The Future of Diabetes Treatment: New Drug Development or Optimizing Existing Diagnosis and Treatment Pathways?

Last week, the U.S. Food and Drug Administration (FDA) approved Rybelsus, a new oral diabetes drug from Danish pharmaceutical company Novo Nordisk, marking a strong conclusion to a period of intense innovation in the type 2 diabetes drug field. Since 2006, three new drug classes and more than ten new drugs have been introduced in this field, with the best among them not only helping patients control high blood sugar but also preventing long-term vascular complications of diabetes.

Today, Novo Nordisk and Eli Lilly have become major producers of diabetes treatments, but they will need to prove more in the future—especially as outcome studies have shown that existing drugs can reduce the risk of cardiovascular disease, the leading cause of death among diabetes patients.

These two companies, along with Sanofi, Hanmi Pharmaceutical, and biotech newcomers like VTV Therapeutics, can no longer rely solely on developing new drugs that are merely as effective at lowering blood sugar as current mainstream drugs such as Victoza or Jardiance.

"In the existing arsenal, there is no room for a single drug that only lowers blood sugar without providing other benefits," said Mads Krogsgaard Thomsen, chief scientific officer at Novo Nordisk.

Because diabetes drug manufacturers have faced criticism for significant price increases, leaving some patients unable to afford their products, proving that the next generation of glucose-lowering drugs is affordable for society will be crucial.

Beyond lowering blood sugar, heart protection is also needed

The results of the EMPA-REG Outcomes trial for Jardiance (empagliflozin) from Eli Lilly and Boehringer Ingelheim were a turning point in diabetes drug research in recent years. In 2015, the study showed that taking this SGLT-2 inhibitor reduced the risk of cardiovascular complications by 14%.

"After the EMPA-REG results were published, the competitive standard for all new entrants changed, because previously we were not required to conduct cardiovascular outcome studies in a way that demonstrated benefit," said Jeffrey Emmick, vice president of product development at Eli Lilly. Previously, diabetes drugs only needed to prove they did not increase the risk of cardiovascular complications.

Now, five other diabetes drugs have met the same standard, raising the bar. To prove a new drug is worth bringing to market, companies must consider enrolling as many as 10,000 patients to attempt to demonstrate cardiovascular benefit, not including the thousands needed to prove blood sugar control benefits. This represents a huge investment, likely limiting diabetes drug development to large pharmaceutical companies.

Thanks to these advances, the current state of diabetes drugs can meet the needs of most patients—provided they can afford and access them—said John Buse, chief of endocrinology at the University of North Carolina and former president of medicine and science at the American Diabetes Association.

"I do believe that for diabetes patients who have access to good medical care—that is, those with insurance and clinicians nearby with expertise and up-to-date knowledge in diabetes care—it is entirely possible for them to have a normal lifespan without disabling complications," Buse said.

Of course, the problem lies in access. "We don't really have a healthcare system; we have healthcare chaos," he said.

Notably, insulin, which has been used for nearly 100 years, has seen double-digit price increases, while newer drugs like GLP-1 receptor agonists and SGLT-2 inhibitors have also risen sharply in price, sparking widespread criticism of pharmaceutical companies in this field.

In April of this year, executives from Novo Nordisk, Eli Lilly, and Sanofi, the maker of Lantus, were summoned to Capitol Hill to explain rising drug prices, amid reports of diabetes patients dying because they could not afford insulin.

In response, drug companies largely pointed to increasing rebates they pay to insurers for formulary access, a defense that sidesteps the access barriers faced by those without insurance or in high-deductible plans. These rebates are not passed directly to consumers, so some patients still pay the full list price rather than the net price.

However, between developing new drugs and better utilizing existing ones, Sanofi seems to favor the latter. The French companyrecently announceda partnership with device maker Abbott to better integrate blood glucose monitoring with insulin delivery devices.

Can do better

Despite cost concerns, diabetes drug companies like Novo Nordisk and Eli Lilly still believe there is demand for new drugs from payers and patients.

Eli Lilly has advanced a drug called tirzepatide to Phase 3 trials, which, like Trulicity, stimulates GLP-1 but also stimulates a second hormone, glucose-dependent insulinotropic polypeptide (GIP).

Sanofi, whose influence in diabetes has waned since Lantus lost patent protection, is now attempting a triple agonist strategy targeting GLP-1, GIP, and glucagon receptors, with the therapy in Phase 1 trials.

Novo Nordisk is testing glucose-responsive insulin, though at an earlier stage, and is also developing long-acting insulin and therapies to protect pancreatic beta cells to help patients with type 1 diabetes.

Their hope is that if some newer experimental drugs can control blood sugar levels more precisely, patients could lower their HbA1c below the recommended 7% to 8% without risking hypoglycemia. Blood sugar levels in people without diabetes are typically below 6%.

The potential benefit may lie in preventing microvascular complications of diabetes, such as eye, nerve, and kidney problems. Additionally, Emmick noted that in a 26-week study of Eli Lilly's tirzepatide, patients who were not obese at baseline saw significant weight loss of up to 11 kilograms.

"We know there is a strong association between weight loss and cardiovascular benefit, as seen with bariatric surgery," Emmick said. "We also anticipate that dual agonists like tirzepatide may provide additional cardiovascular benefits."

Although the correlation between blood sugar levels and cardiovascular complications has not been confirmed, Emmick suggested that perhaps the research has not been thorough enough.

"For heart disease, the lower the blood sugar (level), the better, and the lower the LDL cholesterol, the better," Krogsgaard Thomsen added. "We will make the glucose-sensing device in the molecule extremely sensitive to small changes in glucose molecules, at least that is our vision, so that patients can achieve normal blood sugar levels without putting themselves at risk. That is why sensitive insulin may make more aggressive treatment targets feasible."

However, Buse countered that this goal lacks evidence. "This is simply ill-conceived," he said. "There may be benefits, but every time we try to prove such benefits, we usually fail."

Buse noted that diabetes is already one of the most costly diseases for U.S. healthcare payers, and doctors should be cautious before prescribing expensive new drugs. "I hate to increase costs without knowing if there is a benefit," he said. "Going from 9% to 7% is something society can barely afford; going from 7% to 6% is clearly something we cannot afford."

Buse believes that improving diabetes care in the future may rely less on more new glucose-lowering drugs and more on implementing care pathways known to improve long-term outcomes but not widely followed by healthcare providers and insurers.

"Even some pharmaceutical companies are trying integrated healthcare delivery systems," he said. "Of course, insurers and employers are starting to do this as well."

"I think we have a fairly good understanding of how to minimize the long-term suffering and burden of diabetes, but it has not been widely implemented yet."