Results of two large clinical trials presented at the American College of Cardiology’s 59th annual scientific session in Atlanta, US have failed to deliver breakthrough approaches to cardiovascular disease risk in people with diabetes.

The ACCORD and NAVIGATOR trial data were published simultaneously online in the New England Journal of Medicine. The ACCORD trial did suggest that lowering systolic blood pressure to below standard levels in high-risk adults with type 2 diabetes could significantly lower the risk of stroke. And in the NAVIGATOR trial, Novartis’ antihypertensive Diovan (valsartan) did have a moderate effect on staving off diabetes progression.

Taken overall, though, the results of the two studies look unlikely to have a major impact on current treatment recommendations addressing the relationship between diabetes and heart disease.

The multicentre ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, which was sponsored by the US National Institutes of Health (NIH), looked at three potential strategies to lower the risk of major cardiovascular events in 10,251 adults between the ages of 40 and 79 years who had had type 2 diabetes for an average of 10 years and were at particularly high risk of cardiovascular events (e.g., due to pre-existing cardiovascular disease).

The three strategies were intensive control of blood sugar; intensive control of blood pressure; and multiple control of blood lipids – specifically, HDL cholesterol and triglycerides, in addition to standard therapy aimed at lowering LDL cholesterol. The results of the ACCORD blood sugar study were reported in 2008.

In the blood pressure arm, a variety of existing antihypertensives were used to achieve target systolic blood pressure of either less than 120 mmHg (intensive group) or less than 140 mmHg (standard group) in 4,733 randomised participants with elevated blood pressure levels.

Systolic blood pressure of below 120 mmHg is considered normal, while current guidelines recommend that adults with type 2 diabetes maintain systolic blood pressure at less than 130 mmHg. Observational studies have linked systolic blood pressure levels of 120 mmHg or less to lower cardiovascular disease rates in adults with type 2 diabetes.

In the ACCORD trial, though, the researchers found no significant differences after an average five years’ follow-up between the intensive group and the standard group in the incidence of a combined endpoint that included non-fatal heart attack, non-fatal stroke and cardiovascular death. There were 208 cardiovascular events in the intensive group and 237 in the standard group.

Lowering blood pressure to below the standard level did cut the risk of stroke by around 40% (36 strokes in the intensive group versus 62 in the standard group). However, participants in the intensive group were more likely to have complications such as abnormally low blood pressure or high levels of blood potassium, and some laboratory measures of kidney function were worse in the intensive therapy group.

Lipid trial

The ACCORD lipid trial was the first large study to compare the cardiovascular effects of a statin (simvastatin) plus placebo with combination therapy consisting of a statin (simvastatin) and a fibrate (fenofibrate – Abbott’s Tricor) in high-risk adults with type 2 diabetes. The study involved 5,518 participants in total.

The outcome was that the combination therapy was found to be safe overall but did not significantly lower the risk of heart attack, stroke or death from cardiovascular disease any more than a statin alone.

However, rates of cardiovascular events were 31% lower in a subgroup of participants – 17% of the total – who started the trial with the lowest levels of HDL cholesterol and the highest level of triglycerides, although more research is needed to explore this effect, said the NIH’s National Heart, Lung and Blood Institute.

According to Abbott, the results of the ACCORD study Lipid “were widely expected and not surprising given that two-thirds of patients in the trial would not be treated with fibrates under current guidelines”.
The average triglyceride level of a patient that starting on fenofibrate in the US is 302 mg/dL, while the median level in the ACCORD lipid trial was 162 mg/dL, the company pointed out, adding: “The subgroup of patients in this study with triglycerides at or above 204 mg/dL reflects real-world fibrate usage”.

NAVIGATOR results

The 9,306-patient NAVIGATOR trial, conducted at nearly 800 sites in 39 countries, had a ‘two-by-two factorial’ design whereby participants were randomised to valsartan; nateglinide – Novartis’ Starlix, indicated for improving glycaemic control in adults with type 2 diabetes; valsartan and nateglinide together; or placebo.

The participants had impaired glucose tolerance (IGT), a common pre-diabetic condition, and were either over 50 years old with diagnosed cardiovascular disease or over 55 with at least one risk factor for cardiovascular disease (e.g., high blood pressure, high cholesterol). The median follow-up time was 6.5 years.

The trial had three co-primary endpoints: confirmed progression to overt diabetes; a ‘core’ cardiovascular endpoint that was a composite of time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure; and an ‘extended’ cardiovascular endpoint comprising the core cardiovascular endpoint plus revascularisation and hospitalisation for unstable angina.

Patients given valsartan for at least five years in addition to background therapy and a lifestyle modification programme achieved a statistically significant 14% reduction in their risk of developing new-onset diabetes compared with participants in the non-valsartan group. This equated to 38 fewer cases of diabetes per 1,000 patients treated with valsartan for five years.

But valsartan did not show any significant impact on cardiovascular outcomes, while nateglinide-based therapy did not reduce the incidence of new-onset diabetes, nor did it have a significant effect on cardiovascular events in the study population. Diabetes developed in 36% (1,674 patients) of the nateglinide group and in 34% (1,580) of the placebo group.

“This is a sobering confirmation of the need to continue to focus on lifestyle improvements while also accelerating the efforts to develop new treatments for the exploding epidemics of diabetes and cardiovascular disease around the world, commented Dr Robert Califf, vice chancellor for clinical research at Duke University School of Medicine in the US and co-presenter of the NAVIGATOR trial results.

However, Novartis said it was “very pleased with the findings of the NAVIGATOR study as they add to the large body of information on valsartan”. The company plans to discuss the results with the US Food and Drug Administration, “with a view to applying for a label change for valsartan”. Neither valsartan nor nateglinide is currently indicated for the treatment of patients with IGT.