GlaxoSmithKline (GSK) announced Tuesday that its combination drug, Avandamet, is now approved as a first-line treatment for type 2 diabetes. The drug was approved four years ago as an alternative for those failing metformin, but it's possible the first-line indication could have a meaningful effect on the popularity of various other first-line treatment options and it certainly could increase sales for the Avandia franchise. And this, of course, could have trickle-down effects on how and when doctors are prescribing other diabetes drugs, especially because the stated A1c effect looked like quite something, albeit from a high A1c base.
Avandamet combines the thiazolidinedione (TZD) rosiglitazone maleate (Avandia) and metformin HCL into one pill. We believe that versus taking Avandia and metformin separately, this combo is likely to be popular with patients, because it's one pill versus two, and one co-pay versus two—both these should prove beneficial on the compliance/adherence front (though for most, a metformin co-pay is low). Currently, there are no other combination pills with first-line therapy indications, although a similar combination pill, Takeda’s Actosplus Met has a second-line treatment indication.
And check out the Avandamet results (which oddly, weren't in the press release, but were possible to get going back to our EASD notes from 2005). In the study presented last September in Athens, with starting A1c of 8.8-8.9%, the reductions were -2.3% with Avandamet, -1.6% with Avandia and -1.8% with metformin at the end of 32 weeks treatment.
(While that’s a pretty high starting A1c, it's not like it's much higher than the average A1c in the U.S.! There's no national registry, remember?—although NYC, more forward thinking on this, has begun one. So it's hard to keep track of what that number is, but Dr. Satish Garg of the Barbara Davis Center quoted the average as over 9.0% at a conference on continuous monitoring in Boston last spring organized by technology expert Dr. David Klonoff.)
In addition to countering the weight gain seen with TZDs alone, the combination drug may also lead to fewer side effects. One major concern surrounding TZDs, of course, are the potential side effects – edema, weight gain (see above), and congestive heart failure. Dr. Barry Goldstein, an advising physician to GSK, believes that Avandamet will likely have fewer of the TZD-associated side effects than Avandia alone, mainly due to dosing. When used together, the TZD and the metformin may each be given in a submaximal dose, and doctors know that high doses are where side effects increase dramatically. So, it may be that the TZD-metformin combo assuages some of the concerns about the side effects of TZDs, though this remains to be seen.
Well, you ask, what was the weight gain reported in the study? This was our first question! Actually, check it out, Avandamet, at least officially, was weight neutral (no change) while Avandia used alone on average lead to a 2-3 lb. weight gain in the 32 week study presented at EASD. We thought that sounded low on average for weight gain for a TZD, but this weight neutrality, if it is seen in the real-life setting, this would certainly be an advantage compared to a TZD solo. We'll be looking to learn more at AADE about real-world experience. But in the meantime - that's a terrific result, since weight gain is probably the most common complaint voiced about TZDs (perhaps not too far behind is that TZDs typically take a couple of months to work, unlike incretins and insulin). We do note that something like 30% of patients may have problems with metformin and not be able to take it, so there are some patients for whom this combo won't work for some reason or other - but that's true for all drugs to some extent.
The advantages of a single-pill initial therapy seem obvious, as noted—it will just be interesting to see if the first line therapy vs second line label will make a big difference. It seems it might have already been used first line off-label, but then again, it is important for some doctors, particularly PCPs who have so much else to keep track of, to follow labels to the letter.
It is logical, of course, that Avandamet would be more effective in improving A1c than either rosiglitazone or metformin alone because Avandia increases insulin sensitivity in the tissues and reduces insulin resistance while metformin reduces glucose release from the liver. We imagine, based on ADA data, that a really killer cocktail would also include a shot of a GLP-1, which helps the body make just the right amount of insulin (Byetta, the only one on the market, is glycemic dependent, as it were) and the right amount of glucagon (helping lead to normal post-prandial glucose, how excellent). The Byetta in this combination would also slow gastric emptying, meaning it would slow down the pace at which sugar goes into the bloodsteam, helping avoid high post-meal levels.
