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Diabetes drugs approved in past decade are game changers, with room to improve
Drug therapies approved for type 2 diabetes in the past decade have changed patients’ experience by providing ease of use with better outcomes and fewer adverse effects, according to leaders in the field.
“Historically, the drugs that were originally used [in diabetes management], mainly sulfonylureas, helped fix the symptoms of diabetes, but they didn’t fix the problem,” Susan Cornell, PharmD, CDE, FAPhA, FAADE, associate director of experiential education and associate professor in the department of pharmacy practice at Chicago College of Pharmacy at Midwestern University in Downers Grove, Illinois, told Endocrine Today. “If we look at the body as just having dysfunctional organs or systems, the newer agents actually fix these dysfunctions, so patients feel better.”
Until the 1990s, providers managing diabetes had only two pharmacologic options: insulin and sulfonylureas. In 1995, the FDA approved metformin, which was a major advance, Ralph DeFronzo, MD, of the University of Texas Health Science Center in San Antonio, told Endocrine Today.
“Since then it’s pretty much been an explosion of drugs,” DeFronzo said.
The first GLP-1 receptor agonist, exenatide (Byetta, AstraZeneca), was approved in 2005, followed by the first DPP-IV inhibitor, sitagliptin (Januvia, Merck), in 2006; both drug classes are considered incretin-based therapies. The first SGLT2 inhibitor, dapagliflozin (Farxiga, AstraZeneca), was approved in 2013.
Improved experience
Several agents in each class are now available worldwide, and patients’ management experiences have improved greatly.
“The nice thing about these drugs is that the majority of them don’t cause hypoglycemia, which have typically been a very bad experience for patients,” Yehuda Handelsman, MD, FACP, FNLA, FACE, medical director and principal investigator for the Metabolic Institute of America in Tarzana, California, told Endocrine Today. “Insulin can cause hypoglycemia and sulfonylureas can cause hypoglycemia. Both insulin and sulfonylureas can cause weight gain, but the new drugs don’t cause hypoglycemia or weight gain.”
Because these drugs are oral agents, except for the GLP-1 receptor agonists, patients have options besides injecting insulin, which comes with its own issues for patients and physicians, DeFronzo said.
“Because we are able to control the glucose, without having to go to injection, it makes it easier for the patients,” he said. “Now, the oral medications are quite good, and we can get the majority of our patients well controlled with noninsulin therapies. That’s the advantage because although insulin is eventually required in many patients, it is associated with issues in terms of administration of an injection.”
Patients who are using insulin must take injections several times a day in addition to measuring their glucose with glucose strips three to four times per day.
“This is somewhat of an inconvenience, and it does decrease the quality of life, whereas the patients have a lot more freedom and leeway with the oral agents,” DeFronzo said.
Combination therapy
A significant benefit of these newer drugs — the incretin-based therapies and the SGLT2 inhibitors — is that they work through different mechanisms and can be used with each other, therefore more effectively managing glucose.
“We now have many options to address the different pathophysiology of diabetes, and we know now that diabetes is a condition that has different organs involved,” Handelsman said. “It could be the pancreas or the liver. Several cells in the pancreas that are involved; it’s the intestines; it’s the brain; it’s the muscles; it’s the fat. The drugs that we have today all can address the different parts of the physiology.”
Cornell is a supporter of combination therapy as a good first-line therapy, despite the American Diabetes Association guideline recommending metformin as the preferred initial pharmacologic agent for type 2 diabetes.
“Why don’t we fix all of the body problems right from the get-go and do combination therapy at the beginning? That way you just have better outcomes. But that’s in the process of being studied,” she said.
DeFronzo agreed. “Physicians need to be moving toward combination therapy with two or three of the agents right from the beginning of the diagnosis and not the sequential addition of ‘add one, wait till the person fails, then add the next,’” he said. “We need to start right from the beginning with multiple medications that work adequately or even synergistically and that correct both microvascular as well as macrovascular complications.”
Anticipated upgrades
Despite the efficacy of these agents, improvements are coming down the pipeline, particularly with GLP-1 receptor agonists.
GLP-1 receptor agonists are currently available only as injectables, but an oral agent is being studied by Novo Nordisk. The company’s oral semaglutide is in a phase 3 trial, but FDA approval would take about 3 years, DeFronzo said.
Intarcia Therapeutics submitted a new drug application for continuous subcutaneous delivery of exenatide through a mini pump placed under the skin. Six-month delivery pumps have been tested, but 12-month pumps are in development.
