A report from the Pharmaceutical Research and Manufacturers Association (PhRMA) says there are 180 new medications in the pipeline for type 1 and type 2 diabetes. That number reflects the boundless therapeutic and market opportunities diabetes offers to pharmaceutical companies.
More than 19 million people in the United States have diagnosed diabetes and 7 million more have the disease without being aware of it, according to the Centers for Disease Control and Prevention. Current trends foreshadow that by 2050, 1 in 3 may have diabetes — the confluence of an aging population, increasing numbers of high-risk minority groups in the population, a longer lifespan, and reduced mortality attributable to diabetes. Today, as many as 79 million people may have prediabetes.
Diabetes is a “blue sky” opportunity because a magic pill has not been found. There are multiple classes of antidiabetics, but only about 8 million Americans have their diabetes under control. Patients respond differently to the medications and have comorbidities that require more treatment options. There is still a need for long-acting agents that achieve glucose homeostasis and that reduce dosing frequency and injections.
There are also opportunities for niche drugs like Afrezza, an inhaled insulin, which has just cleared regulatory hurdles. Delivering insulin to the blood-rich lungs speeds its entry to the bloodstream, sparking rapid glucose control.
The limitations of the diabetes medications on the market today present both a challenge and an opportunity for health plans. The challenge lies in devising formularies that provide access to the best medications and simultaneously control costs. The opportunity lies in improving medication outcomes and reducing the total cost of care.
The drugs in development span the gamut of mechanisms of action and also pursue new avenues. The more prevalent agents in development are insulins and those focused on improving pancreatic alpha- and beta-cell functioning.
The loss of beta cells is the primary cause of diabetes, and existing medications largely focus on controlling blood glucose after beta-cell demise. There is now an emphasis on drugs that target the core regulatory function for blood glucose. Homeostasis is governed by two hormones, insulin and glucagon, both secreted by the pancreas. When blood glucose levels are low, alpha cells in the pancreas secrete glucagon, which triggers the liver to release glucose into the blood. When blood glucose levels are high, beta cells in the pancreas release insulin, which triggers fat and muscle cells to absorb glucose from the blood, thus returning it to normal levels.
“Medicines in Development: Diabetes,” a PhRMA report, identifies stem cell research among recent research activities and discoveries that may lead to new treatments. Researchers at Harvard have discovered a hormone that stimulates production of insulin-secreting pancreatic beta cells. In London, scientists have manipulated stem cells into becoming insulin-secreting cells. And in Australia, researchers have isolated stem cells from the pancreas and turned them into insulin-producing cells for type 1 diabetes.
Drug development efforts also focus on combination agents and long-acting agents that offer the potential to improve adherence and homeostasis.
There is a need and opportunity for new medications because individually, current antidiabetics do not control diabetes in most patients.
“Look at the reduction you get from most individual antidiabetics except for insulin,” says Brian Solow, MD, chief medical officer at Optum Rx, a PBM subsidiary of United Healthcare. “You may see an average reduction of 1% or slightly higher across the classes. But doctors see patients who come in with HbA1c levels above 9%, so you have a long way to go.”
“Because of the evidence of vascular benefits, we are seeing increased use of second- and third-line agents,” says Brian Solow, MD, chief medical officer at Optum Rx.
The 2014 American Diabetes Association (ADA) guidelines say, “Comparative effectiveness meta-analyses suggest that overall, each new class of noninsulin agents added to initial therapy lowers HbA1c around 0.9–1.1%.”
However, new drugs will have to carve out roles for themselves. The clinical guidelines from the ADA and others have clear treatment algorithms. In addition, health plans have their own programs for managing diabetes and new medications will have to demonstrate their efficacy and value.
Current ADA guidelines include a diagram of the therapy algorithm, starting with metformin monotherapy, then progressing to two- and three-drug combinations. It is a true Chinese menu, allowing for open selection of a sulfonylurea, thiazolidinedione (TZD), DPP-4 inhibitor, GLP-1 agonist, or insulin. The ADA does not prefer one class over another in combination therapy, leaving it up to clinicians to determine the safety and efficacy of each drug in each patient. Open choice also gives health plans some latitude in designing their formularies and utilization management programs.
The ADA treatment diagram helps in selecting add-on agents by listing the effect of different classes on HbA1c reduction, the risk of hypoglycemia, weight gain or loss, major side effects, and cost.
Physicians appear to be following guidelines more closely, thus creating a possible barrier for new agents. “Physician behavior is changing, in part because there are guidelines from so many different organizations,” says Solow. “For example, doctors have finally figured out that you’re supposed to use metformin as the first-line medication.”
“We keep a close eye on utilization, and metformin is the driver in first-line treatment,” says Daniel McConnell, PharmD, clinical coordinator at Geisinger Health Plan.
Physicians are trying two or three oral drugs before turning to insulin, says Daniel McConnell, PharmD, clinical coordinator at Geisinger Health Plan.
“Today physicians are more interested in driving toward HbA1c goal levels,” says Solow. “I can remember when patients would be on medications for years and their HbA1c would remain elevated and unchanged,” says Solow. “Now physicians are taking more responsibility for driving A1c levels down because of the evidence of the vascular benefits, so we are seeing increased use of second- and third-line agents.”
The add-on medications are a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 agonist, or insulin. Health plans are using several different techniques to manage two- and three-drug combination therapy.
“We have step therapy on many of the second- and third-line agents,” adds Solow. “We allow the use of DPP-4s or GLP-1s when that is appropriate, but we want to see a history of the use of the first-line agents.”
“As we review what physicians are doing, it seems they’re sticking to two or three orals and then finally using insulin,” McConnell comments. “We don’t see much differentiation in the efficacy of the sulfonylureas, the TZDs, and the DPP-4s. That’s why we steer as many patients as possible to metformin, and then if they are resistant to insulin add on a sulfonylurea or a DPP-4. If people have progressed to a point where they need three orals, we try to get as many of them to insulin as we can.”
Solow points out that managing diabetes is more than managing existing and new medications. “Broad-based clinical programs are important,” he says. “Diabetes is still very fluid because of the large number of patients and the complexity of the disease and its relationship to comorbidities. The management of diabetes medication therapy is very involved.
“Adherence is a real problem — you have to be sure you are running a very thorough adherence program,” adds Solow. “Then the accompanying disease processes such as cardiovascular disease, and the appropriate use of ACE inhibitors and ARBs in patients with nephropathy or hypertension, are important. According to the new guidelines, making sure patients are on a statin is also important. Our focus is to work with our customers and take advantage of the data that we can provide in identifying diabetes patients and informing them about their needs for medication therapy.”