Will this indication of first line therapy ultimately delay people moving to Byetta or insulin? (Right, right - yes, of course we know not enough people can get Byetta now as want it ... and we think that since right now it's hard to get, this will do more for demand longer term than anything else we could think of.) So big picture, regarding Byetta, if people want to lose weight, this combo pill's new first line indication probably won't really delay those patients who want to go on Byetta, although for conservative PCPs, it could dampen recommendations a bit. For insulin, we think on one hand, if they can get their A1cs down below 7 and they can keep them there, yes it would delay a move to insulin. But, maybe there will be so many more people trying to get in earlier control, that it will actually make the move to ALL drugs earlier, including incretins and insulin and all combinations thereof (remember incretin availability overall will likely make insulin much more attractive and we'll see combination use of that sooner than later).
It DOES seem the possibility of delaying the need for insulin will be attractive to patients and doctors and earlier, more aggressive therapy should do that. Payors, on the other hand, would likely rather see insulin use, which is cheaper. Nearly 70% of people with type 2 diabetes have an A1c that is too high, and we would bet that many of those with A1cs technically under 7 still have a poor glycemic variability. Again, more research is needed in that area. The Avandamet combo may help that, although it works more on fasting than post-prandial glucose levels, per se.
Dr. Goldstein advocates using Avandamet primarily in diabetes patients early on in their treatment to avoid negative side effects as well as disease progression, and he seemed not worried about using it in pre-diabetes even though there is no label for this yet. He too commented that he is eager to see such data. “What I advise is using this combo in early diabetes and in patients with pre-diabetes perhaps but not in people who have had diabetes for a while, because that is where you see problems. We know there’s some edema, some weight gain, and that the patients using TZDs are more insulin sensitive," he said. Dr. Goldstein encouraged using TZDs earlier in disease therapy so as to help avoid the macrovascular problems that emerge and that are perhaps exacerbated by TZDs. "Usually patients who have heart disease is where you get into the more serious problems ...” he concluded.
Certainly, there is a possibility that TZD therapy, and hence Avandamet, will be used at some stage as a preventive treatment in patients with pre-diabetes or at treatment to slow disease progression. We do not think the FDA will move fast on this, and we don't think TZDs will be used much off label for this by PCPs. But, DREAM and ADOPT are highly-awaited clinical trials in which TZD use is analyzed for its ability to halt progression to diabetes from pre-diabetes and as a first-line therapy in newly diagnosed type 2 patients. Look for DREAM results at EASD in September in Copenhagen and ADOPT in Capetown in December. Stay tuned to explore this with us—and perhaps we’ll see Avandamet come up again in the "earlier more aggressive therapy" discussions later this year.
(Press release below)
GLAXOSMITHKLINE ANNOUNCES FDA APPROVAL AND THE LAUNCH OF AVANDAMET® (rosiglitazone maleate and metformin HCl) as INITIAL therapy IN THE TREATMENT OF TYPE 2 DIABETES
Avandamet combines two oral agents - rosiglitazone, the most widely used insulin sensitizer, with a leading diabetes therapy, metformin - to help patients improve blood sugar control
Philadelphia, PA, [July 11, 2006] “ GlaxoSmithKline announced today FDA approval of Avandamet® (rosiglitazone maleate and metformin HCl) for use as initial treatment of type 2 diabetes as an adjunct to diet and exercise. Avandamet was previously approved as a second-line therapy “ it was indicated for use in patients who were uncontrolled on metformin monotherapy. Now, with this recent approval, physicians can start their type 2 diabetes patients on Avandamet.
Avandamet is the only combination of a thiazolidinedione, rosiglitazone maleate (separately marketed as Avandia®) and metformin HCl, with approved use as initial therapy of type 2 diabetes. Avandamet is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with dual rosiglitazone and metformin therapy is appropriate.
The announcement of the FDA approval for Avandamet for use as initial therapy in type 2 diabetes coincides with GlaxoSmithKline™s announcement that its supply of Avandamet has been re-established.
