The next question for industry to answer is more complex: What are the effects of using cardiovascular and diabetes drugs
to prevent or treat heart disease and diabetes? Several clinical trials are already underway to answer that. Three of the
most prominent are:
DREAM. In November 2000, GSK and Aventis announced the Diabetes Reduction Approaches with Ramipril (Altace) and Rosiglitazone (Avandia)
Medications (DREAM) study. The 4,000-patient trial builds on two earlier studies: TRIPOD and a subgroup analysis done in HOPE
(Heart Outcomes Prevention Evaluation), which found that Altace reduced the number of patient self-reported cases of diabetes
by 34 percent.
NAVIGATOR. Launched in September 2001, Novartis' Nateglinide (Starlix) and Valsartan (Diovan) in Impaired Glucose Tolerance Outcome
Research study is designed to determine whether long-term administration of either drug can reduce or delay the development
of type 2 diabetes and cardiovascular disease in individuals with impaired glucose tolerance and at increased risk for CVD.
It is the largest diabetes prevention trial ever, with more than 7,500 patients in 40 countries.
BARI 2D. The University of Pittsburgh Graduate School of Public Health, with funding from Bristol-Myers Squibb, GSK, and several public
institutions, is conducting the Bypass Angioplasty Revascularization Investigation 2 Diabetes study to determine whether,
in patients with type 2 diabetes, initial treatment with angioplasty or bypass surgery is better than initial treatment with
a medical program. At the same time,
BARI 2D will compare two approaches to control blood sugar: providing insulin-stimulating medication or providing medication
that sensitizes the body to the available insulin.
Right now, thiazolidinediones (TZDs) have garnered the most interest because they work by decreasing insulin resistance. Handelsman
says that TZD drugs are being studied for their roles in a variety of other conditions, including congestive heart failure,
polycystic ovary syndrome, and liver disease.
However, various medical societies have cautioned against the prophylactic use of type 2 diabetes drugs because of a problematic
side effect. Buse says that in animal studies in which those agents were used to prevent diabetes "the mice became massively
fat." In addition, European physicians only use TZDs as a last line therapy among type 2 diabetics because the class is associated
So, thought leaders are looking to other drugs to find effective therapies without the side effects. "It's more than just
diabetes drug makers that are interested-it's across the board," says Handelsman. "Gerald Reaven and I were laughing that
some of the obesity drug makers are shy in coming on board [to sponsor the World Congress on the Insulin Resistance Syndrome]
because not everyone with insulin resistance is obese. Yet 80 percent of obese patients have it. So we push forward for obesity
research and treatment."
Based on positive results of the XENDOS trial, Roche will again try to pursue an indication of prevention of type 2 diabetes
through promotion of weight loss with Xenical. Obesity products seem promising to treat metabolic syndrome because they have
a short-term effect of weight loss, as well as longer-term benefits. Pfizer and Amgen have Phase II and III obesity products
in the pipeline that not only aim to treat obesity, but also type 2 diabetes.
However, it remains to be seen how angiotensin II-receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors,
and statins fit in. "Type 2 diabetes patients often get a statin because people recognize that they are likely to eventually
die of a heart attack," says Buse. "There's less evidence that ACE inhibitors, ARBs, and statins reduce the risk of developing
type 2 diabetes."
However, clinical trials are underway. Olsson says AstraZeneca is testing its statin Crestor (rosuvastatin) in the metabolic
Kos Pharmaceuticals also has a few promising treatments. "We have shown in recent trials that Niaspan (niacin) and Advicor
(niacin/lovastatin) can be safely used in patients with diabetes with a minimal impact on blood glucose," says McGovern, "and
they have tremendous benefits in terms of raising HDL and lowering triglycerides." Kos researchers will present a paper on
the use of Advicor for metabolic syndrome at the American College of Cardiology meetings in March.
One of the most promising developments is perioxisome proliferator-activated receptor (PPAR) products. In this era of highly
specific therapies, this is one class of drugs that target multiple risk factors and treat underlying insulin resistance and
lipid abnormalities, thereby reducing the risk of developing both CVD and type 2 diabetes. And they reduce the number of pills
patients must take.
The front-runner for that class, Merck and Kyorin's Phase III compound MK-767, was pulled in late November 2003 because of
toxicity issues. Other promising compounds include AstraZeneca's Galida (tesaglitazar), a dual PPAR agonist, which is in phase
III development. AstraZeneca
estimates it will file its MAA and NDA in 2006.
"Pharma companies are running for this market," says Ajit Baid, manager of Frost & Sullivan's pharmaceuticals group. After
all, the metabolic syndrome patient population encompasses feeder markets that are massive in their own right, including patients
with type 2 diabetes and CVD.
But most patients are asymptomatic. And many would respond well to lifestyle changes. Finding pharma's niche in a massive,
prevention-oriented campaign against metabolic syndrome won't necessarily be easy.
Already, some critics complain that the syndrome is simply the industry's effort to medicalize obesity. "Pharma companies
understand the potential market, so they are trying to bring some light to it and push their products towards it," says Nikolaos
Karachalias, Datamonitor senior endocrinology specialist.
"It is being medicalized-but not just by the pharma companies," says Buse. "The American Diabetes Association is also doing
so by giving it a name and calling it a risk marker. Although there are some overweight people who don't have the syndrome,
obesity is, in essence, the problem."
First, pharma companies must harness clinical evidence to show physicians the benefits of using pharmacologic therapy to prevent
patients from developing CVD and type 2 diabetes. In addition, there's a need for longer-term trials that address safety,
morbidity, and mortality outcomes, according to Jeremy Quirk, PhD, MBA, a cardiovascular analyst for Decision Resources.
In the short run, the key to unlocking the potential of the metabolic syndrome market may lie in the establishment of a "pre-diabetic"
state. The diagnostic criteria are already in place. In fact, Nesto says that the ATP III diagnostic criteria make it easier
to diagnose metabolic syndrome than using the Framingham risk score for coronary disease. However, in a society in which even
hypertension is undertreated, companies face a formidable challenge in moving physicians to think about treating patients
10 or 15 years before they get sick.
"Physicians are wary of defining 35-year-olds who work in an office and don't exercise enough as a target for receiving drugs
for the rest of their life," says Quirk. "Especially when they may or may not develop a disease in the future and when the
agents have side effects. Physicians are saying 'Show me the evidence.'
Because without it, why would physicians prescribe massively expensive drugs to a patient who appears healthy, when they can
just tell them to exercise three times a week?"