1. In diabetics, does a HbA1cgoal of 7.0 vs. 6.5 result inless microvascular diseaseand all cause mortality? Daniel Wu
2. ADA Standards of Medical Care 2012 Goals should be individualized based on ○ duration of diabetes ○ age/life expectancy ○ comorbid conditions ○ known CVD or advanced microvascular complications ○ hypoglycemia unawareness ○ individual patient considerations More- or less-stringent glycemic goals may be appropriate for individual patients Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals
3. ADA Standards of Medical Care 2012 Lowering A1C to below or around 7% has been shown to reduce microvascular complications of diabetes, and if implemented soon after the diagnosis of diabetes is associated with long-term reduction in macrovascular disease. Therefore, a reasonable A1C goal for many nonpregnant adults is <7%. (B) Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, long life expectancy, and no significant CVD. (C)
4. AACE Guidelines for Diabetes Plan 2011 Glucose targets should be individualized and take into account residual life expectancy, duration of disease, presence or absence of microvascular and macrovascular complications, CVD risk factors, comorbid conditions risk for severe hypoglycemia. Glucose targets should also be formulated in the context of the patient’s psychological, social, and economic status
5. AACE Guidelines for Diabetes Plan 2011 In general, therapy should target a A1C level of 6.5% or less for most nonpregnant adults, if it can be achieved safely. In certain patients, a less stringent goal may be considered (A1C 7%-8%). Such individuals as those with history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing DM in which the general goal has been difficult to attain despite intensive efforts
6. Same Evidence BaseDiabetes Control and Complications Trial (1993)U.K. Prospective Diabetes Study(2000)
7. Diabetes Control and Complications Trial Will intensive therapy prevent the development of diabetic retinopathy in patients with no retinopathy (primary prevention) Will intensive therapy affect the progression of early retinopathy (secondary intervention)? Retinopathy was the principal study outcome, but they also studied renal, neurologic, cardiovascular, and neuropsychological outcomes and the adverse effects of the two treatment regimens.
8. Eligibility Criteria The major criteria for eligibility included insulin dependence, as evidenced by deficient C-peptide secretion; an age of 13 to 39 years absence of hypertension absence of hypercholesterolemia absence of severe diabetic complications or medical conditions
9. Therapy Conventional therapy consisted of one or two daily injections of insulin, including mixed intermediate and rapid-acting insulins, daily self-monitoring of urine or blood glucose, and education about diet and exercise Intensive therapy included the administration of insulin three or more times daily by injection or an external pump. The dosage was adjusted according to the results of self-monitoring of blood glucose performed at least four times per day, dietary intake, and anticipated exercise. The goals of intensive therapy included preprandial blood glucose concentrations between 70 and 120 mg per deciliter (3.9 and 6.7 mmol per liter), postprandial concentrations of less than 180 mg per deciliter (10 mmol per liter), a weekly 3-a.m. measurement greater than 65 mg per deciliter (3.6 mmol per liter), and hemoglobin A1c (glycosylated hemoglobin), measured monthly, within the normal range (less than 6.05 percent).
10. A1c Levels
11. Differences in Intervention Outcomes: Retinopathy in Cohorts
12. Differences in Intervention Outcomes
13. Rate of Progression of Retinopathy vs. Rate of Severe Hypoglycemia
14. U.K. Prospective Diabetes Trial To determine the relation between exposure to glycemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation).
15. Participants The 3867 patients who had fasting plasma glucose concentrations between 6.1 and 15.0 mmol/l and no symptoms of hyperglycemia were randomized to a policy of conventional glucose control, primarily with diet, or to an intensive policy with sulfonylurea or insulin.
18. ACCORD Trial: Glycemic Control Investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%).
19. HbA1c Levels Achieved
20. Primary Outcomes This trend was not significant, with rates of 6.9% in the intensive-therapy group and 7.2% in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16)
21. All Cause Mortality The rate of death from any cause was higher in the intensive-therapy group than in the standard-therapy group (5.0% vs. 4.0%; hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04).
22. Cessation of Study The finding of higher mortality in the intensive-therapy group led to a decision to terminate the intensive regimen in February 2008, 17 months before the scheduled end of the study. Rates of death in the two study groups began to separate after 1 year, and the differences persisted throughout the follow-up period. The effect on mortality was consistent within the subgroups with no evidence of heterogeneity and persisted in models adjusting for differences in the receipt of medications for blood pressure and lipids.
23. Adverse Events
24. Analysis of the ACCORD Trial The prespecified composite outcomes were dialysis or renal transplantation high serum creatinine (>291.7 μmol/L) or retinal photocoagulation or vitrectomy (first composite outcome) or peripheral neuropathy plus the first composite outcome (second composite outcome)
25. Primary Composite OutcomesFaramarz Ismail-Beigi , Timothy Craven , Mary Ann Banerji , Jan Basile , Jorge Calles , Robert M Cohen , Robert C...Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORDrandomised trialThe Lancet Volume 376, Issue 9739 2010 419 - 430http://dx.doi.org/10.1016/S0140-6736(10)60576-4
26. All Microvascular Outcomes
27. Analysis of the ACCORD Trial The primary composite outcome of advanced nephropathy and diabetic eye complications did not differ between groups at transition or at study end. The second composite endpoint, which added a peripheral neuropathy outcome to the primary composite outcome, also did not differ at transition or at study end. Intensive glycemia therapy led to a 21% reduction in development of microalbuminuria at transition and this effect was attenuated (15%) but remained significant at study end. Incidence of macroalbuminuria was reduced in the intensive group compared with the standard group at transition and at study end.
28. Changes to ADA Recommendations Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. (C) Less stringent A1C goals (such as <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. (B)
29. Conclusions from Studies DCCT Intensive therapy of patients delays the onset and slows the progression of clinically important retinopathy, including vision- threatening lesions, nephropathy, and neuropathy, by a range of 35 to more than 70 percent. Because of the risk of hypoglycemia, intensive therapy should be implemented with caution, especially in patients with repeated severe hypoglycemia or unawareness of hypoglycemia. UKPDS No threshold of glycemia was observed for a substantive change in risk for any of the clinical outcomes examined The lower the glycemia the lower the risk of complications Suggests that there is no specific target value of hemoglobin A1c for which one should aim but that the nearer to normal the hemoglobin A1c concentration the better.
30. Conclusions from Studies ACCORD No significant effect of intensive glycemia therapy on the two prespecified composite microvascular outcomes—1) advanced renal or eye complications, or 2) these two outcomes or peripheral neuropathy. The beneficial effects of intensive therapy on surrogate secondary microvascular outcomes compared with standard therapy should be balanced against observed risks. Therapeutic strategy targeting HbA1c levels of 6.0% increased the rate of all cause death as compared with a target level of 7.0 to 7.9%.
31. Recommendation for Patient Target level for HbA1c of 7.0% Long duration of diabetes and significant CVD- rules out the criteria for possible intensive management Side effects of intensive therapy: weight gain, fluid retention, and hypoglycemia Benefit of decreased micro- and macroalbuminuria does not outweigh the side effects of intensive therapy Target of 7.0% has a significantly lower risk of all cause death General goal of attaining the 7.0% is difficult for many patients and is reasonable to reduce microvascular disease and all cause death
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