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Combination products offer alternative for Type 2 diabetes patients
Lingering doubts about the strength of the single pill/combination pill market for Type 2 diabetes were laid to rest in late August. The Food & Drug Administration approved Actoplus Met (pioglitazone [Actos]/metformin, Takeda), the fourth diabetes combination product on the U.S. market.
"In order to properly take care of diabetes, many patients require multiple medications," said Robert Rizza, M.D., president of the American Diabetes Association (ADA). "Combination pills can help that process."
Clinicians have recognized the value of combination therapy for years, noted geriatric pharmacist Stephen Setter, Pharm.D., CDE, associate professor of pharmacy at Washington State University College of Pharmacy in Spokane. Setter is also a diabetes spokesman for the American Pharmacists Association.
Type 2 diabetes is an inability to properly respond to insulin because cells are resistant to the protein. The disease is typically treated with diet, exercise, and oral medication.
"Type 2 is a rather complex disease," Setter explained. "You can get significantly better therapeutic effects by targeting different systems: a sulfonylurea to help the pancreas, metformin to work on the liver, and a thiazolidinedione for muscle cells. Combining drugs can give you lower doses, fewer side effects, and better glycemic control."
There is no doubt that combo products are every bit as effective as the individual ingredients taken as single products, Setter said. There are even preliminary data suggesting that combo therapies are effective in children, data that are largely absent for the same treatments when used as single products.
A recent article in Pharmacotherapy showed that oral medications are just as effective as insulin therapy at reducing hemoglobin A1c levels in children with Type 2 diabetes. Combination products, monotherapy, and insulin all reduced A1c levels by an average of 2%.
"When you have tried and failed with diet and exercise, you can use oral medications appropriately," said Milap Nahata, M.S., Pharm.D., professor of pediatrics, pharmacy, and internal medicine at Ohio State University. "Realistically, diet and exercise cannot control every Type 2 diabetic, child or adult. We can go directly to oral treatment. Metformin alone is not enough for many patients. You need to combine it with at least one other agent."
The problem is that every additional prescription increases the number of pills the patient must down each day. As the number of pills increases and the number of times pills must be taken each day rises, compliance falls. Reducing the number of times medications must be taken each day increases compliance.
"Once you are diagnosed with diabetes, you are typically prescribed a large number of medications," said Mongthuong Tran, clinical pharmacy specialist in endocrinology and diabetes for Kaiser Permanente in Denver. "There has to be a discussion about compliance. There are data showing that decreasing the number of times a drug is dosed daily increases compliance. I am not aware of any data relating to the number of pills taken daily, but it could make sense that fewer pills is better than more pills in terms of compliance."
Drugmakers have recognized the potential advantages of combination products for years. The first Type 2 diabetes combo, Glucovance (glyburide/metformin, Bristol-Myers Squibb), was approved in 2000 (see table at the end of the article).
At least two more combination products, Avandaryl (rosiglitazone/glimepiride, GlaxoSmithKline) and an as-yet unnamed combination of pioglitazone and glimepiride from Takeda, are moving toward FDA approval.
Market research firm Decision Resources reported that single-pill combo products accounted for just 10% of the Type 2 diabetes oral med market in 2003, or about $700 million. A year later, said analyst Donny Wong, single-pill combo product sales had jumped to $900 million. The company predicted 3.7% annual growth in oral Type 2 meds through 2014.
One reason for this growth is the mounting realization by drugmakers, clinicians, and patients that more drugs can equal better treatment in many cases. A second reason is the continuing increase in the occurrence of Type 2 diabetes as the population ages. There were about 50.6 million Type 2 patients in 2004, according to Decision Resources. That number is expected to grow toward 57 million by 2014.
The research firm said physicians are identifying patients earlier in the course of the disease and introducing multiple agents at the onset of drug treatment rather than as second-line therapy.
Changing health dynamics are also playing a role. "When I started in pharmacy 30 years ago, I never saw obesity, hypertension, and Type 2 diabetes in kids," Nahata said. "That's why we called it adult-onset diabetes. Today, you don't think twice about diagnosing Type 2 diabetes in a 10-year-old."
Combination products will account for a growing percentage of overall prescribing to treat Type 2 diabetes, Wong said, but not necessarily a growing percentage of product dollars.
