Control Mechanism
by Lisa Zamosky
July 2008
A rapidly increasing rate of type 2 diabetes has researchers scrambling for new interventions to combat the chronic condition.
Photography by
With almost 21 million Americans and 246 million people affected worldwide, type 2 diabetes is rapidly becoming a major threat to global public health. In fact, the World Health Organization (WHO) estimates that in less than 20 years, approximately 350 million people worldwide will suffer from type 2 diabetes, with the vast majority of new cases occurring in developing countries.
These numbers translate to an overwhelming health care expense. In the United States alone, the economic cost of type 2 diabetes reached US$174 billion in 2007, according to a report by the American Diabetes Association. A worldwide explosion of type 2 diabetes calls for increased attention to the development of treatment options aimed at gaining control over this chronic disease. A number of well-established and effective anti-diabetic medications exist on the market today, as do a number of novel therapies. But in the coming years, the need for increasingly effective and targeted treatments will continue to grow, as will the opportunity for biopharmaceutical companies to work toward developing medicines to reverse or slow the progression of the disease.
New Understanding, New Promise
Aside from insulin and a variety of pharmacological agents including biguanides, sulfonylureas and thiazolidinediones, new classes of drugs—namely DPP-4 inhibitors and incretin mimetics—have more recently come to market and shifted the approach and perspective of treatment for type 2 diabetes. “Not every insulin-resistant person becomes a diabetic,” says Dr. Alan J. Garber, professor of medicine, biochemistry and molecular biology and cellular molecular biology at Baylor College of Medicine in Houston, Texas, USA. “Only those who have the genetically required beta cell defect that produce diabetes [become diabetic]. And so now we are [reviewing] treatments that look at beta cells, the most promising of which are incretin-oriented therapies.”
Incretin hormones, which are produced by cells in the intestinal tract in response to food absorption, have been found to play a critical role in maintaining glucose control in the body. The production of incretins is an impaired function in a person with type 2 diabetes. The hormone glucagon-like peptide-1 (GLP-1) has been shown to lower glucose levels, but the hormone is quickly broken down in the bloodstream by the DPP-4 (dipepetidyl peptidase-4) enzyme. As a result, newer therapies have focused on enhancing the level of GLP-1 in the diabetic’s body, while offsetting the effect of DPP-4.
Research has shown that incretins improve the functioning of cell clusters in the pancreas that produce metabolic hormones. Among this cluster of cells are beta-cells, which are responsible for the production of insulin, and their breakdown and dysfunction has been shown to play a critical role in the development of type 2 diabetes.
“The DPP-4 inhibitors and the incretin mimetics are quite interesting because they seem to work in a more natural way in managing glycemia without increasing weight,” says Dr. Ameet Nathwani, global head for the cardiovascular, metabolism and atherosclerosis franchise at Novartis in Basel, Switzerland. They also have demonstrated some positive benefit in key areas such as lipid profile and blood pressure, he says.
Even with the great advance these innovative therapies are considered to represent in the treatment of type 2 diabetes, Nathwani points out that no single drug today is effective enough such that a patient only needs one drug. “Some drugs affect the beta cell and ideally you’d want one drug that affects both—that reduces insulin resistance and improves islet cell function but without the ancillary consequences of increase in weight, worsening blood pressure and worsening lipids.”
These newer incretin-based therapies improve beta cell function. Concurrently, there is a class of drugs known as insulin sensitizers, according to Nathwani, that are fantastic at reducing insulin resistance and very effective at reducing blood sugar. However, one of the consequences of the mode of action of these sensitizers is the resultant weight gain, he notes.
“As your insulin becomes more effective and your blood sugar drops, it needs to be stored somewhere, and it tends to be stored in fat, so you end up increasing your total body fat,” Nathwani says. “These new incretin targeted therapies are very good drugs because they don’t make you put on weight, they don’t give you the hypoglycemia that you see with other insulinotropic drugs, but they [also] don’t have a profound effect on reducing insulin resistance. So there’s still a gap for therapies that have an effect on both islet cell function and insulin resistance or have a wider effect on managing the pathophysiology.”
The Role of the Beta Cell
The United Kingdom Prospective Diabetes Study (UKPDS)—which began in 1977—examined blood glucose and blood pressure control and their impact on the development of complications in patients with type 2 diabetes. It has informed many of the underpinnings used for the development of today’s newer therapies as well as many currently under development. “Our understanding of the progressive nature of type 2 diabetes, which results from a worsening progressive beta cell defect, arises in large measure from the observations of the UKPDS,” Garber says.
