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Reducing Insulin Use and Improving Glycemic Control Via Single Dose of Glucagon-Blocking Drug

People with type 1 diabetes receiving once-daily injection of glucagon-blocking drug, REMD-477 can reduce their insulin use considerably and improve blood glucose levels without altering hypoglycemia.

It has been widely studied that glucagon has opposing actions to insulin by raising blood glucose levels through gluconeogenesis and glucose efflux from the liver. When present simultaneously in the healthy pancreatic islet, insulin serves to prevent glucagon secretion and allow for lipid and carbohydrate storage. The presence of insulin in islets of Langerhans allows a-cells to receive high concentration levels of insulin. However, because the range of paracrine levels reaching a-cells is high (2000-4000 UL/mL), it becomes difficult to achieve via the administration of insulin alone. In instances where insulin is deficient, an imbalance between the insulin-glucagon ratio arises. As such, glucagon begins to overproduce glucose and as a result leads to hyperglycemia in diabetics. Therefore, rather than administering monotherapy insulin to treat hyperglycemic episodes and improve clinical outcomes of people with type 1, the more ideal treatment method is to minimize the actions of glucagon.

Many studies have been formulated to minimize the actions of glucagon as an alternative to administering higher doses of insulin, in treating hyperglycemia. A study conducted on the first orally available glucagon antagonist BAY 27-9955 was tested on healthy men but was later discontinued. Several other attempts to block glucagon’s actions were made, including Merck’s MK-0893, which helped reduce fasting, and post-prandial plasma glucose levels in people with type 2 diabetes.  Moreover, in an issue of Diabetes Care, Christof Kazda et al review outcomes of phase 2a and 2bc clinical trials of the glucagon receptor antagonist (GRA) LY2409021. It was discovered that this GRA lowered blood glucose levels without increasing LDL levels. Administration of LY2409021 also reduced HbA1c levels by >2% thus placing emphasis on the fact that GRAs improve glycemic control without altering hypoglycemia better than providing insulin treatment alone. This discovery opened opportunities to explore GRAs actions in treating type 1 patients.

In more recent studies, the GRAs effects have been observed in people with type 1. In an article titled Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes, researchers observed the effects of a single dose of a glucagon-blocking drug REMD-477 in controlling blood glucose, without affecting hypoglycemia levels, in people with type 1 diabetes. A double-blind, randomized, placebo-controlled study was conducted with 21 adults; 8 of which were men and 13 were women. Prior to the study, individuals’ blood glucose levels were monitored via Continuous Glucose Monitoring (CGM). The patients were also given the same meals and IV insulin infusions. Of the patients, 10 received a single 70 mg injection of REMD-477 while the remaining 11 received a placebo injection. Patients receiving REMD-477 and the placebo injection were observed on the first day of the study and again on the fourth day.

With daily insulin use and continuous blood glucose monitoring, results indicated that individuals receiving REMD-477 were able to reduce their insulin use by 12 units versus those receiving the placebo (p=0.02). Blood glucose levels assessed for 8 weeks were 20-31 mg/dL lower in patients receiving REMD-477 compared to those receiving the placebo (p<0.05). Because the effects of REMD-477 are long acting, this poses a possibility for the drug to be administered once weekly versus every day.

This study supports the assumption that blocking glucagon levels can greatly impact the treatment of people with type 1 diabetes. However as with all small molecule antagonists, there has been some elevation in plasma liver enzymes but no elevation in bilirubin levels or indication of liver damage. The elevation in liver enzymes is associated with the pharmacology of glucagon, therefore posing no drug-drug interaction when combining GRAs with other anti-diabetic agents. Since the study focused on a single dose of REMD-477, researchers are inclined to perform alternate studies using more patients and observing the effects of weekly injections of two different strengths of said drug over a longer time period.

Practice Pearls:

  • Past studies have been conducted to observe the effects of glucagon receptor antagonists in the treatment of diabetes.
  • The glucagon-blocking drug, REMD-477 has shown promising results in the treatment of people with type 1 diabetes without altering hypoglycemia.
  • More studies showing the effects of REMD-477 and other glucagon receptor antagonists on a wider population and over a longer time period are under way.

References:

Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes.” American Diabetes Association. N.p., n.d. Web. 28 June 2017.

McCormack, James. “Glucagon antagonism.” Management – Diapedia, The Living Textbook of Diabetes. N.p., n.d. Web. 28 June 2017.

Pearson, Mackenzie J., Roger H. Unger, and William L. Holland. “Clinical Trials,     Triumphs, and Tribulations of Glucagon Receptor Antagonists.” Diabetes Care. American Diabetes Association, 01 July 2016. Web. 28 June 2017.

 

Nuha Awad, Doctor of Pharmacy Candidate: Class of 2018; ACCP|FSHP