13 DCCT Research Group. N Engl J Med. 1993;329:

14 DCCT: Conventional Therapy Regimen INTENDED TO MIMIC CONVENTIONAL CARE Clinical goals: No symptoms of hyper- or hypoglycemia 1 or 2 injections per day Daily self-monitoring Quarterly hemoglobin A1C Pregnant women treated intensively Diet and exercise education Quarterly visits 14 DCCT Research Group. N Engl J Med. 1993;329:

15 DCCT: Intensive Therapy Goals Same clinical goals as conventional therapy (no symptoms of hyper- or hypoglycemia) PLUS Maintain blood glucose levels as close to nondiabetic range as possible Preprandial Postprandial Weekly 3 AM mg/dl <180 >65 A1C <6.05% (mean + 2 SD) 15 DCCT Research Group. N Engl J Med. 1993;329:

16 DCCT: Intensive Therapy Methods 3 daily injections or insulin pump 4 or more blood-glucose tests daily Frequent dietary instruction to help achieve goals Monthly clinic visits 16 DCCT Research Group. N Engl J Med. 1993;329:

17 DCCT: Summary of Results Median A1C: 7.3% and 9.1% for intensive and conventional, respectively Retinopathy Development reduced by 76% in primary prevention cohort Progression reduced by 54% in secondary prevention cohort Nephropathy (primary and secondary cohort results combined) Microalbuminuria development decreased by 39% Albuminuria development decreased by 56% Neuropathy (clinical exam, nerve conduction, or autonomic function) Prevalence reduced by 69% in primary prevention cohort Prevalence reduced by 57% in secondary prevention cohort Increase in hypoglycemia and weight gain 17 DCCT/EDIC Research Group. JAMA. 2002;287: DCCT Research Group. N Engl J Med. 1993;329:

18 DCCT: Relation of A1C to DMC Risk Relative Risk Retinopathy Nephropathy Neuropathy A1C (%) The risk for development of DMC is increased at all A1C values above the normal range 18 Permission granted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25: DCCT Research Group. Diabetes. 1996;45:

19 DCCT: Applying Results to Clinical Populations Patient population typical of type 1 diabetes patients seen in practice Start intensive treatment as soon as safely possible Aim for A1C of 7% Hypoglycemia and weight gain are increased with intensive glycemic control 19 DCCT/EDIC Research Group. JAMA. 2002;287:

20 UK Prospective Diabetes Study 35 (UKPDS 35): Objective and Study Design Objective: Determine relation between glycemia and the risk of microvascular and macrovascular complications over time Study design Prospective, observational study Intensive (FPG* <6 mmol/l) vs conventional (FPG <15 mmol/l) therapy Median follow-up of 10 years 20 *FPG = fasting plasma glucose. Stratton I, et al. BMJ. 2000;321: UKPDS Group. Diabetologia. 1991;34:

21 21 UKPDS 35: Study Population and Results Population N = 3,642 for relative risk analysis Newly diagnosed type 2 diabetes patients Mean age 53 years Exclusion criteria: ketonuria, evident cardiovascular disease, serum creatinine >175 µmol/l, severe retinopathy, malignant hypertension, uncorrected endocrine abnormality, severe concurrent illness Results A1C: 7% (intensive) vs 7.9% (conventional) 1% A1C reduction leads to 37% decrease in risk of DMC No glycemic threshold for risk of DMC Stratton I, et al. BMJ. 2000;321: UKPDS Group. Lancet. 1998;352:

22 No Lower A1C Threshold for Increased DMC Risk in Type 2 Diabetes Patients Microvascular Endpoints 10 Hazard ratio A1C Stratton I, et al. BMJ. 2000;321:

23 UKPDS 35: Applying Results to Clinical Populations UKPDS 35 is an epidemiological study meant to estimate expected results in practice Estimates are consistent with the actual trial results Existing hyperglycemia-induced tissue damage may pose limitations Study population likely to be at lower risk for complications Newly diagnosed Old and ill patients excluded Patients seen in practice may have other characteristics of excluded patients 23 Stratton I, et al. BMJ. 2000;321:

24 Postprandial Glucose as a Therapeutic Target 24

25 Targeting PPG to Improve Glycemic Control Recommended glycemic targets are difficult to achieve Even with near-normal, long-term glucose levels, patients may experience postprandial hyperglycemia Glucose levels are routinely assessed by A1C and premeal blood glucose testing Routine assessment may not provide an indication of postprandial hyperglycemia PPG excursions may contribute to DMC 25 ADA. Diabetes Care. 2001;24:

