DM Full Guideline (2010) - VA/DoD Clinical Practice Guidelines Home

Version 4.0
VA/DoD Clinical Practice Guideline
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 DM and type 2 DM, 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 DM. 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 DM (ADVANCE,2008; ACCORD,2008; VADT,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 DM treated with insulin.
• Data from the DCCT showed that the risk of severe hypoglycemia in patients with type 1 DM was three
times higher in the intensive treatment arm (DCCT, 1993).
• Aggressive management of patients with type 2 DM 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., 2010) 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 ADVANCE 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, VADT, and ADVANCE 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