Generic DPP-4 Inhibitors Would Be a 'Shot in the Arm'

In September, Indian drug manufacturer Alembic received a tentative nod from the US Food and Drug Administration (FDA) to manufacture generic alogliptin as well as the alogliptin/metformin fixed-drug combination. As the first generic DPP-4 inhibitor class of medications enters the US market, it will be interesting to see how the prescriptions of other DPP-4 inhibitors that are still on patent, as well as other classes of diabetes medications, are affected.

Akshay B. Jain, MD

In 1984, Congress passed the Hatch-Waxman Act, which made it easier for the pharmaceutical industry to produce and market generic medications in the United States.^[1] As of 2012, 84% of all US prescriptions were dispensed as generics.^[1] Today, pharmacists in many states are required to dispense the generic version of a drug unless a doctor specifies otherwise.

The FDA approval of a generic drug requires demonstrability of bioequivalence or similar quality and performance as the original innovator drug. Although manufacturers aren't required to prove therapeutic equivalence in clinical trials, it is presumed that one would see similar efficacy, as the chemical composition is similar.

Mixed Perceptions About Generics

Despite the intense regulations and criteria laid down by the FDA for the quality of generic medications, perceptions of generic drugs by the public seem to be mixed.

In a survey^[2] of more than 1000 people, conducted by researchers at Brigham and Women's Hospital, 94% of respondents agreed that generics were less expensive than branded drugs, and fewer than 10% felt that generics were associated with more side effects. Yet, when asked if they preferred taking generics versus branded drugs, only 37.6% of the respondents said yes.

The general public is not alone in harboring these perceptions. When the same researchers analyzed physician perceptions about generic medications,^[3] half of approximately 500 physicians expressed negative perceptions about the quality of generic medications, and more than 25% would not want to use generics for themselves or their family members.

Physicians older than 55 years of age were 3.3 times more likely to report negative perceptions about the quality of generic drugs, 5.8 times more likely to report that they would not use generics themselves, and 7.5 times more likely to state that they would not recommend generics for family members (P < .05 for all).

Events like the $500 million lawsuit against Ranbaxy in 2013 for manufacturing subquality generic atorvastatin, or the 2012 discontinuation of the 300-mg generic formulation of extended-release bupropion hydrochloride, may have contributed to some of this mistrust, but most people agree that these instances are few and far between.

Despite the ambiguity in perception, there is no denying that the generic drug market is omnipresent and has led to significant savings for the cash-strapped healthcare budget. In 2017 alone, generic drugs generated a total of $265 billion in savings. Savings for Medicare and Medicaid were $82.7 billion and $40.6 billion, respectively.^[4]

How Generic DPP-4 Inhibitors Have Changed a Market

Since their original launch more than a decade ago, DPP-4 inhibitors quickly became one of the most popular classes of medications to be prescribed after failure of metformin monotherapy for the management of type 2 diabetes.

Factors that helped the surge in prescriptions include the low risk for side effects (eg, a very low rate of hypoglycemia compared with sulfonylureas), once-daily dosing, weight neutrality, availability of fixed-drug combinations, and cardiovascular outcomes trials suggesting no increase in the rate of 3-point major adverse cardiovascular events (MACE) when compared with placebo.

Generic DPP-4 inhibitors have been available in other countries for several years, and their uptake has been quite overwhelming. Case in point is the success story of teneligliptin in India.

This DPP-4 inhibitor, originally developed in Japan, was launched in India in 2015 as a generic molecule. Within 1 year, its annual growth was 100%, versus the annual growth rate of 40% for other agents, such as sitagliptin, vildagliptin, saxagliptin, and linagliptin.^[5] This was largely attributed to the fact that teneligliptin was less than a fourth of the cost of other DPP-4 inhibitors.

However, the story doesn't end there. By 2017, the annual growth rate for teneligliptin shot up to 250%.^[6] With more than 100 generic versions of teneligliptin now available on the Indian market, intense competition led to a further reduction in the cost, making it widely affordable.

The current market share of teneligliptin in India is estimated to be about $70 million annually, despite teneligliptin having no prospective cardiovascular outcomes trials, unlike its counterparts.

How Does Alogliptin Compare?

In the United States, the average wholesale price per unit of alogliptin is about $7.80, nearly 55% cheaper than the brand-only molecules in its class, and this might get even cheaper depending on the number of entrants in the generic domain.

There remains a relative paucity of data evaluating head-to-head trials between alogliptin and other DPP-4 inhibitors, and most of the information we have is from meta-analyses showing that alogliptin, when compared with other DPP-4 inhibitors, can be either similar^[7] or less effective^[8] in terms of A1c reduction potential. However, in the absence of properly conducted head-to-head trials, the definitive answer remains elusive.

Cost Savings and Other Benefits

An important consideration would be whether the availability of generic DPP-4 inhibitors could affect the prescription pattern of other classes of agents, such as sulfonylureas or thiazolidinediones (TZDs).

In an Italian study,^[9] researchers reported that when compared with sulfonylureas, higher drug costs related to sitagliptin were offset by other management costs (less frequent utilization of test strips for self-monitoring of glucose, lower incidence of hypoglycemia and MACE, and delay in initiation of insulin).

The study estimated that over 3 years as an add-on to metformin, the use of DPP-4 inhibitor therapy could lead to an estimated cost savings of $ 69.6 million for the Italian National Health Service. It also estimated that utilization of DPP-4 inhibitor therapy in 100,000 patients with diabetes would avoid 26,882 minor hypoglycemic events, 6528 severe hypoglycemic events, and 1562 MACE.^[7]

A recent study conducted from a US third-party payer perspective estimated that the discounted incremental cost of metformin + DPP-4 inhibitor compared with metformin + sulfonylurea was $11,849, with 0.61 life-years gained on DPP-4 inhibitor therapy.^[10] This could further change dramatically if the costs of DPP-4 inhibitor therapy were to decrease once generic variants are available.

Conclusion

Currently, most guidelines accept the role of DPP-4 inhibitor therapy as an effective second- or third-line therapy in the management of type 2 diabetes. These agents are particularly useful in reducing postprandial hyperglycemia, and the incretin effect stimulates insulin production and inhibits glucagon levels in these patients.

DPP-4 inhibitors are typically associated with a mild to moderate A1c reduction potential, with greatest efficacy when used earlier following the diagnosis of diabetes. The low risk for hypoglycemia makes this class of agents particularly lucrative when compared with sulfonylureas.

The EXAMINE trial showed noninferiority of alogliptin when compared with placebo in the occurrence of 3-point MACE in high-risk patients following ACS.^[11] The average patient with type 2 diabetes is already burdened by the costs of medications such as antihyperglycemic and antihypertensive agents, along with costs associated with the self-care of diabetes.

DPP-4 inhibitors have wide applicability for patients with type 2 diabetes because of their efficacy, durability, lack of hypoglycemia, and weight neutrality. The availability of cheaper generic options will be a shot in the arm for this class of agents by significantly increasing access for patients.

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