Adjunct therapies in treatment of type 1 diabetes

Abstract

In spite of developments with novel insulin preparations, novel modes of insulin delivery with insulin infusion pumps, and the facility of continuous glucose monitoring, only 20% of patients with type 1 diabetes are under adequate control. The need for innovation is clear, and, therefore, the use of adjunct therapies with other pharmacological agents currently in use for type 2 diabetes, has been tried. Currently, pramlintide is the only agent licensed for use in this condition in addition to insulin. Global trials have been conducted with liraglutide, a glucagon‐like peptide 1 receptor agonist (GLP‐1RA), dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and sotagliflozin, an inhibitor of both SGLT1 and SGLT2 transporters. While dapagliflozin and sotagliflozin have now been licensed for clinical use in this condition in Europe and Japan, they have hitherto not been licensed in the United States due to a small increase in the risk of diabetic ketoacidosis. However, these agents reduce glycosylated hemoglobin (HbA1c) by 0.4%, reduce glycemic oscillations, and do not increase the risk of hypoglycemia. Liraglutide, on the other hand, induced a smaller reduction in HbA1c and thus was not considered for a license. However, further trials are currently being conducted with a combination of semaglutide, the most potent GLP‐1RA, and dapagliflozin to determine whether this approach would yield better outcomes.

Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials

“…Moreover, despite the finding that the incidence of hyperglycaemia with ketosis observed in both trials was numerically higher with liraglutide than with placebo, the risk of DKA was very low with all doses of liraglutide As delineated above, it should be noted that several smaller trials have added to the evidence of the effects of liraglutide in people with type 1 diabetes. [11][12][13][14][15][16][17][18][19] The investigations have unanimously found no major safety concerns, including no increased risk of hypoglycaemia, and a meta-analysis has reported a lower risk of hypoglycaemia with liraglutide than with placebo. 11 Furthermore, no evidence has been reported to indicate increased risks of ketosis-accompanied hyperglycaemia or DKA with liraglutide, corroborating the results from the ADJUNCT trials.…”

“…These findings have been confirmed and expanded on by multiple investigations. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 In the ADJUNCT trials, a more pronounced placebo‐adjusted effect of liraglutide on HbA1c and a lower risk of hypoglycaemia were found for participants with residual beta‐cell function (as measured by C‐peptide levels) compared with participants without. Residual beta‐cell function, a clinically fundamental variable in the disease, remains the hitherto only identified anthropometric with significant impact on the effect of liraglutide in type 1 diabetes.…”

Multi-Faceted Influence of Obesity on Type 1 Diabetes in Children – From Disease Pathogenesis to Complications

“…As a synthetic analogue of amylin, a hormone that is secreted together with insulin, pramlintide supplements the action of insulin by decreasing postprandial glucagon output, delaying gastric emptying and promoting satiety ( 156 ). The Food and Drug Administration (FDA) has officially approved pramlintide as the only drug that can be used as a additional therapy to insulin to treat patients with type 1 diabetes in United States, but it should be noted that it is not approved for use in Europe ( 157 , 158 ). Studies show that pramlintide as an add-on therapy to insulin for patients with type 1 diabetes brings beneficial effects such as improving glycaemic control, reducing insulin dose and body weight, while causing transient hypoglycemia and gastrointestinal side effects such as nausea, vomiting and anorexia at the beginning of treatment ( 159 ).…”

“…Therefore, drugs that inhibit this transporter affect this process ( 83 ). SGLT2 inhibitors are available for the treatment of type 2 diabetes and the results of many studies have proven that they are safe and effective in treating this disease ( 157 ). In some countries, a few SGLT-inhibitors can be used as add-on therapy for patients with type 1 diabetes.…”

Minimising hypoglycaemia in the real world: the challenge of insulin

“…The purpose of these adjunct therapies is not to replace insulin but to achieve equal or better overall glycaemic control (reduced HbA 1c ), with more stable glucose curves (higher time in range [TIR]), less weight gain or less risk of hypoglycaemia. In particular, pramlintide, metformin and SGLT2 inhibitors have progressed to acceptance as adjunct therapies for type 1 diabetes by regulators or found their way into guidelines [39]. In particular, SGLT2 inhibitors have shown a clear effect on HbA 1c lowering and increased TIR (3.9-10.0 mmol/l [70-180 mg/dl]), while being insulin-dose sparing and resulting in reduced weight and systolic blood pressure in individuals with type 1 diabetes.…”