Decision Resources predicted that combo product sales would hit $1.6 billion annually by 2014. Dollar sales would be even higher, except that all of the individual ingredients will be available as generics by 2014. That will help hold prices down.
"Combination therapy is increasingly important," Wong said. "Physicians are finding that aggressive treatment provides superior long-term outcomes. Primary care physicians like these combos because compliance is a tremendous issue with multiple medications. Anything that can reduce the number of pills a patient has to take is a real plus." Payers, he said, are less enthusiastic about single-pill combinations. The primary question is not efficacy or compliance, but cost.
"All of these combo products include at least one generic, metformin," Wong said. "Some contain two generics. Either way, there is a tremendous cost difference between the individual meds and the brand-name combos, so these combination agents typically get very poor formulary placement."
The cost of single-pill combination drugs varies widely, Wong said. Variables include the patient's insurance status, the patent status of each drug in the combination product, health plan buying contracts, and formulary status.
"Combination products can decrease costs to the patient with fewer co-pays, but the combination increases the actual cost of the drug compared with the individual agents," agreed Les Krenk, president of Maui Clinic Pharmacy in Hawaii. "Whether or not a combo makes sense financially depends on the patient and his or her health coverage."
Patients paying out of pocket may well prefer individual drugs to the single-pill combo. Tran said a quick check on Lexi-Comp showed that single-pill combos are about 50% more expensive than individual ingredient prices.
The metformin side of all four combo products is available as a generic. So are glipizide and glyburide, the sulfonylurea components in Metaglip and Glucovance. Combining existing products into a new entity lets manufacturers extend patent and price protection.
"That method to extend protection and increase prices is being caught on to by physicians and patients," Krenk said. "If that kind of product extension is actually more convenient for the patient, I'm all for it, but not as a financial move to boost profits."
Manufacturers are pursuing line-extension strategies regardless of what practitioners think of the practice. Recent combo introductions include Vytorin (ezetimibe/simvastatin, Merck/Schering-Plough) to reduce cholesterol levels or Epzicom (abacavir/lamivudine, GlaxoSmithKline) to treat HIV/AIDS. Type 2 diabetes is one more opportunity.
"All of the drug companies are trying to get some kind of combo product out there," Setter said. "But the four existing combos cover most of the therapeutic basics for Type 2. The problem is that as the components become available as generics, insurance companies are not going to be willing to pay extra." Payers see two problems, he explained. One is the lack of data showing that fewer pills boost compliance in practice. Less frequent dosing leads toward better compliance, but there are scarce data showing that taking fewer pills with each dose has the same effect.
ADA sees the same fuzzy link between numbers of pills per dose and compliance. "Intuitively, it is more convenient to take a single medicine than to swallow two medicines," Rizza said. "But I am not aware of strong data supporting that idea. We need to be cautious about the conclusions in this area until we have more studies and more data."
Kaiser is just as cautious about the lack of data showing that reducing the number of individual pills boosts compliance. All four Type 2 diabetes combo products contain metformin, Tran noted. Because the combo products do not include an extended-release formulation, the combo products must be taken at least twice daily. That is no improvement over metformin as monotherapy or metformin plus any other single agent.
Combo products also raise questions about dosing. The combination products are available in only a few dosage strengths, while dosing for the individual ingredients can be varied dramatically. "A lot of clinicians don't like the fixed doses," Tran said. "They like to be able to titrate the individual components for optimal control. The limited-dosage combinations complicate your ability to evaluate therapy."
Actoplus Met, for example, is available in two dosage forms, 15 mg pioglitazone plus 500 mg metformin or 15 mg pioglitazone plus 850 mg metformin. Actos (pioglitazone, Takeda) is available in 15-mg, 30-mg, and 45-mg tablets. Glucophage (metformin, Bristol-Myers Squibb) is available in 500-mg, 850-mg, and 1000-mg tablets.
"Physicians like combo products because they are seen as helping with patient compliance, but the dosage limitations can be a significant downside," Wong said. "For some patients and some providers, it can be a real barrier."
Kaiser Permanente is one of those providers that saw the barrier and stopped. Between doubts about the real impact on compliance and lack of flexibility in dosing, the HMO giant has yet to add a single Type 2 diabetes combo product to its formulary, Tran said.
"Until we have good evidence that combination products enhance compliance, most providers will steer away, at least as an initial treatment," Tran said. "Clinically, there is no clear-cut advantage, just some degree of convenience."