Many people with type 2 diabetes need to take more than one medication to treat the disease in different ways. The combination of rosiglitazone and metformin provides two complementary mechanisms of action said Barry Goldstein, M.D., Ph.D., director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Philadelphia. Rosiglitazone targets insulin resistance, an underlying cause of type 2 diabetes, whereas metformin primarily works to reduce the amount of blood sugar (or glucose) produced by the liver. In fact, a clinical trial comparing Avandamet to both rosiglitazone alone and metformin alone showed that patients taking Avandamet achieved significantly lower blood sugar levels than with either monotherapy alone.
Nearly 18 million Americans (sic) have type 2 diabetes, the most common form of diabetes. Type 2 diabetes is characterized by high blood sugar levels that occur when the body does not produce enough insulin or does not respond properly to its own natural insulin, a condition called insulin resistance. To manage diabetes, it is important for patients to achieve the blood sugar goal set by their physicians. Blood sugar control is measured by the HbA1C test, or A1C, which reflects a person’s average blood sugar levels over the previous two to three months. The American Association of Clinical Endocrinologists recommends an A1C of 6.5% or lower. The American Diabetes Association recommends an A1C of less than 7%. Lowering blood sugar levels can help reduce the risk of diabetes-related complications, such as heart disease, stroke, blindness, loss of limbs and kidney disease.
GlaxoSmithKline is committed to developing diabetes therapies to treat a disease that has reached epidemic proportions in the United States and throughout the world, said Anne M. Phillips, MD, vice president of Clinical for North America Cardiovascular-Metabolic, GlaxoSmithKline. With the approval of Avandamet for use as initial therapy as an adjunct to diet and exercise, GSK offers this effective and convenient option now for initial treatment of type 2 diabetes. This combination of rosiglitazone and metformin can help patients get their blood sugar under control.
Importance of Aggressive Diabetes Management
Diabetes experts are setting more stringent standards that reflect the importance of maintaining tight blood sugar control. Combination therapy with medications that work in different ways is often needed to help patients reach and maintain blood sugar goals said Dr. Goldstein. An advantage of Avandamet is that it combines two medications with complementary mechanisms of action in one convenient tablet.
Avandamet: Initial Therapy in Diabetes Management
Avandamet was originally approved in the U.S. in 2002, and is available in four tablet strengths of rosiglitazone/metformin, respectively: 2 mg/500 mg, 4 mg/500 mg, 2mg/1000mg, and 4mg/1000mg. Avandamet, as a two-in-one therapy, is the most economical thiazolidinedione (TZD)-metformin combination on the market.
Important Safety Information for Avandamet
Avandamet, along with diet and exercise, helps improve blood sugar control. It is a combination of two drugs - rosiglitazone maleate and metformin HCl.
A small number of people who have taken metformin, one of the components of Avandamet, have developed a rare yet serious condition called lactic acidosis (a buildup of lactic acid in the blood). Lactic acidosis occurs most often in people with kidney problems and can be fatal in up to one half of the cases. You should not take Avandamet if you have kidney problems. Tests should be used to check your kidneys before and while taking Avandamet. You should not drink alcohol excessively when taking Avandamet. If you are taking medicines for heart failure, you may be at increased risk of lactic acidosis.
Tell your doctor if you have heart problems or heart failure. Avandamet can cause your body to keep extra fluid which leads to swelling and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. If you have swelling or fluid retention, shortness of breath or trouble breathing, an unusually rapid increase in weight, or unusual tiredness while taking Avandamet, call your doctor right away.
You should not take Avandamet if you have liver problems. Blood tests should be used to check for liver problems before starting and while taking Avandamet. Tell your doctor if you have liver disease, or if you experience unexplained tiredness, stomach problems, dark urine or yellowing of skin while taking Avandamet.
Tell your doctor about all of the medicines you are taking.
Avandamet may increase your risk of pregnancy.
Talk to your doctor before taking Avandamet if you could become pregnant or if you are pregnant.
If you are nursing, you should not take Avandamet.
Your doctor should check your eyes regularly. Very rarely, some people have experienced vision changes due to swelling in the back of the eye while taking rosiglitazone, a component of Avandamet.
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