Adjuvant Liraglutide and Insulin Versus Insulin Monotherapy in the Closed-Loop System in Type 1 Diabetes

Abstract

Background: The closed-loop (CL) system delivers insulin in a glucose-responsive manner and optimal postprandial glycemic control is difficult to achieve with the algorithm and insulin available. We hypothesized that adjunctive therapy with liraglutide, a once-daily glucagon-like peptide-1 agonist, would be more effective in normalizing postprandial hyperglycemia versus insulin monotherapy in the CL system, in patients with type 1 diabetes. Methods: This was a randomized, controlled, open-label, crossover design trial comparing insulin monotherapy versus adjuvant subcutaneous liraglutide 1.2 mg and insulin, using the CL system in 15 patients. Blood glucose (BG), insulin, and glucagon concentrations were analyzed. Results: The liraglutide arm was associated with overall decreased mean BG levels ( P = .0002). The average BG levels from 8:00 pm (day 1) to 9:00 pm (day 2) were lower in the liraglutide arm (144.6 ± 36.31 vs 159.7 ± 50.88 mg/dl respectively; P = .0002). Two-hour postbreakfast and lunch BG profiles were better in the liraglutide arm ( P < .05) and the insulin and glucagon assay values were lower ( P < .0001). Postprandially, the area under the curve (AUC) for 2-hour postbreakfast and lunch BG levels were significant ( P = .01, P = .03) and the AUC for glucagon, postbreakfast ( P < .0001) and lunch ( P < .05), was also significant. The incidence of hypoglycemia did not differ between arms ( P = .83, Fisher’s exact test). Overall, adjunct liraglutide therapy plus CL was well tolerated even with expected side effects. Conclusion: This is a proof-of-concept study showing liraglutide can be a potential adjunctive therapy in addition to CL with insulin to reduce postprandial hyperglycemia in type 1 diabetes.

Short‐acting glucagon‐like peptide‐1 receptor agonists as add‐on to insulin therapy in type 1 diabetes: A review

“…[36][37][38][39][41][42][43][44]49 Significant reductions in total daily insulin dose in the ranges of 0% to 46% for bolus insulin and 0% to 49% for basal insulin have been reported, with only 1 study reporting an increase in total daily insulin dose. [36][37][38][39][40][41][42][43][44]48,49 In addition, reductions in body weight of −3.6% to −6.6% compared with baseline have been observed in these studies. [36][37][38][39][41][42][43][44]49 Recently, results from the 2 large-scale, randomized and placebocontrolled trials, Liraglutide as Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes (ADJUNCT) ONE and ADJUNCT TWO, were published.…”

“…These studies including liraglutide, mostly small‐scale, have reported conflicting effects on HbA1c, ranging from no significant changes to reductions between −0.4% and −0.9% (−4.4 and −9.8 mmol/mol) . Significant reductions in total daily insulin dose in the ranges of 0% to 46% for bolus insulin and 0% to 49% for basal insulin have been reported, with only 1 study reporting an increase in total daily insulin dose . In addition, reductions in body weight of −3.6% to −6.6% compared with baseline have been observed in these studies …”

Pramlintide but Not Liraglutide Suppresses Meal-Stimulated Glucagon Responses in Type 1 Diabetes

“…The Journal of Clinical Endocrinology & Metabolism; Copyright 2017 DOI: 10.1210/jc.2017-02265 gastric emptying (14,16,18,19,22,(28)(29)(30) with liraglutide surprisingly increasing the glucagon responses to mixed meal feedings after chronic treatment in type 2 diabetes and pramlintide being highly effective in delaying gastric emptying but with conflicting effects on glucagon secretion in T1D. (14,24) Our parallel studies of the use of pramlintide and liraglutide as adjunctive agents to improve control of post-prandial glucose excursions during closed-loop insulin delivery provided a unique opportunity to examine and compare the effects of these agents on dysregulated increases in plasma glucagon levels after meals.…”

Dual‐hormone artificial pancreas: benefits and limitations compared with single‐hormone systems

“…Novel adjunctive therapies may also obviate certain benefits of glucagon in the artificial pancreas. Recent studies have examined the effect of adjuncts such as pramlintide and glucagon‐like peptide‐1 agonists in combination with closed‐loop systems for prandial glucose control in Type 1 diabetes. These alternative therapies could affect the utility of the dual‐hormone artificial pancreas if prandial glycaemic excursions are stabilized, thereby limiting postprandial hyperglycaemia and the risk of late postprandial hypoglycaemia in a similar manner to that observed with the use of glucagon.…”