26 Recommended Glycemic Targets Organization Glycemic Target ADA ACE IDF A1C (%) < <6.5 Fasting glucose (mg/dl) * <110* <100 Postprandial glucose (mg/dl) <180* <140* < *Plasma equivalent. 2 h. Self-monitored blood glucose. ADA. Diabetes Care. 2005;28:S4-S36. American College of Endocrinology (ACE). Endocr Pract. 2002;8(suppl 1):S5-S11. International Diabetes Federation (IDF). (Europe). Diabet Med. 1999;16:

27 Recommended Glycemic Targets Are Difficult to Achieve ~60% of people with diabetes have A1C >7% (NHANES/NHANES III) <5% of patients receiving intensive therapy maintained A1C within normal levels (DCCT) Only 28% of insulin-treated patients maintained A1C <7% (UKPDS) 27 Saydah H, et al. JAMA. 2004;291: DCCT Research Group. N Engl J Med. 1993;329: Turner RC, et al for the UKPDS Group. JAMA. 1999;281:

28 FPG and PPG Contributions to Hyperglycemia (FPG and PPG): Objective and Study Design Objective: Calculate relative FPG and PPG contributions to hyperglycemia based on diurnal glycemic profiles at various A1C levels Study design Overnight fast with test breakfast (8 AM) and lunch (12 PM) Blood samples at 8 AM, 1 PM, 2 PM, and 5 PM 28 Monnier L, et al. Diabetes Care. 2003;26:

29 29 FPG and PPG: Study Population and Results Study population N = 290 Type 2 diabetes Stable diet and/or metformin therapy Patients on acarbose or insulin were excluded Divided into quintiles based on A1C Results FPG and PPG increase with A1C Relative contribution of PPG to hyperglycemia was greatest at lower A1C Relative contribution of FPG to hyperglycemia was greatest at higher A1C PPG contributes ~30% to hyperglycemia at high A1C Monnier L, et al. Diabetes Care. 2003;26:

30 FPG and PPG: Contribution to A1C As patients approach target A1C, the need to manage PPG increases 100 % Contribution % 60% 55% 50% 30% 70% FPG PPG 20 30% 40% 45% 50% 30 0 > <7.3 A1C Range (%) FPG = Fasting Plasma Glucose PPG = Postprandial Plasma Glucose Monnier L, et al. Diabetes Care. 2003;26:

31 FPG and PPG: Applying Results to Clinical Populations Patient population seems consistent with patients seen in practice PPG control is important in patients with mild or moderate hyperglycemia (fairly well-controlled) PPG contribution to hyperglycemia in poorly controlled patients is still ~30% 31 Monnier L, et al. Diabetes Care. 2003;26:

32 Postprandial Blood Glucose: ADA Consensus Statement Individuals with diabetes should be tested for PPG in the following circumstances: Suspected postprandial hyperglycemia Premeal glucose targets are obtained A1C indicates poor glycemic control Monitoring treatment aimed specifically at lowering PPG Hypoglycemia 32 ADA. Diabetes Care. 2001;24:

33 Postprandial Blood Glucose: ADA Consensus Statement Elevated PPG concentrations may contribute to suboptimal glycemic control Outstanding questions: Does postprandial hyperglycemia play a unique role in the pathogenesis of diabetes complications? Should PPG be a therapeutic target? Additional research is necessary to clarify the role of PPG in the medical management of diabetes 33 ADA. Diabetes Care. 2001;24:

34 Postprandial Hyperglycemia: Expert Panel Position Statement 34 The potential importance of PPG control in the development of diabetes complications is widely recognized PPG may disproportionately contribute to DMC Targeting chronic and acute glucose fluctuations is necessary in the prevention and management of DMC 2-hour PPG measurement is practical and recommended Additional research is needed to clarify epidemiological associations between PPG and excess mortality Heine RJ, et al. Diabet Med. 2004;21:

35 Agents That Target PPG Control Pharmacological treatments to improve PPG levels may be beneficial, particularly in patients who have difficulty attaining target A1C levels despite good FPG control No study has evaluated the effect of oral antihyperglycemics targeting PPG on diabetes complications Agents that target postprandial hyperglycemia Short-acting insulin analogues α-glucosidase inhibitors Short-acting insulin secretagogues Glyburide-metformin tablets Amylin replacement therapy Incretin mimetics 35 Abrahamson MJ. Arch Intern Med. 2004;164: Kendall DM. Medscape Diabetes & Endocrinology. 2005;7. Available at: Kruger DF, Gloster MA. Drugs. 2004;64:

36 36 Summary DMC cause substantial morbidity and mortality Tight glycemic control reduces the risks of DMC development and progression in type 1 and type 2 diabetes patients Tight glycemic control is difficult to achieve FPG and PPG levels contribute to glycemic control Evidence suggests that therapeutically targeting postprandial hyperglycemia may be beneficial Improves overall glycemic control Questions remain as to unique benefit in preventing complications