Version 4.0 <strong>VA</strong>/<strong>DoD</strong> <strong>Clinical</strong> <strong>Practice</strong> <strong>Guideline</strong> for the Management of Diabetes Mellitus microvascular complications was directly linear, with each 1.0% (absolute) reduction in mean HbA 1 c associated with a 37% decline in microvascular complications, as measured by reduced rates of laser therapy and cataract surgery. Long-term follow-up (for about 10 years) of the DCCT (aka EDIC) and UKPDS cohorts demonstrated that tight control early in the course of type 1 <strong>DM</strong> and type 2 <strong>DM</strong>, respectively, was strongly associated with a reduction in complications. This was true even though the HbA 1 c level of the original intensive and control treatment groups became indistinguishable (about 8%) after the termination of the original randomized trial. Macrovascular Complications The relationship between improved glycemic control and macrovascular complications is less clear-cut. Early studies, such as that by Gaede et al. (2003), demonstrated a relationship between improved glycemic control and reduced cardiovascular disease (CVD) events. A relationship between glycemic control and CVD risk was also supported by the UKPDS; each 1% reduction in HbA 1 c resulted in a 14% lower rate of myocardial infarction (MI) and fewer deaths from diabetes or any cause (UKPDS 33). However, such studies were criticized because they employed multiple pharmacologic agents that simultaneously targeted multiple risk factors (hyperglycemia, hypertension, dyslipidemia, and microalbuminuria) and were therefore not able to isolate the impact of strict glycemic control on macrovascular complications. More recently, Nathan et al. (2005) published evidence that improved glycemic control reduced the risk of CVD in patients with type 1 <strong>DM</strong>. Over 11 years, the risk of CVD morbidity and mortality was reduced by 42 to 57% in the intensive insulin therapy group). Unfortunately, large randomized controlled trials have failed to show similar benefit for people with type 2 <strong>DM</strong> (AD<strong>VA</strong>NCE,2008; ACCORD,2008; <strong>VA</strong>DT,2009). Risks of Intensive Management In some circumstances, aggressive management of glycemic control may cause frank harm. This is particularly true for patients with type 2 <strong>DM</strong> treated with insulin. • Data from the DCCT showed that the risk of severe hypoglycemia in patients with type 1 <strong>DM</strong> was three times higher in the intensive treatment arm (DCCT, 1993). • Aggressive management of patients with type 2 <strong>DM</strong> enrolled in the ACCORD trial was halted after a mean 3.5 years of follow-up because of safety concerns. The incidence of death was 11 per 1000 per year in the conventional treatment group (median achieved A1C of 7.5%) vs. 14 per 1000 per year in the intensive treatment group (median achieved HbA 1 c of 6.4%). Furthermore, intensive treatment was also associated with a significantly higher risk of severe hypoglycemia requiring medical assistance (3.1% in the intensive treatment group vs. 1.4% in the conventional treatment group) and weight gain. • Post hoc analyses of the ACCORD study (Bonds et al., <strong>2010</strong>) reported an association of serious hypoglycemia with mortality that was weaker in the intensive group than in the standard group (HR 1.28 versus 2.87). • In the AD<strong>VA</strong>NCE trial (2008), although intensive treatment (median achieved HbA 1 c of 6.5%) decreased nephropathy by 21%, weight gain and severe hypoglycemia occurred more frequently than in the conventionally treated group (median achieved HbA 1 c of 6.5%). At least one large RCT (Gerstein et al., 2008), has produced higher mortality rates. • Identification of the clinical characteristics that are associated with hypoglycemia, cardiovascular events and death are currently under investigation by ACCORD, <strong>VA</strong>DT, and AD<strong>VA</strong>NCE investigators. Risk Stratification Given these considerations, the Working Group advocates an individualized approach based on the patient's absolute risk for developing microvascular complications balanced against known co-morbidities, projected life expectancy, presence or absence of pre-existing microvascular complications, the risk of polypharmacy with attendant drug-drug interactions, exposure to medications with limited post-marketing experience, the risk of and ability to perceive hypoglycemia, and patient preference. Recommendations for determining HbA1c target range are summarized in the Table G-1: Module G: Glycemic Control Page 47
Version 4.0 Table G-1. Determination of Target HbA 1 c Level (1) (2) <strong>VA</strong>/<strong>DoD</strong> <strong>Clinical</strong> <strong>Practice</strong> <strong>Guideline</strong> for the Management of Diabetes Mellitus Major Comorbidity (d) or Physiologic Age Absent >10 years of life expectancy Present (e) 5 to 10 years of life expectancy Marked (f)
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