The Power of Fixed-Dose Combinations – What SGLT-2 and DPP-4 Inhibitors Can Do in a Single Pill

By Rebecca Xu, Michelle Xie, Manu Venkat, and Emily Regier

Twitter summary: Combining SGLT-2 inhibitors and DPP-4 inhibitors into a single pill – how it works, who can benefit, & when it should be on the market

Short summary: Fixed-dose combination drugs combine multiple drugs into a single pill. Combinations of SGLT-2 inhibitors and DPP-4 inhibitors for type 2 diabetes are in development, with the potential to improve A1c and time-in-range. They may even lower co-pays. We explain how one pill can work through two completely independent mechanisms, as well as the advantages and disadvantages of using this new combination.

What are Fixed-Dose Combinations?

Fixed-dose combination (FDC) pills are pre-mixed combinations of usually two different drug classes into a single pill. Ideally, a fixed-dose combination pill will bring even greater benefits overall compared to the separate individual components – the key is combining two drugs that act on different targets in the body. In addition, combination pills can often use lower doses of the individual drugs, leading to fewer side effects. DPP-4 inhibitors (Januvia, Onglyza, Tradjenta, Nesina) and the newer SGLT-2 inhibitors (Invokana, Farxiga, Jardiance) are already used for managing type 2 diabetes, and combining them is an opportunity to further improve glucose control and increase convenience for patients. Indeed, Eli Lilly recently reported that one in four people with diabetes taking an SGLT-2 inhibitor are also separately taking a DPP-4 inhibitor, so many patients may already be familiar with taking these two drug classes separately. Pills in development include the combination of AstraZeneca’s Onglyza (saxagliptin) and Farxiga (dapagliflozin) and the combination of Eli Lilly/Boehringer Ingelheim’s Tradjenta (linagliptin) and Jardiance (empagliflozin).

How do DPP-4/SGLT-2 fixed-dose combinations work?

In combination, the individual DPP-4 inhibitor and SGLT-2 inhibitor components work as they would if they were in separate pills.

DPP-4 inhibitors increase the action of certain hormones (called incretins) to lower blood glucose by stimulating insulin production and reducing the output of glucagon (a hormone that releases sugar into the blood). DPP-4 inhibitors (pills) have only moderate effect in lowering A1c, although their side effects are usually minimal. They only stimulate insulin release when blood sugar levels are high, so the risk of hypoglycemia is low.

SGLT-2 inhibitors are novel in that they reduce blood glucose levels through an insulin-independent pathway – this is why they might one day be used to help type 1 patients. This drug class causes the kidneys to release glucose through urine, leading to a reduction in blood glucose only when glucose levels are high (the drug stops working when glucose levels come in to range). In an added benefit, the loss of glucose in the urine typically means 100-300 calories per day are not absorbed, explaining why SGLT-2 inhibitors are often associated with slight weight loss for some patients. There is some evidence of increased genital infections from SGLT-2 inhibitors, though these effects are modest and easily managed in most cases.

What do the clinical trials for AstraZeneca and Lilly/Boehringer Ingelheim’s combination pills (DPP-4 + SGLT-2 inhibitors) tell us? In past trials, both combinations have led to impressive A1c reductions (greater than 1% A1c reduction), as well as improvements in fasting and after-meal glucose levels. While no head-to-head studies have been conducted that compare the two fixed-dose combinations currently in development, they have both shown fairly similar results in their separate clinical trials.

What are the advantages and disadvantages of DPP-4/SGLT-2 fixed-dose combination drugs?

Who might benefit from DPP-4/SGLT-2 fixed-dose combination drugs?

• DPP-4/SGLT-2 inhibitor combinations are intended to be used primarily by people who …
• Have type 2 diabetes
• Don’t like needles
• Are currently taking other oral medications but are not reaching A1c goal levels
• Are currently taking a DPP-4 inhibitor and SGLT-2 inhibitor as separate pills
• Do not have an elevated risk of pancreatitis
• Do not have renal impairment

What options are there for DPP-4/SGLT-2 fixed-dose combination drugs?

There are no DPP-4/SGLT-2 FDCs currently available, though some are expected to come to market in the near future. The Jardiance/Tradjenta combo is already undergoing review by the FDA, and the Onglyza/Farxiga combo could be submitted to the FDA later this year. Assuming that the FDA review process takes about one year, Jardiance/Tradjenta could be available by early to mid-2015, and Onglyza/Farxiga could be available by late 2015 to early 2016.