Incretin combination therapy: a breakthrough for type 2 diabetes?

Allie Nawrat 12 December 2018 (Last Updated December 12th, 2018 15:06)

With unmet needs remaining in type 2 diabetes, pharmaceutical companies are becoming more experimental when developing new treatments. One trend includes combining drugs in one class to determine if they are more efficacious than one drug alone. This trend has been applied to incretins, GLP-1 and GIP, with Eli Lilly recently publishing positive results for its drug candidate LY3298176.

Incretin combination therapy: a breakthrough for type 2 diabetes?
Investigating the combined mechanism of action of GIP and GLP-1. Credit: Max Pixel.

Despite being one of the most prevalent diseases in the world, diabetes, and particularly type 2 diabetes, remains a challenge for drug developers, which has pushed them to become increasingly innovative in creating therapies for the condition.

One therapeutic approach being studied and trialled by the pharma industry involves taking advantage of the mechanism of action of incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).

Despite success for some patients with GLP-1 receptor agonists, the industry is beginning to investigate if combining the two incretins into one medication can better treat type 2 diabetes.

Eli Lilly recently demonstrated superior clinical benefit from its combination of the two incretins compared to both placebo and GLP-1 receptor agonists.

Why is type 2 diabetes problematic for drug developers?

According to data from the International Diabetes Federation, globally 425 million people had diabetes in 2017, which represents 8.8% of the world’s population, and type 2 diabetes accounts for 90% of all cases.

Although the condition is massively prevalent on a global scale, prompting no small investment in drug development, there are many aspects of type 2 diabetes that remain a challenge to pharmaceutical companies.

There are some issues with sustaining glycaemic control. GlobalData managing healthcare analyst Dr Jesus Cuaron says: “All currently available treatments for type 2 diabetes are initially effective and reduce complication rates, but they lack the ability to maintain glycaemic control in the long term because of the progressive nature of pancreatic β-cell dysfunction. None of these agents has been shown to alter the natural history of the disease.”

He says there is a need for “treatments that bring sustained improvement in glycaemic control, with a focus on decreasing insulin resistance and preserving β-cell function”.

This challenge is not helped by suboptimal adherence to therapies, linked to the cost of drugs and the fact they are usually injectable rather than oral.

Diabetes UK research communications officer Dr Faye Riley also notes the importance of the industry using research to “better understand the underlying biology of type 2 diabetes”.

She adds: “It’s also vital that new drugs for type 2 diabetes do more than just lower blood glucose levels if they are to genuinely improve the lives of people living with the condition.

“They should, for example, take into account ease of use for people living with type 2 diabetes, how they affect people’s weight management and carry low risk of hypoglycaemia.”

Understanding the mechanism of incretins

GLP-1 receptor agonists such as Eli Lilly’s Trulicity and AstraZeneca’s Byetta represent a common treatment option for type 2 diabetes.

This treatment approach has a long history. In the early 20th century, researchers discovered gut hormones called incretins, which work by stimulating insulin secretion in a glucose-dependent manner from pancreatic ß cells; type 2 diabetics do not produce sufficient amounts of them.

The first incretin to be discovered was GIP and attempts were made to correct the low quantity in diabetics by providing them with naturally occurring doses of the hormone.

However, this approach failed to increase insulin secretion in patients, primarily because the hormone is rapidly metabolised by endoprotease dipeptidyl peptidase IV, and led to the search for a second incretin and the discovery of GLP-1, which acts more directly on islets in the ß cells.

At this point scientists began to develop analogue versions of the incretins, in which one amino acid was different. For GLP-1 receptor agonists, analogues are primarily superior to pure forms because they do not need to be administered through subcutaneous infusion.

Over time GIP has lost most of its insulinotropic effect in type 2 diabetes patients, but GLP-1 receptor agonists remain effective at stimulating insulin secretion.

Combining GIP and GLP-1 into a single therapy: Lilly’s LY3298176

Cuaron notes that combination therapies within one drug class have become popular in the type 2 diabetes field, which has led to investigation into whether a combined GIP and GLP-1 treatment could improve on the clinical benefits of GLP-1 receptor agonists.

Eli Lilly has been developing a dual GIP and GLP-1 receptor agonist called LY3298176 and, at the European Association for the Study of Diabetes’s 54th annual meeting, the company announced improvement across different endpoints in a Phase II trial compared to its GLP-1 receptor agonist Trulicity and placebo.

The trial specifically recruited patients whose type 2 diabetes was inadequately controlled by diet or stable treatment with metaformin.

National Research Institute president and principal investigator Juan P. Frias said: “The next wave of innovation in the study of incretins for treating type 2 diabetes is fascinating. We’re taking the already proven benefits of GLP-1 receptor agonists and looking at a new molecule that integrates GIP action to see what additional benefits are possible.”

At six months, primary analysis using statistical approaches showed an average reduction in Haemoglobin A1c (HbA1c) levels, a measure of glycaemic control, of 2.4% and an average weight reduction of 12.7% across the three doses of LY3298176.

The study also found that 69.1% of those taking 5mg, 90% of those taking 10mg and 77.4% of those taking 15mg of combination therapy achieved the recommended HbA1c target of 7% or less.

Unsurprisingly, the most significant reductions in HbA1c levels were observed for higher doses; 30% of those who received 15mg of the combination therapy and 18% of those who took 10mg achieved HbA1c levels of less than 5.7%, which is the normal range for people without diabetes.

HbA1c reduction for placebo was 0.1% and for Trulicity was 1.1%. Only 51.4% of those who took the latter achieved the 7% HbA1c target.

The safety profile of LY3298176 was similar to Trulicity and no participants experienced severe hypoglycaemia.

Frias continued: “These phase 2b clinical trial results for GIP/GLP-1 RA are unprecedented, and the impressive blood glucose and weight reductions seen may lead to a new treatment option for people with type 2 diabetes.”

Lilly Diabetes vice president of product development Jeff Emmick said: “We’re excited to continue studying GIP/GLP-1 RA and hope to add it to our wide range of therapies for people with diabetes.”

The company plans to further evaluate the safety and efficacy of the combination therapy in a larger Phase III study.

Although this data has shown efficacy compared to GLP-1 receptor agonist alone, Cuaron sounds a note of caution: “Late-stage trial data is still required in order to cement this claim, and also to provide information on which subset of T2D patients may benefit most from this therapy.”