According to Garber, the observations made during the course of the UKPDS, as well as a series of other observations about the progression of diabetic and pre-diabetic states, refocused the medical community’s attention back on the beta cell defect and away from insulin resistance.
Dr. David Moller, vice president of endocrine and cardiovascular research and clinical investigation with Eli Lilly and Company in Indianapolis, Ind., USA, points to numerous genome-wide association studies as a critical part of the growing body of knowledge about the role beta cells play in the development of type 2 diabetes. “Just in the last year the numerous genome-wide association studies that have been done on tens of thousands of type 2 diabetics have clearly shown that the genetic basis of type 2 diabetes is much more often involving beta cells and insulin secretory pathways than it is necessarily involving insulin signaling pathways or insulin resistance related pathways.”
It is this understanding of the underlying beta cell dysfunction—found to be involved in the development of type 2 diabetes—that has led to the development of the novel therapies that have most recently come to market and continue to be the focus of development within the drug industry. “Within the pharmaceutical industry, we’ve been following these trends very closely,” Moller acknowledges.
The Obesity Link
The science has been undeniable in pointing to the key role obesity plays in the development and exacerbation of type 2 diabetes. “We now understand that obesity not only leads to insulin resistance per se, but also leads to beta cell dysfunction,” Moller says. One possible explanation for this, according to Moller, is fatty acid accumulation in the beta cell that might arise as a consequence of obesity or inflammation.
Gaining control over the staggering numbers of type 2 diabetics and anticipated cases predicted for the future, as well as the related obesity epidemic, has the pharmaceutical industry engaged in a search for treatments aimed at preventing the development of type 2 diabetes by reducing body weight, which could be an effective means of staving off the future complications associated with prolonged type 2 diabetes.
“What we are looking at is even a small amount of weight, even 5 or 10 kilos (about 11 to 22 pounds),” Nathwani says. “If you lose the right amount of fat—the fat which is harmful in the abdomen—it could have a dramatic effect on your risk of developing diabetes, and a profound effect on preventing the accelerated cardiovascular disease seen in these high-risk individuals,” he adds. “So that’s the strategy many companies in the industry are looking at.”
Pre-Diabetes: Stopping the Snowball Effect
With more than 300 million people worldwide thought to have pre-diabetes, the issue of whether and how to treat this population with medication in an effort to prevent their entry into a full-blown diabetic state is a topic of heated discussion. To date, no medicines have been approved for the treatment of pre-diabetics (those with impaired fasting glucose levels or impaired glucose tolerance), although there have been a number of studies that assessed the feasibility of doing so. The largest study to date to address this question was The Diabetes Prevention Program (DPP), which demonstrated that the use of metformin reduced the risk of developing type 2 diabetes by 31 percent; compared to a reduction of 58 percent through a regimen of diet, exercise and behavior modification.
More recently, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, which looked at the use of rosiglitazone maleate (Avandia) in pre-diabetics, showed a reduction in the risk of developing diabetes by 62 percent. “Think about the downstream benefit to society if you could prevent diabetes,” says Dr. George Grunberger, a clinical professor at Wayne State University and chairman of the Grunberger Diabetes Research Institute in Detroit, Mich., USA.
Nathwani agrees, but adds a note of caution: “A diabetes diagnosis is based on glucose,” he says. “So if I take that drug, which lowers blood glucose, of course I’m going to delay the ability for blood glucose to reach a threshold definition at which diabetes is diagnosed. The bigger issue is: Has this delayed the downstream consequences sufficiently to justify being treated earlier and longer?”
Moller shares Nathwani’s concern. “If you put someone on a drug for a year or two who has pre-diabetes and you show their progression to diabetes is less than the placebo group, are you really preventing the diabetes or delaying it?” Moller is skeptical about the studies that have looked at treating patients identified as pre-diabetic: “If you stop the drug, do you just go back to the exact same curve that would have occurred prior to starting the drug? There are some unresolved issues in terms of how we define the outcome of this kind of trial in the future.”
Moller does say, however, that he believes drugs ultimately will have a role in managing pre-diabetes. “I think there will be drugs approved for that indication within the next five to 10 years,” he says.
