If the last 10 years is any indication, we have entered an era in which morbid obesity and related metabolic disorders are so prevalent that they are becoming the norm. Between 1993 and 2013, the prevalence of diabetes in the U.S. increased 135%, from 3.06% of the population to 7.18%, according to the Centers for Disease Control and Prevention (CDC).
But even though the prevalence of diabetes has increased substantially in the last 20 years—29 million Americans now have diabetes—the CDC recently reported that the rate of death from diabetes-related complications has declined significantly in the last 20 years. This decline is largely a function of patients having access to better treatment options, resulting in improved long-term glycemic control and stability.
Across every category in the oral and injectable diabetes treatment markets—thiazolidenediones, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, meglinitides, biguinides, alpha-glucosidase inhibitors, and insulins—there has been some degree of innovation, and in some cases, major treatment advances.
Whether it’s implementing better glycemic control, more weight loss, a lower incidence of hypoglycemia, more convenient drug delivery, or a unique mode-of-action, drug companies are advancing the standard of care for type 2 diabetes (T2DM), and there’s even more to come—the latest Pharmaceutical Researchers and Manufacturers of American report cites 86 diabetes-related therapies in the pipeline.
Game-changing clinical trial results
A little more than a year after Eli Lilly and Boehringer Ingelheim’s Jardiance (empagliflozin), an SGLT2 inhibitor, was approved by the FDA for treatment of T2DM, the companies jointly announced the results of an FDA-mandated, randomized, controlled, phase 3, cardiovascular (CV) safety trial. The trial showed that Jardiance was not only safe in terms of CV risk, but provided patients with a CV treatment-related benefit.
In the 7,000-subject EMPA-REG OUTCOME trial, patients who received Jardiance (in addition to background treatments, such as metformin, insulin or other drugs) had a 38% reduction in the risk of CV-related death, a 35% reduction in the risk of hospitalization, and a 32% reduction in the risk of all-cause mortality.
This precedent-setting data was, and still is, astonishing for the medical community, as well as Americans with T2DM—not to mention the 387 million people worldwide with this disease. Even the research team at Eli Lilly, normally a pragmatic and reserved group, stood up and applauded when Jan Lundberg, Executive VP of Science and Technology and President of Lilly Research Laboratories, revealed the EMPA-REG OUTCOME results to his team.
Suddenly, an overlooked flozin is on the radar
Many of the internists, diabetologists, and primary care physicians on the front lines of treating patients with diabetes are still digesting the news, but the implications are clear. Considering the fact that about two-thirds of patients with T2DM die of CV disease, Jardiance (in combination with other therapies and lifestyle modifications) could improve long-term outcomes for many, if not most, of their patients with T2DM.
In addition, it might be time for them to take a look at two recently introduced combo drugs—Synjardy (empagliflozin/metformin) and Glyxambi (empagliflozin/linagliptin), both of which were approved within the last 12 months.
The physician perspective
Dr. Barry Mennen is a Washington, D.C.-based physician has been treating obese patients and patients with T2DM for years. Although the SGLT inhibitors (also known as flozins) have been around since Johnson & Johnson’s Invokana (canagliflozin) was approved in 2013, Dr. Mennen has not used them—mainly because of his concerns about the risk of ketoacidosis associated with this class.
After reviewing the results of the Jardiance CV safety trial, including the 0.1% rate of ketoacidosis in Jardiance patients, Dr. Mennen told BioPharma Dive, "I am heartened to see the very low levels of ketoacidosis in the Jardiance trials. As far as whether or not I would prescribe Jardiance, the answer is yes—but not yet."
Before predicting immediate blockbuster status for Jardiance, it’s important to remember that diabetes is treated within the framework of an algorithm that generally relies on major lifestyle changes and combinations of oral antidiabetics, while saving insulin as a last-resort treatment option. (Note that almost 50% of sales of diabetes drugs are for insulin).
