GLP-1 receptor agonists and type 1 diabetes

Type 1 diabetes is characterised by autoimmune destruction of insulin-producing cells, with the result that the person is either absolutely or relatively insulin-deficient. The treatment must always be insulin replacement. If this is the case, why would we consider adding other medications given that we are already replacing the missing hormone? The answer is that people with type 1 diabetes are not exempt from other illnesses or causes of ill health. Overweight and obesity are as much of a problem for people with type 1 diabetes as for those without the condition. Indeed, the consequences of obesity may be more severe for people with type 1 diabetes as their risk of cardiovascular disease is already greater. Although overweight is not the primary driver of the disease in type 1 diabetes, it may contribute to further beta-cell loss.

There is also the argument that although we are replacing the human insulin normally produced by the beta-cells with injections of synthetic insulin, doing so can never completely mimic normal physiology. For a significant proportion of people with type 1 diabetes, achieving optimal glucose control with minimal hypoglycaemia is very difficult. What we therefore need is a medication that helps make glucose control easier and reduces the risk of obesity and the associated cardiovascular risk.

Glucagon-like peptide-1 (GLP-1) receptor agonists are now an established group of medications for the treatment of type 2 diabetes. They are modifications of the hormone GLP-1, which is produced by the gut during a meal. The naturally occurring hormone acts to enhance insulin production, decrease glucagon production and slow gastric emptying. There are also effects on satiety via actions within the brain. How can this help the treatment of type 1 diabetes? There will be minimal effects on insulin and glucagon production, as both are already significantly impaired in type 1 diabetes, and slowing gastric emptying is not an obvious advantage. We are left with the effects on weight.

A number of studies have looked at the use of GLP-1 analogues in type 1 diabetes. The results suggest that there are beneficial effects on weight and, with that, reductions in insulin dose. There are modest improvements in glucose control but perhaps increased rates of hypoglycaemia. Importantly, there were no worrying data about adverse events. The paper by Dejgaard and colleagues reviewed here represents a subanalysis of two studies published in 2016. The new information we have here is that no specific subgroup of the participants with type 1 diabetes particularly benefited from GLP-1 analogue use.

Perhaps most telling is the fact that the original studies were published 5 years ago and yet we have not seen any GLP-1 analogue licensed for use within type 1 diabetes. This does not necessarily mean that these medications do not have a place in the management of the condition, however.

Since the original papers were published, the management of type 1 diabetes has advanced: continuous and flash glucose monitoring give us a much better idea of glucose variability within an individual, and we now regularly measure C-peptide levels and are starting to get a clearer view of residual beta-cell function in people with type 1 diabetes. We would probably not use GLP-1 analogues in an individual with significant glucose variability and a high risk of hypoglycaemia. However, we might perhaps consider them in an individual with a higher BMI and a majority of glucose readings above target. The measurement of some residual C-peptide would further strengthen the case for using these medications. Unfortunately, such a clinical trial has not yet been performed.

Click here to read the Digest.