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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
The VADT (Veterans Affairs Diabetes Trial): Further Evidence on the Question of Glucose Control and Vascular Complications in Type 2 Diabetes
Chantal Mathieu |
Click here to download PowerPoint slides of this commentary. |
Background
Like numerous clinical trials before it, the Veterans Affairs Diabetes Trial (VADT) sought evidence relevant to the question, can intensive control of blood glucose reduce cardiovascular events in individuals with Type 2 diabetes? The question follows logically on epidemiological evidence of a direct relationship between higher glycaemic levels and higher cardiovascular risk, even in the absence of frank diabetes (Barr et al, 2007; Port et al, 2006; Selvin et al, 2005). However, the relationship between intensive glucose control and cardiovascular risk has been harder to define. The intervention trials that have explored it offer insights on aspects of the question but not a full or consistent answer.
For example, we learned from the Steno-2 Study that intensive glycaemic control aimed at a glycated haemoglobin (HbA1c) of <6.5 %, as part of a multi-factor intervention strategy, resulted in a 53% reduction in cardiovascular risk in individuals with diabetes and microalbuminuria (Gæde et al, 2003). The difference has widened over time (Gæde et al, 2008). We found from the United Kingdom Prospective Diabetes Study (UKPDS) that intensive glycaemic control begun early after diabetes diagnosis and targeting an HbA1c <7 % showed delayed cardiovascular benefits 10 years after the trial, whether or not intensive control had been maintained post-trial (Holman et al, 2008; UKPDS, 1998). We also learned from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial that intensive therapy targeting an HbA1c <6 % in a population with diabetes and pre-existing cardiovascular disease was associated with increased mortality over an average of 3.5 years (ACCORD, 2008). A more consistent finding in the use of intensive therapy has been an excess risk of hypoglycaemic episodes.
The VADT offers helpful new information on the vascular therapeutic potential of intensive glycaemic control. The information, gleaned from a population of individuals, chiefly men, with poorly controlled and long-standing Type 2 diabetes, is particularly relevant to questions about the timing of initiation of intensive therapy, the intensity of HbA1c targets, the timing of anticipated benefits, and the safety of therapy.
Methods and Key Results
Enrollment in the VADT took place between December 1, 2000, and May 30, 2003. The patient population consisted of 1791 military veterans (1739 men, 52 women; mean age, 60.4 years) with Type 2 diabetes for a mean of 11.5 years. Their baseline HbA1c levels averaged 9.4 % despite maximum doses of oral anti-diabetic agents or insulin therapy. Forty percent of the participants had already had a cardiovascular event but not in the 6 months prior to enrollment, and no participants had advanced congestive heart failure or severe angina. Body mass index (BMI) for the group averaged 31.3 kg/m2.
The VADT participants were randomized to standard or intensive glucose control, with BMI determining the initial treatment regimen regardless of assigned group. Accordingly, all individuals with a BMI ≥27 kg/m2 began with metformin plus rosiglitazone, while all with a BMI <27 kg/m2 began with glimepiride plus rosiglitazone. However, half-maximum doses were used for the standard group and maximum doses for the intensive group. Insulin was added if these oral drug doses did not achieve an HbA1c <9 % in the standard group or <6 % in the intensive group; later adjustments to therapy were made at the discretion of the investigator. All individuals received aspirin, statin therapy, lifestyle therapy, diabetes education, and treatment for other risk factors as recommended by current and updated guidelines of the American Diabetes Association (ADA).
The primary outcome during follow-up was time to first occurrence of a major cardiovascular event—a composite of myocardial infarction, stroke, cardiovascular death, congestive heart failure, cardiac or vascular surgery, inoperable coronary artery disease, or amputation. Microvascular end points were ophthalmological disorders (retinopathy, cataract surgery, vitrectomy, photocoagulation), severe nephropathy, and new neuropathy.
The median follow-up was 5.6 years, during which these outcomes were observed:
- A stable median HbA1c of 8.4 % with standard therapy and 6.9 % with intensive therapy
- No significant differences between groups in time to first cardiovascular event (hazard ratio for intensive therapy, 0.88; 95% confidence interval, 0.74 to 1.05, P=0.14)
- Significantly more sudden deaths with intensive (11) than with standard (4) therapy (P=0.08)
- No significant differences between groups in microvascular complications except worsening albuminuria, which occurred in significantly more individuals with standard (6.6%) than with intensive (4.1%) therapy (P=0.05)
- Significantly greater increases in weight and BMI with intensive versus standard therapy (P=0.01)
- Significantly more hypoglycaemic episodes with intensive (1566) versus standard (432) therapy (P<0.001)
- Similar improvements between treatment groups in blood pressure and lipid levels
In summary, intensive glucose control over a median period of 5.6 years did not improve macrovascular or microvascular outcomes in the VADT population of individuals with advanced diabetes. It was associated with weight gain and increased risk of hypoglycaemic episodes.
Clinical Implications
In its findings on lack of vascular benefits and increased hypoglycaemic risk, the VADT suggests that late, relatively short-term use of intensive glycaemic control has little to add in the way of cardiovascular benefits to individuals with poorly controlled, advanced diabetes. We might consider, as the VADT investigators did in their discussion, whether initiation of glycaemic control earlier in the course of diabetes, along with avoidance of severe hypoglycaemia, might prove beneficial for this group. The Steno-2 Study and UKPDS give strong support to a strategy of early and long-term intensive control, but one that is also aimed at more moderate glycaemic goals than that attempted in the VADT (HbA1c<6 %) . This aggressive goal was also established in the ACCORD trial (HbA1c<6 %), which reported increased risk for both cardiovascular events and hypoglycaemia. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial targeted an HbA1c ≤6.5 % in a high cardiovascular risk population; after a median of 5 years of follow-up, evidence of vascular benefit had emerged chiefly via reduced nephropathy. ADVANCE also found significantly higher rates of hypoglycaemia with intensive therapy (ADVANCE, 2008).
At this point in research progress, evidence continues to indicate that vascular effects and particularly cardiovascular effects of intensive glycaemic control take time to evolve and will yield the most in benefits if begun early in the course of diabetes. This general statement needs further evidence to help refine it and to better characterize the groups whose potential gains outweigh the potential risks of intensive glycaemic goals. The impact of glycaemic control in the presence of other risk factor therapies, such as blood pressure and lipid control, lifestyle therapy, and aspirin therapy, is a subject that also merits much further study. Optimization of vascular protection depends on our full understanding of each therapy alone and in combination.
This Website Feature is funded by an educational grant from Bristol-Myers Squibb/AstraZeneca.
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