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Toujeo and Afrezza: New and Improved Insulins, Limited by FDA Labeling Constraints

Andrew Smith
Two new insulins marketed by Sanofi offer improved options for patients: Toujeo is longer acting than its predecessor, Lantus. Afrezza, an inhaled insulin, is gaining praise from patients, if not from Wall Street.

Existing treatments are effective enough to control diabetes in most patients, but drug makers spend huge sums to keep developing new products and improving old ones.

Indeed, Sanofi just rolled out 2 novel versions of the very oldest diabetes treatment, an insulin glargine formulation called Toujeo and an inhalable form of human insulin called Afrezza.

Sanofi officials say both products will benefit large numbers of insulin users with both type 1 and type 2 diabetes mel-litus (T1DM, T2DM). Outsiders express a wide range of opinions.

Trial data indicate that Toujeo controls glycated hemoglobin (A1C) levels about as well as Lantus, an insulin glargine formulation approved in the year 2000 that has just lost patent protection after years of blockbuster sales. Toujeo lasts longer than Lantus, however.1 It also provides the body a steadier stream of insulin1 and is associated with a significantly lower risk of nocturnal hypoglycemia.1

Afrezza performed similarly in a phase 3 trial. It roughly matched an existing competitor, insulin aspart (Novolog), in A1C reduction, and slightly outperformed it in several secondary ways. Afrezza use was associated with less hypoglycemia, lower fasting blood glucose, and slight weight loss rather than slight weight gain. It also reached peak levels very quickly, in just 12 to 14 minutes on average.2

That said, Afrezza’s medical importance will likely hinge on something that no trial can measure: how the change from injection to inhalation affects patient behavior. If the delivery method inspires patients to medicate themselves more consistently, Afrezza could produce huge health benefits. If patients use Afrezza like they use insulin aspart (a fast-acting insulin analogue), the new product could prove to be an expensive convenience.

Financial analysts mostly predict solid but unspectacular sales for both drugs, in part because federal regulations for-bid Sanofi from touting the comparative advantages of either drug. (The FDA did not allow language about less hypoglycemia in the label it approved, and therefore Sanofi cannot mention it in language it uses to promote the drug.)

Consensus estimates reported by Bloomberg predict annual Toujeo sales will reach about $1.3 billion by 20203 far below the $7.1 billion that Lantus generated in 2014. As for Afrezza, annual projections range from a paltry $182 million up to $2 billion, with the median in the $600 million range. The treatment’s unexpectedly poor performance during its first month on the market led Goldman Sachs to cut its annual sales projections by $1 billion.4

In other respects, however, both medications have gotten a good reception.

“The response to Afrezza on social media has been tremendous,” Rachele Berria, MD, PhD, who heads the Diabetes Medical Unit for Sanofi US, told Evidence-Based Diabetes Management in an interview. “Healthcare providers don’t seem to anticipate that patients will see much of a need to move away from injections, but actual patients see this as a valuable feature.”

Berria says the company will study real-life Afrezza use to see if patient enthusiasm translates into patient compliance, and that it will follow real-world Toujeo users to measure the practical effect of its longer, steadier flow of medication. “The goal in treating diabetes is to avoid peaks and valleys in both insulin and sugar, and Toujeo does that to a degree that once seemed impossible,” she said. “There’s no insulin spike when each new injection gets absorbed, and there’s no loss of efficacy in the final few hours. It’s a big stride forward from Lantus.”

Physicians have been using insulin to treat diabetes since 1922, when Frederick Banting and Charles Best injected the hormone into a diabetic teenager at a hospital in Toronto. Eli Lilly began producing it commercially within the year, and diabetes was transformed, virtually overnight, from a speedy death sentence to a chronic condition.5

Intermediate acting Neutral Prot-amine Hagedorn (NPH) insulin arrived about a quarter century later, in 1950. Long-acting insulin, on the other hand, didn’t reach patients until 2000, when Lantus went on sale in the United States and Europe.

The new drug reduced A1C levels about as much as NPH insulin, but trials demonstrated that it produced a greater reduction in fasting plasma glucose and fasting blood glucose as well as a far lower risk of nocturnal hypoglycemia.6

The other big advantage of Lantus was the convenience of longer action. Patients who had spent years toting around basal insulin and setting alarms for midday injections suddenly had nothing to carry and nothing to remember except a single injection before bed. By then, of course, insulin was not the only effective treatment for T2DM. The FDA had approved metformin in 1994, and its huge success spurred drug companies to develop the other oral treatments that now crowd the market.

Many of these treatments are quite effective, especially when used in combination. Indeed, if used properly, their excellent disease control could greatly reduce diabetic complications and the need for new drugs.

Yet pharmaceutical companies continue developing treatments like Toujeo and Afrezza because a huge percentage of diabetics fail to control their condition with current options. A recent study that examined records from more than 43,000 patients found that less than 55% of all Americans who have been diagnosed with diabetes, and prescribed medication to control blood sugar, actually man-age to keep their A1C level under 7%.7

The main cause of this problem seems to be patient behavior. Studies have found that patient adherence to oral treatment protocols can range from more than 90% down to just over 50%. Strict adherence to guidelines concerning injectable medications and proper diet tends to be lower, while strict adherence to guidelines concerning mod-erate, regular exercise and blood sugar checks is downright rare.8 The chance that any patient will adhere perfectly to a complex regimen is low, and studies of people with all types of chronic disease have typically found that only about half of them will make a serious effort to manage their condition.8

The consequences of this behavior are dire.

Diabetes is the nation’s seventh-lead-ing cause of death. It increases the risk of stroke (by 50%), heart attack (by 80%), and death from cardiovascular disease (by 70%). It is also the leading cause of kidney failure and non-traumatic lower limb amputation. The American Diabetes Association estimates that the di-rect medical cost of treating diabetes reached $176 billion in 2012, and indi-rect costs such as lost productivity add-ed another $69 billion to the tally.9

Studies have demonstrated that in-creased adherence to a treatment regi-men can reduce A1C levels,10 and many other studies have shown that A1C reductions prevent complications. A 1% reduction in A1C is associated with a 14% reduction in the risk of heart attack and a 40% reduction in the risk of eye, kidney, and nerve disease.11 (Logic says that better adherence would also slash healthcare costs, but the findings from research on that topic are mixed.10)

A number of experiments have tested different strategies for improving ad-herence to existing treatment regimens. Many have failed, but many others have produced significant gains, at least over the study period, with simple ap-proaches such as asking pharmacists to provide patients a little extra information.12 While some researchers continue to study ideas for motivating patients, others work to improve treatments.

Some people, for example, respond poorly to existing medications, so even if patients used existing options perfectly, there would still be a need for more effec-tive options. The biggest need, however, appears to be medications that promote compliance by making treatment regimens less arduous and more tolerable. Only real-world use will show if Toujeo and Afrezza meet that second need, but there are several reasons for hope.

For one, the reduction in nocturnal hypoglycemia associated with using Toujeo rather than Lantus is reasonably large. A meta-analysis of 3 of the drug’s phase 3 trials found a 31% reduction in such reactions among 2476 patients (risk ratio, 0.69; 95% CI, 0.57-0.84; P = .0002).13

While the biggest original selling point for Lantus may have been the relatively low rate of nocturnal hypoglycemia, low blood sugar remains a serious problem. Hypoglycemia is the primary cause of roughly 282,000 emergency department visits each year,9 and many patients fear it enough to risk high blood sugar by taking less insulin than their doctors prescribe.14

Thus, the lower nocturnal hypoglycemia incidence associated with Toujeo could produce 2 distinct benefits for patients who switch from Lantus:

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