Pharmacogenomics: Personalizing Diabetes Treatment
Targeted therapies for specific patient genotypes and the promise of personalized medicine are not yet a reality in diabetes treatment, but are undoubtedly on the horizon. “We now know there’s upward of 10 different gene defects associated with type 2 diabetes, and they tend to run in ethnic groups,” Garber says. He points out that the defects seen among various ethnic populations—Latinos, Asian and Europeans—are somewhat different from each other. “Interestingly enough,” he adds, “all of the gene-specific defects that we’ve noticed in terms of association with type 2 diabetes are all beta cell genes.”
According to Moller, most companies, including Lilly, are collecting samples for DNA for almost every trial they conduct, and have been measuring the presence or absence of polymorphisms in at least certain genes in their ongoing clinical studies. “I think probably within five years there will be more sophisticated—and probably in some cases genetic—tests that can be administered conveniently to determine who is a better candidate for certain therapies for diabetes as there is now for cancer,” Moller says.
Additional Approaches
The diabetes landscape seems poised for change, both in terms of the patient population and its expansion, as well as with regard to the developments underway in the drug industry to address this overwhelming threat to global public health. Therapies focusing on the beta cell function continue to offer new promise.
Lilly recently partnered with a small biotech company to explore the clinical utility of analogs of the hormone gastrin. “Their hypothesis is that the approach involving gastrin can stimulate beta cell regeneration in vivo,” Moller says. “Beta cells make insulin and this would attack one of the primary underlying defects in type 2 diabetes, which is a loss of functional beta cell mass. There is no therapy right now that has proven to have that kind of disease-modifying effect.”
According to Nathwani, Novartis is working on a number of approaches that look at the way that inflammation derived from the visceral fat cells affects the longevity and functioning of the beta cell, as well as drugs that lower blood sugar by managing the way that the body regulates fat. “We’re looking at a number of programs that explore the way one metabolizes fat, including the role of the muscle as an energy regulator,” he says. “There are ways to simulate that and really create a sort of a low-level background energy burn in the muscles.”
Moller points to another possible breakthrough over the next decade, which would be additional medications that don’t treat glucose alone, but treat the glucose and the additional cardiovascular risk factors that are associated with obesity and diabetes. The hope is that patients wouldn’t have to take four or five different medications at once, but rather could take one or two to address multiple aspects of the underlying pathogenesis, he says.
Following Januvia’s Footsteps
Experimental drugs from Bristol-Meyers Squibb, AstraZenca and Takeda may give type 2 diabetics effective alternatives to Januvia, the once-daily prescription pill developed by Merck & Co.
Januvia, which was launched in the United States in October 2006, has proved to effectively enhance the type 2 diabetic’s ability to naturally control blood sugar levels. Research presented at a recent American Diabetes Association meeting in San Francisco found that some of the experimental drugs from the aforementioned pharmaceutical companies reduced blood sugar levels just as effectively as Januvia with few side effects.
A recent 24-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III study of 401 people found that saxagliptin, a drug developed jointly by Bristol-Meyers Squibb and AstraZenca, produced significant reductions in key measures of glucose control such as glycosylated hemoglobin level and fasting plasma glucose. The medication’s effects were seen as early as four weeks into treatment, and more than one-third of patients receiving the medication reached the recommended blood sugar level of 7 percent or less by the end of the study. There were a few side effects, such as upper respiratory tract infections, headaches and runny nose. On the other hand, there were no confirmed cases of hypoglycemia or weight gain, which are concerns with previous medications.
Like Januvia, saxagliptin works by prompting the body to produce more insulin and less glucose. The companies are seeking U.S. Food and Drug Administration (FDA) approval for the drug later this year and, if approved, they intend to sell it under the trade name Onglyza.
Phase III studies conducted in over 2,000 patients in 220 centers worldwide found that Takeda’s alogliptin had a similar effect. The data revealed that alogliptin effectively reduced blood sugar in patients, whether taken alone or when used in combination with another oral treatment. Patients taking alogliptin, in addition to Takeda’s FDA-approved Actos—a once a day insulin sensitizer—had much lower glucose levels than those merely given a placebo.
When administered once daily, alogliptin demonstrated significant reductions in hemoglobin A1c. Experts predict that the approval of alogliptin could be crucial to diabetes research and ultimately help patients improve their blood glucose control.
Januvia, saxagliptin and alogliptin are DDP-4 inhibitors, a class of compounds that work by sparking the action of incretions. Incretions decrease glucose levels by increasing the body’s use of sugar and ultimately reducing the liver’s production of glucose.
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