At a symposium on future therapies for patients with diabetes mellitus type 1 at the virtual Annual Conference 2020 of the European Association for the Study of Diabetes in September, Björn Eliasson presented non-insulin-containing therapies, of which only dapagliflozin has been approved to date in the EU. Eelco de Koning, (Leiden University Hospital), discussed the advantages and disadvantages of pancreatic and beta-cell transplantation.
Eliasson recalled that type 1 diabetes is characterized by the pancreas producing very little or no insulin. This severe insulin deficiency leads to a catabolic state with hyperglycemia and metabolic acidosis. The decisive pathophysiological mechanism is the destruction of beta cells in the pancreas. There is currently no convincing data suggesting that other mechanisms are involved in the development of the disease.
In the USA, the synthetic amylin analog pramlintide has so far been approved for patients with type 1 diabetes, but it is not widely used. Pramlintide is injected with food.
Amylin is a polypeptide hormone consisting of 37 amino acids, which is secreted by beta cells together with insulin. It is missing in type 1 diabetes. Amylin slows down gastric emptying, gives a feeling of satiety via hypothalamic receptors, inhibits glucagon secretion, and regulates the first postprandial phase of insulin secretion.
In clinical trials, pramlintide has been shown to reduce HbA1c and body weight, particularly in patients with a high baseline BMI.
Metformin is a standard therapy for diabetes mellitus type 2. Its benefit in type 1 diabetes is still being studied. A meta-analysis of 18 randomized trials and 1,183 people with type 1 diabetes showed that metformin reduces BMI, the required insulin dose, and total cholesterol levels. However, there was an increase in severe hypoglycemia and gastrointestinal adverse effects.
The double-blind, randomized REMOVAL trial with almost 500 type-1 diabetics showed that metformin led to better HbA1c levels and significant weight loss. The authors concluded from the results that long-term administration of metformin is less suitable for blood glucose control, but that it could reduce cardiovascular risk by lowering body weight and LDL cholesterol levels.
The combination of insulin with GLP-1 receptor agonists can reduce HbA1c by 0.21 percentage points, body weight by 3.5 kg, and insulin dosage, according to the results of a meta-analysis of 7 clinical trials involving only 206 type-1 diabetics.
In the ADJUNCT trials, the combination of insulin plus liraglutide led to an increased rate of hypoglycemia and increased hyperglycemia with ketoacidosis. Exenatide also failed to produce convincing results in the MAG1C trial.
So far it seems unlikely that GLP-1 receptor agonists will be indicated in addition to insulin for the treatment of patients with type 1 diabetes mellitus. Nevertheless, this therapeutic approach could be helpful for individual patients after careful individual testing.
The role of SGLT2 inhibitors is also not yet clear. Several studies, such as the DEPICT trials of dapagliflozin and the EASE trial of empagliflozin, have shown beneficial effects on body weight and an improvement in glycaemic control. There were no serious hypoglycemia or urinary tract infections. However, there was an increase in ketoacidosis and genital infections. So far there is no long-term data.
Dapagliflozin is authorized in the EU. It can be used to treat inadequately controlled type 1 diabetes mellitus in adults in addition to insulin in patients with a BMI ≥ 27 kg/m² if insulin alone does not control blood sugar sufficiently despite optimal insulin therapy.
Beta-cell replacement therapy includes pancreas transplantation, islet transplantation, and regenerative procedures. When assessing these procedures, however, other modern techniques that set the standard for the use of a transplant procedure must be considered - said Eelco de Koning. He mentioned closed-loop systems, which make the patient the "device operator". Modern techniques such as insulin pumps make many things easier for patients today. As a result, the risk of serious complications, such as amputations or kidney disease, is reduced.
At Leiden University Hospital, the Transplant and Diabetes Centres work closely together. Around 500 pancreas transplants have been carried out since 1984 and around 100 islet transplants since 2007.
For patients with type 1 diabetes and renal failure (GFR < 30 ml/min), who have no other serious concomitant disease and are not older than 55 years, a simultaneous pancreas-kidney transplant (SPK) is considered. If the patients are not suitable for this, a kidney transplant is considered. If only the pancreas is transplanted, the organ usually has a worse survival prospect. It is often rejected relatively early.
The waiting lists for this type of treatment are decreasing, however, because other forms of therapy such as pumps have made further progress, and complications are relatively common.
Type 1 diabetics after a kidney transplant can receive an islet transplant. The procedure is relatively low-risk. The most difficult part is isolating the islets from a pancreas. With islet transplantation, insulin independence can only be achieved in about 40 to 50% of patients. The function of the islets decreases relatively quickly. Only a partial remission is achieved.
A major disadvantage of the transplantation procedure is the side effects of the immunosuppression that is required throughout life. In addition, the isolated islets of Langerhans contain not only beta cells but a large number of other cells.
Source:
Symposium "What is the future of type 1 diabetes treatment", Virtual EASD Annual Meeting 2020. p14.