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Two new drugs have received approval from the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes. In clinical trials, Avandia (rosiglitazone maleate) and ACTOS (pioglitazone hydrochloride) lowered blood sugars an average of 76 mg/dl and 95 mg/dl respectively, when compared to a placebo.
These two new competitors will vie for type 2 customers against Rezulin, which was previously the sole "glitazone" on the market. Ever since its launch in March 1997, Rezulin enjoyed incredible popularity among people with type 2 diabetes. It was recognized as one of the top 10 fasting growing pharmaceutical agents between June 1997 and June 1998, with sales of $543 million. In December 1997, however, Rezulin was withdrawn from the U.K. drug market when it was reported that six people had died from liver damage after taking the popular drug. The removal from the U.K. market prompted the first of several FDA-mandated liver monitoring guidelines. Since December 1997, there have been an additional 22 deaths reported from liver damage after taking Rezulin, and the FDA recently recommended that Rezulin be prescribed in combination therapy only.
No Liver Toxicity
In their respective clinical trials, Avandia and ACTOS demonstrated no instances of liver toxicity.
"If the clinical experience matches the clinical trial experience, then the first distinction I would make about Avandia and ACTOS is that they are safer than Rezulin," says Steven Leichter, MD, FACP, FACE, codirector of the West Georgia Center for Metabolic Disorders in Columbus, Georgia. "That would be positive because it would mean that there would not be the severe worries you have had with Rezulin."
Avandia, manufactured by SmithKline Beecham, won FDA approval on May 25 for the treatment of type 2 diabetes as both monotherapy and in combination with Glucophage. In clinical trials involving more than 2,300 patients with type 2 diabetes, an 8 mg. dose of Avandia effectively lowered blood sugar levels in patients by an average of 76 mg/dl compared to a placebo group. In addition, people achieved an average HbA1c reduction of 1.5 percentage points.
"This 76 mg/dl drop in blood sugar is impressive," says Barry Goldstein, MD, an Avandia study group investigator. "In trials of this type, it is rare to see a reduction in blood sugar levels greater than 60 mg/dl with any drug."
In a group receiving a 4 mg. dose of Avandia, blood sugar levels were reduced by an average of 58 mg/dl, while HbA1c levels dropped 1.2 percentage points.
Harold Lebovitz, professor of medicine, division of endocrinology and metabolism/diabetes at the State University of New York, calls Avandia an "important advance in the treatment of type 2 diabetes," and says the drug offers new hope for people living with this disease.
"Unlike most traditional drugs, Avandia helps the body's own insulin work more effectively, resulting in significant blood sugar control," says Lebovitz.
According to SmithKline Beecham, the usual starting dose of Avandia, when used as monotherapy, is 4 mg. per day, given as a single dose or in two divided doses. For patients who respond inadequately by 12 weeks of treatment, as determined by reduction in fasting plasma glucose, the dose may be increased to 8 mg. per day.
Combination Therapy With Glucophage
In a 26-week clinical trial of 348 patients, 8 mg. per day of Avandia, in combination with Glucophage, dropped HbA1c levels an average of 1.2 percentage points, versus Glucophage alone. Also, the Avandia and Glucophage combination demonstrated improvement in both insulin resistance and estimated beta cell function. Insulin resistance declined by an average of 20.4 percent, and estimates of beta cell function increased by an average of 94.2 percent.
"Avandia can be used alone or with [Glucophage] to produce good glucose control, and may ultimately prove beneficial in combination with other standard antidiabetic therapies such as sulfonylureas or insulin," says Alan J. Garber, MD, PhD, chief of endocrinology, diabetes and metabolism at Methodist Hospital in Houston.
On April 23, SmithKline Beecham agreed to copromote Avandia with Bristol-Myers Squibb, the maker of Glucophage.
Combined With Insulin
People combining Avandia and insulin reduced their insulin requirements by 12 percent. In a study of 319 patients whose blood sugar was not well controlled, despite taking two insulin shots a day, the addition of 8 mg. per day of Avandia produced an average decline in blood sugars of 55 mg/dl, and lowered HbA1c by an average of 1.3 percentage points. The addition of Avandia to two daily insulin shots, however, was associated with an increased frequency of hypoglycemia.