"First, I want to be clear that I spend a fair amount of time with patients explaining how their overweight/obesity/visceral fat is related to their disease," Dr. Mennen said. "I then explain the dual issues of increased insulin resistance and decreased beta-cell insulin response. I give them a program of weight reduction and maintenance that emphasizes decreased carbohydrate intake above all else.
"As for treating garden variety type 2 diabetes, metformin forms the foundation, and I add a gliptin to that if needed. If patients need more, then a flozin would make sense, especially if they have trouble maintaining their weight. Type 2 diabetes is not a one-size-fits-all disease, and different patients require different approaches. The more I see with the flozins—and the Jardiance data is impressive—the more I am being pulled to prescribe them."
Currently, the market for diabetes is dominated by ten blockbuster drugs, which together generated $28.6 billion in revenues last year. At the top of the list are Sanofi’s long-acting basal insulin, Lantus, and Merck’s oral DPP-4 inhibitor, Januvia (sitagliptin). Merck has the largest oral diabetes franchise, with a total of $6 billion in sales when you add Janumet (sitagliptin/metformin). Much has been made of whether or not Jardiance could muscle in on Merck’s oral antidiabetic market share, but the conversation is premature.
Combined, the three drugs that comprise the SGLT2 inhibitor class—Invokana, AstraZeneca’s Farxiga (dapagliflozin), and Jardiance—only represent 4% of all prescriptions for oral antidiabetics. However, growth is expected for the entire class, with Invokana favored as a frontrunner (at least until now). Clearly, the new CV data for Jardiance will accelerate its uptake, and most likely have a positive class effect. J&J has even said that it expects this class effect to occur.
It should also be noted that the label has not been updated to reflect the new CV data. "We are providing the CV data to global regulators and can’t speculate on decisions the regulators may make on inclusion of these data in the Jardiance label," Dr. Thomas Seck, Vice President of Clinical Development and Medical Affairs-Metabolism at Boehringer Ingelheim, told BioPharma Dive in an interview.
Recalibrating the competitive landscape
Regardless of what’s happening with the Jardiance label, this drug is still the first and the only diabetes medication (at least for now) to show a significant reduction in both CV risk and CV-related death in a dedicated outcome trial. In addition, it can easily be used as part of combination therapy.
"Jardiance is not contraindicated to be used with any anti-diabetic medications, though it would not make sense to combine it with another SGLT2 inhibitor," said Seck. That being said, treating physicians, who are well aware that their patients with T2DM face a two- to four-fold increased risk of CV, are going to consider adding it to the prescribing mix.
Even before the news came out, many analysts were becoming bullish about Jardiance after previewing data that Lilly put out in August. Several days ahead of the announcement about the Jardiance CV data, Jeffrey Holford from Jefferies & Co. increased his peak sales estimate for Jardiance from $1.2 billion per year to $6 billion per year.
Still, the question is how long Jardiance will hold onto to its CV outcomes-related advantage. "Other companies are also testing their antidiabetic drugs in CV outcomes trials," said Oscar Virgilio, Senior Strategic Consultant for Swat Team Inc. in New York City, in an interview.
"However, CV outcomes data is not expected for Farxiga until 2019. This provides the Lilly/BI Jardiance marketing team with a considerable time period in which to promote Jardiance’s combined advantages on blood glucose levels and CV outcomes without direct competition."
The spillover effect
At the same time that Jardiance sales are expected to increase, most analysts predict that there will also be a spillover effect to the other SGLT2 inhibitors. But Dr. Seck is cautious about the tendency to extrapolate benefits just because drugs are in the same class.
"It is important to highlight that every molecule is unique and different," he said. "SGLT2 inhibitors have differences in several pharmacological features, such as potency, target selectivity and drug metabolism and excretion."
Competition is part of the innovation game, but in a therapeutic area like diabetes, having numerous treatment options allows for more flexibility with combination therapy. For companies involved in diabetes therapeutics, including Sanofi, Merck, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Johnson & Johnson, Novartis, AstraZeneca, OraMed, Mannkind, as well as the companies that manufacture diagnostics and devices, there is recognition that there is a great need for different types of diabetes therapies—and lots of room for innovation.