Additionally, closed-loop devices are being tested in patients with type 2 diabetes, similar to systems that offer continuous glucose monitoring and insulin delivery to patients with type 1 diabetes, such as the recently approved MiniMed 670G system (Medtronic), Handelsman said.
Aside from new devices and drugs, recommendations for first-line therapy may move away in the future from metformin to one of these newer drugs.
“If I had a crystal ball, it would say the GLP-1 receptor agonists are soon going to knock metformin off its No. 1 drug throne and take over as a first-line therapy,” Cornell said.
DeFronzo agreed. “I personally believe that [GLP-1 receptor agonists] should be first-line therapy.”
What is needed
Even with these advancements coming down the pipeline, there remain gaps that could be filled with new treatment options.
Cornell said there is a need for a single agent that fixes as many of the organ dysfunctions as possible while limiting risk for hypoglycemia and weight gain.
“How intuitive is it that most people who have type 2 diabetes and insulin resistance are overweight?” she said. “It’s stupid to give them a drug that causes them to gain weight. So logically, the drugs that promote weight loss with low hypoglycemic risk in addition to blood-glucose lowering are going to be the drugs that are moving up as first-line therapies.”
According to Handelsman, many of these newer agents depend on kidney function, which can limit the number of drugs available for those with health problems.
“If you have issues with kidney function, sometimes thiazolidinediones are not good because they will also cause fluid overload,” Handelsman said. “And if people have congestive heart failure, they cannot take a [TZD], so often we don’t have good enough drugs for people who are later in the disease, who may have some kidney problems and congestive heart failure.”
Another avenue that should be explored, according to DeFronzo, is addition of an insulin-sensitizing drug other than pioglitazone.
“There are a number of combinations of peptide hormones that are injectable that are being looked at. Some of these have some promise. Now that it looks like we can get drugs that are peptide drugs through the [gastrointestinal] tract, that will actually open up new vistas in terms of oral therapies and medications in the past that had to be given by injection,” he said.
Barriers to drug therapy
Despite the benefits of the newer therapies, access to them remains a problem, according to Cornell.
Type 2 diabetes treatment is often initiated in the primary care sector, where there is more resistance to these noninsulin treatments, as opposed to specialty care, she said.
“This is the role of team-based care. Having a certified diabetes educator or a pharmacist — who is better versed in the newer drugs — on that primary care team can help get the patient on board and pick more appropriate therapies,” Cornell said.
A second barrier is cost.
“Until we get some reform on the cost of the newer drugs — and I’m not blaming pharma, I’m blaming the intermediate people, the middle men that are coming in mainly to pharmacy benefit managers to start driving up these costs — until that gets fixed, the drug does no good if the patient can’t afford it,” she said. “We have to get back to getting these drugs into the patients’ hands and making them affordable for our patients.”
Despite room for improvement in cost and access, treatments for type 2 diabetes are good, according to Handelsman.
“At some time, we will need some more efficacy from drugs, but we are in a good place now, where we don’t have as many gaps as we used to,” he said. “For the large majority of patients, we can get them to goal safely now. The main issue is the cost of drugs.” – by Cassie Homer
- Reference:
- Standards of Medical Care in Diabetes. Diabetes Care. 2016;doi:10.2337/dc16-S001.
- For more information:
- Susan Cornell, PharmD, CDE, FAPhA, FAADE, can be reached at scorne@midwestern.edu.
- Ralph DeFronzo, MD, can be reached at defronzo@uthscsa.edu.
- Yehuda Handelsman, MD, FACP, FNLA, FACE, can be reached at yhandelsman@yahoo.com.
Disclosures: Cornell reports serving on the speakers’ bureaus for Novo Nordisk and Sanofi. DeFronzo reports serving on advisory boards for AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen and Novo Nordisk and on the speakers’ bureaus for AstraZeneca and Novo Nordisk, and receiving support from AstraZeneca, Boehringer Ingelheim, Janssen and Takeda. Handelsman reports receiving consultant, speaker fees and research grants from various pharmaceutical companies, including Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, diaDeux, Daiichi Sankyo, Eisai, Gilead, GlaxoSmithKline, Grifols, Hamni, Halozyme, Intarcia, Janssen, Lexicon, Lilly, LipoScience, Merck, Novo Nordisk, Regeneron, Sanofi, Salix, Takeda and Vivus.