Combined with Sulfonylurea
In studies using 4 mg. per day of Avandia in combination with a sulfonylurea, patients demonstrated a 37 mg/dl reduction in blood sugars, as well as a .9 percentage point reduction in HbA1c.
"In the study, [Avandia] appeared to be free of clinically significant liver side effects," says Lebovitz. "This could potentially eliminate the need to perform costly and routine liver function tests on patients, if additional and continuing studies do not show evidence of any significant liver toxicity."
Twenty-eight out of 1.2 million Rezulin users have died as a result of liver failure. According to spokespersons at SmithKline Beecham, Avandia is "structurally very similar to Rezulin." However, there was no incidence of liver toxicity or failure in 4,598 clinical trial subjects. Avandia labeling recommends liver monitoring before taking Avandia, and every two months during the first year of therapy.
Increases in Weight and Cholesterol Levels
Although Avandia reduced blood sugar levels, there was an average weight gain of 4 to 7 pounds over 12 months. It was also associated with increases in total cholesterol, LDL (bad cholesterol), and HDL (good cholesterol). Lebovitz explains that LDL cholesterol appears in two forms: a "light and fluffy" form and a "small and dense" form. He adds that elevations in the small and dense form appear to be more harmful to the cardiovascular system.
"The data from Avandia's clinical trials suggest that when the LDL goes up after taking the drug, it is the light and fluffy form of LDL that increases," says Lebovitz.
The FDA granted marketing approval for ACTOS on July 16, and it arrived in pharmacies last month. The approval was based on a review of data from six double-blind, placebo-controlled studies involving more than 4,500 patients with type 2 diabetes. ACTOS can be used on its own or in combination with sulfonylureas, Glucophage or insulin, for the treatment of type 2 diabetes. ACTOS will be marketed in the United States by Takeda Chemical Industries of Japan and Eli Lilly and Co.
Reductions in BGs and HbA1c
In clinical research studies, ACTOS, taken once daily in 45 mg. doses, lowered fasting blood sugar levels by as much as 94.5 mg/dl when compared to a placebo. Patients also experienced reductions in HbA1c levels by an average of 2.6 percentage points as compared to placebo.
Labeling recommends that monotherapy with ACTOS be started at 15 or 30 mg. once daily, and, if necessary, increased to 45 mg. once daily.
ACTOS and Glucophage
Researchers at Takeda say ACTOS, in combination with Glucophage, is safe and significantly improves blood sugar control. In a 16-week study conducted in Princeton, New Jersey, 328 patients with type 2 diabetes received 30 mg. per day of ACTOS in combination with their current Glucophage dosages. Researchers report that the combination improved blood sugars by 43 mg/dl and decreased HbA1c by .8 percentage points. No liver function problem was reported.
ACTOS and Insulin
In a trial of ACTOS plus insulin, 566 type 2s were randomized to receive 16 weeks of therapy with their current insulin, combined with 15 or 30 mg. per day of ACTOS, or a placebo. Researchers discovered that 15 and 30 mg. of ACTOS combined with insulin lowered blood sugar levels an average of 35 and 49 mg/dl respectively when compared to a placebo. It also reduced HbA1c by an average of .73 and 1 percentage points respectively. Like Avandia, the addition of ACTOS to daily insulin shots was associated with an increased frequency of hypoglycemia.
The potential for insulin requirement reduction, when used in combination with ACTOS, has not been determined yet. Jeffrey L. Miller, director of clinical endocrinology at Jefferson Medical College in Philadelphia, suggests that a glitazone's insulin-sensitizing effects make it an appropriate candidate for combination therapy in patients taking insulin.
"What these glitazones do is dampen down on the beta cell function of the pancreas," he says. "They allow a lesser amount of insulin to be more effective and, in turn, cut down on the ravages of diabetes on the vascular system."
