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Making insulin better

22nd March 2023

Over the one hundred years since its first use, insulin has undoubtedly saved many lives, yet it still does not fully meet the needs of people living with diabetes. However, there is cause for optimism, according to Melanie Davies CBE, Professor of Diabetes Medicine at the University of Leicester. She discussed improvements in insulin formulation and delivery – past, present and future – at ‘Revolutionising Diabetes Care: Celebrating 100 Years of Insulin Therapy’, a recent online conference organised by the Royal College of Physicians and Surgeons of Glasgow. Dr Susan Aldridge reports.

The original insulin was extracted from the pancreases of cows and pigs. When demand from people with diabetes looked as if it would exceed supply from animal sources, the semi-synthetic insulins were developed and entered general use from the 1970s – several with improved properties are now available. “However, there is still a significant unmet need for insulin,” said Professor Davies. Currently, up to 40% of people with diabetes worldwide – 150 to 200 million people – need it.

Fear of injection may be why there are often delays in initiation of insulin therapy, particularly among people with type 2 diabetes who could benefit. 

“Injections are still undoubtedly a major burden to insulin therapy,” said Professor Davies. Research shows that up to one third of people are not adherent to insulin, 93% would prefer to control their glucose without needing to inject and 59% of physicians identified multiple injections as a difficulty in diabetes care.

Meanwhile, people with type 1 diabetes have between one and three severe hypos per year, and those with type 2 diabetes have around one such event. Severe hypoglycaemia causes many emergency visits every year and has a serious impact on both health and quality of life. 

Innovation in insulins

Modern insulins do go some way to addressing these unmet needs. For instance, longer acting insulins mean fewer injections. They can be injected just once a day and now weekly insulin analogues are in development. “A once-weekly insulin could redefine diabetes management by reducing injections from 365 to 52 a year,” said Professor Davies. And research so far on weekly insulins shows that they can achieve comparable glucose lowering and safety to daily insulins. For instance, the ONWARD series of trials is studying insulin icodec, a weekly insulin. ONWARD2 looked at switching people with type 2 diabetes from insulin degludec to insulin icodec and showed a slight benefit in HbA1c and more participants reaching their 7% (53 mmol/mol) target with icodec, as well as more satisfaction with treatment.

The ideal insulin would be exactly like endogenous insulin and there have been many attempts to create a synthetic insulin that would mimic natural physiology and, in particular, to make it more hepatoselective. Natural insulin is distributed more to the liver than the periphery, whereas with synthetic insulins, distribution tends to be 50:50.

Basal insulin peglispro (BIL) is a more hepatoselective insulin. In the IMAGINE trial, which reported in 2015, BIL was compared with insulin glargine in a 78-week study involving people with type 1 and type 2 diabetes. “The results were really very impressive,” Professor Davies said. Mean HbA1c was 7.06% (54 mmol/mol) on BIL and 7.43% (58 mmol/mol) on insulin glargine. “You don’t often see such an improvement in HbA1c with analogue insulins and a reduction of 0.4% is clinically meaningful,” she continued.

BIL also had the advantage of reducing body weight by around 2 kg on average – another drawback of insulin being weight gain – and it reduced the rate of nocturnal hypos, although it did increase the rate of hypos overall. However, development of BIL had to be discontinued because of lipohypertrophy at the injection site and increases in liver enzymes and liver fat. However, efforts to develop a more hepatoselective insulin continue. 

Focus on insulin delivery

On insulin delivery, “this is where some of the exciting data exists and may be paradigm shifting,” said Professor Davies. For instance, so-called smart insulins are glucose responsive, which can already be achieved to a certain extent with continuous glucose monitoring and responsive pumps.

There are also innovations in insulins formulated in a glucose-sensitive polymer matrix that are in animal or early-stage clinical trials and may be introduced into diabetes care over the next few years. And the technical revolution in terms of apps and connected insulin pens has allowed progress such that 80% time in range is now achievable with hybrid closed loop systems.

Of course, oral insulin is perhaps the ultimate goal when it comes to insulin delivery. Discussions around oral insulin started back in the 1920s and it has always been pursued with enthusiasm. The various barriers in the gastrointestinal tract that prevent the delivery of peptide have been studied in detail and there has been some success with the delivery of oral peptides, such as GLP-1.

There has been development of pulmonary and nasal insulins on the way to an oral version, but these have not been particularly successful. Exubera, an inhaled insulin, was withdrawn from the US market in 2007 for commercial reasons and Afrezza, another inhaled insulin, is beset by practical issues. And then there is Oramed, a nanoparticle-based oral insulin, which got as far as a phase-3 clinical trial in type 2 diabetes. Unfortunately, results reported in January this year showed that Oramed is no better than placebo in lowering HbA1c, so the product has now been withdrawn.

“There have been significant advances in insulin therapy in the last 100 years,” Professor Davies concluded. “While there has been no breakthrough yet in oral insulin, there has been progress in basal insulins, while advances in diabetes technology like pumps and continuous glucose monitoring have improved our ability to make the most of the potential of insulin for people living with diabetes.”

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.