Monday March 15 2010
Valsartan and nateglinide are approved diabetes drugs
“Two key treatments do not halt diabetes in people with early signs of the disease,” BBC News reported. The story is based on a large trial assessing the effects of two approved diabetes medications, valsartan and nateglinide, on the development of diabetes and cardiovascular disease in high-risk populations.
As BBC News reports, the results indicate that neither drug reduced the risk of cardiovascular disease, and there was only a small reduction in the risk of diabetes with valsartan. This trial was in people showing an early warning sign for diabetes, not in people with the disease. Anyone taking these drugs should not change their treatment on the basis of this study.
There is good evidence that changing diet and exercise are the best ways of reducing the risk of diabetes in those with raised glucose levels, an early indicator of the condition. Systematic reviews in high risk populations have shown that a change in physical activity and diet could reduce the number of new diabetes cases by about 37%. In comparison, this trial found that valsartan reduced diabetes by only 14%.
Where did the story come from?
The study was carried out by the NAVIGATOR study group, consisting of a number of researchers with affiliations to various research and medical institutions in the UK and around the world. The study was funded by Novartis Pharma, the manufacturer of both drugs trialled in this research. The papers were published in the (peer-reviewed) New England Journal of Medicine.
This large randomised controlled trial in people with impaired glucose tolerance across 40 countries was accurately described by BBC News. The results of the study are published as two separate papers in the medical journal, one for each drug.
What kind of research was this?
The NAVIGATOR study (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) is a large, double-blind, randomised-controlled trial. This research investigated whether two drugs, nateglinide (a diabetes treatment) and valsartan (a blood pressure treatment) could lower the risk of developing diabetes or new cardiovascular events in people at higher risk of these conditions. Both drugs were used in combination with a lifestyle-modification programme.
Specifically, the participants had impaired glucose tolerance (where the concentration of glucose in the blood soon after drinking a glucose drink is raised) and had known cardiovascular disease or cardiovascular risk factors. Previous research suggests that impaired glucose tolerance is an early warning sign for the later development of diabetes and is linked closely with cardiovascular risk, more so than the level of blood glucose after fasting. The means that impaired glucose tolerance may be a distinct target for therapies to prevent diabetes.
What did the research involve?
The researchers recruited 9,306 participants from 806 centres in 40 countries. All had impaired glucose tolerance and one or more cardiovascular risk factors or known cardiovascular disease. The participants were randomised to receive just nateglinide (up to 60mg three times a day), just valsartan (up to 160mg a day), both drugs, or a placebo.
All participants were also given a lifestyle-modification programme aimed at helping them to achieve and maintain 5% weight loss, to reduce their intake of saturated and total dietary fat and to increase their physical activity to 150 minutes a week. Patients were seen every six months for the first three years and then annually for a total of about six-and-a-half years. During each study visit, the participants’ fasting plasma glucose levels were measured. Oral glucose tolerance tests were performed annually.
The main outcomes of interest were the number of people who developed diabetes and the number who experienced events related to cardiovascular health. There were two cardiovascular endpoints, a “composite cardiovascular” outcome (nonfatal myocardial infarction, nonfatal stroke, hospitalisation for heart failure or unstable angina or arterial revascularisation) and a “core cardiovascular” outcome (death from a cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure).
Two papers based on this research have been published. The first looks at the effects of nateglinide (with or without valsartan) compared to placebo (with or without valsartan). The second compared the effects of valsartan (with or without nateglinide) with placebo (with or without nateglinide). The researchers also broke down their analysis by a variety of factors including gender and levels of fasting glucose, to see whether there were any particular differences between subgroups.
What were the basic results?
The groups were broadly similar at baseline (beginning of the study) to each other on a range of characteristics, as expected in a properly randomised study. There were 1,532 (33%) people in the valsartan group (with or without nateglinide) who developed diabetes, compared with 1,722 (37%) with placebo (with or without nateglinide). This indicated a significant 14% reduction in the risk of diabetes (Hazard Ratio (HR) 0.86, 95% Confidence Interval (CI) 0.80 to 0.92).
The ‘composite cardiovascular’ outcome occurred in 672 people (15%) in the valsartan group and 693 people (15%) in the placebo group, while the core cardiovascular outcome occurred in 8% of people in both groups. Statistical tests show the drugs had no significant effect on the risk of having either a composite or core cardiovascular event.
In people taking nateglinide (with or without valsartan), 1,674 (36%) developed diabetes compared to 1,580 (34%) of people receiving a placebo (with or without valsartan). This represented a non-significant increased risk of diabetes with treatment (HR 1.07, 95% CI 1.00 to 1.15).
For cardiovascular events, 658 people (14%) experienced a composite cardiovascular event in the nateglinide group (with or without valsartan), compared with 707 (15%) in the placebo group (with or without valsartan). This represents a non-significant change in risk (HR 0.93, 95% CI 0.83 to 1.03). About 8% in each group experienced the core cardiovascular outcome (no significant difference between the groups). More patients in the neteglinide group reported hypoglycaemia.
How did the researchers interpret the results?
When combined with a lifestyle intervention, valsartan at a daily dose of 160mg reduced the risk of diabetes but did not affect cardiovascular outcomes in patients with impaired glucose tolerance. The researchers say that no safety concerns were identified.
They conclude that nateglinide did not reduce the incidence of diabetes or cardiovascular outcomes for people with impaired glucose tolerance and cardiovascular disease or cardiovascular risk factors, compared with placebo. The drug was given at a dose of 60mg, three times a day, and was combined with a lifestyle-modification programme.
Overall, this large, industry-funded study found that nateglinide had no effect on the incidence of diabetes or cardiovascular disease in this population and that valsartan had a small effect on diabetes risk but not on cardiovascular outcomes.
This was well-conducted research and used the most robust study design for comparing the effectiveness of one treatment with another. There are some points to highlight, including the fact that 20% of participants in each trial arm dropped out of the study (they either withdrew their participation, died or were lost in the follow-up). Other important points relating to the research and its interpretation are raised in an accompanying editorial in the journal, written by Dr. David Nathan from the Diabetes Centre at Harvard Medical School.
The main aim of the trial was to determine whether using nateglinide or valsartan to lower glucose could reduce the risk of diabetes and cardiovascular outcomes in high-risk individuals when used in combination with a lifestyle-modification programme.
However, Dr Nathan explains that the study was not able to answer this question because the average glucose levels in the nateglinide group two hours after a glucose challenge were higher than in the placebo group in the annual oral glucose-tolerance tests. This is a paradoxical finding that the researchers have attempted to explain saying that it may be because the nateglinide was not administered on the mornings of the glucose tolerance tests (although there is no data to support this).
The editorial also says it is possible that the effects of the medications may have been masked by the large effects of the lifestyle intervention that all participants were receiving. The finding that valsartan did not affect cardiovascular outcomes is surprising and contradicts other research. It is possible that the high drop-out rates and the use of other medications in the placebo group may explain the lack of significance here.
Dr. Nathan concludes that these results do not support the theory that reducing postprandial hyperglycemia has a specific role in preventing diabetes or reducing cardiovascular disease. He says, “The prevention of diabetes remains a critical public health priority, but for now we should steer away from these two drugs and use effective lifestyle interventions and, in selected persons, metformin to combat the epidemic.”
This is sensible advice, as systematic reviews have shown a reduction of about 37% of new cases of diabetes with physical activity and diet for people whose profiles were similar to those in this trial. This compares with only 14% with the drug valsartan used in this trial.
Diet and exercise remain the most important way of reducing the risk of developing diabetes in those showing early signs of elevated glucose.