ACTOS Combined With a Sulfonylurea
Researchers conducted studies using 15 and 30 mg. per day of ACTOS in combination with a sulfonylurea. Blood sugars were reduced by 39 and 58 mg/dl respectively when compared to a placebo, and HbA1c was reduced .9 and 1.3 percentage points.
Better on the Lipids Than Avandia
Miller stresses that lower triglycerides and better cholesterol levels are major issues in type 2 treatment. ACTOS significantly decreased mean triglyceride levels and increased average HDL (good cholesterol) levels in monotherapy and in combination therapy. In contrast, no significant changes in mean total cholesterol or mean LDL (bad cholesterol) levels were seen with ACTOS when used either as monotherapy or in combination therapy.
"One of the major issues I have [with Avandia] is the unfavorable elevation in LDL cholesterol," says Miller. "I think Rezulin and ACTOS are more neutral on LDL and have the benefit on triglycerides."
Similar to Avandia, the FDA concluded that ACTOS has no clinically significant side effects on the liver. ACTOS labeling, like Avandia, also recommends liver monitoring at baseline and every two months during the first year.
Miller warns not to get too comfortable too soon.
"It took hundreds of thousands of people on Rezulin to appreciate the significance of the liver reaction," says Miller. "I think we have to wait for the same amount of people to take Avandia and ACTOS before we can really draw any comparisons."
Symptoms of liver problems include nausea, vomiting, abdominal pain and fatigue.
Public Citizen, the U.S. consumer protection agency that was instrumental in exposing the liver toxicity problems related to Rezulin, has only just recently begun researching the safety of Avandia and ACTOS. According to Dr. Sydney Wolfe, director of Public Citizen, "There are hundreds of pages of data we have to review before we can make a statement."
According to pharmacists at several Walgreens throughout the San Francisco Bay Area, the maximum 8 mg. dose of Avandia costs between $145 and $150 per month. The maximum 45 mg. dose of ACTOS costs between $188 and $191 per month.
The Exodus to Avandia and ACTOS
So, will type 2s begin their exodus to this new breed of glitazones?
According to SmithKline Beecham, new prescriptions for Avandia were 64 percent higher than new prescriptions for Rezulin during its first four weeks on the market. Avandia has already generated $71 million in sales, and no liver toxicity has been reported.
The FDA still cautions physicians to regularly monitor the liver function of everyone taking Avandia and ACTOS.
The Future of Oral Therapy in Type 2 Diabetes
So is glitazone therapy the new wave of oral treatment for people with type 2 diabetes?
Leichter feels that Avandia and ACTOS present better treatment options for people with type 2 diabetes, but also emphasizes that type 2 diabetes is not a "one size fits all" disease. He feels other treatment options should not be eliminated.
"We tend to look at adult people with diabetes as all having the same class of disease," he says. "I don't think that's right. If you look at the health and lab characteristics of these patients, they vary. I don't see [Avandia and ACTOS] as being competitive with or displacing another class of drugs...I see them as offering an expanded concept of design therapy."
Lebovitz feels that monotherapy will take a back seat to combination therapy in the near future. For the time being, however, he says physicians will most likely continue starting people on monotherapy, depending on their insulin resistance or obesity, and then switch them to combination therapy when they realize the monotherapy is not working.
"We have a large number of patients who are on [Glucophage] or sulfonylureas, and still can't get good control of their BGs," says Lebovitz. "When you add a glitazone into the mix, you will get a dramatic improvement in [blood sugar] control."
Miller feels that glitazones, like Avandia and ACTOS, will displace sulfonylureas as primary treatment options in the future of type 2 diabetes.
"In practice, most physicians don't understand the whole syndrome of insulin resistance, so they're very comfortable prescribing the sulfonylureas," says Miller. "But I think, in the real world, sulfonylureas should be back-up therapy to Glucophage and the glitazones."
Leichter points to the United Kingdom Prospective Diabetes Study, which emphasized the need to think about complex combination therapies.
"I see [Avandia and ACTOS] as two more treatment options that we could put into the mix."
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