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Use of non-insulin medications for type 1 diabetes

DiabetesDialogue_PBMarApril17_Bregman
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People with type 1 diabetes are not able to produce insulin and therefore treatment has primarily focused on replacing insulin via injectable therapy.

 

By Shelley Diamond, BScPhm

Illustration by Martin Bregman

 

The current technologies using insulin analogs and insulin pumps combined with continuous glucose monitoring systems have resulted in significant improvements in type1 diabetes management. There are still challenges, however, that remain and these include the added risk of hypoglycaemia that occurs with tight glycemic control as well as weight gain, a potential side effect of intensive insulin therapy.

Although insulin resistance is thought to occur mainly in those with type 2 diabetes, it has been increasingly identified in type 1 diabetes, largely due to genetic mutations of the disease as well as the increasing occurrence of obesity in this population. This means that medications that have largely been limited to treating type 2 diabetes, may offer a potential therapeutic benefit for those with type 1 diabetes. Therapies that improve insulin sensitivity and glycemia as well as those that decrease cardiovascular risk factors have been considered.

 

Metformin

Metformin has gained significant interest in recent years as an adjunct therapy for type 1 diabetes due to its role as an insulin sensitizer. Metformin has shown mixed effects on glycemic control and some studies have shown modest improvements in A1C and/or reduction in the total daily insulin dose. Some studies that have shown significant improvement in weight reduction while others have not shown any benefit. Metformin appears to be beneficial in adolescents with type 1 diabetes with evidence of insulin resistance, leading to reduction in total daily insulin dose.

 

Thiazolidinediones

Studies using thiazolidinediones in type 1 diabetes have not shown any benefit to date. The decrease in their use based on their potential side effect profile makes them less desirable as an add-on medication for people with type 1 diabetes.

 

Alpha-glucosidase inhibitors

Although this class of drugs helps to reduce the postprandial glycemic peak in individuals with type 1 diabetes, similar to their use in those with type 2 diabetes, gastrointestinal side effects may limit their use.

 

DPP-4 inhibitors

Of the currently marketed DPP-4 inhibitors, sitagliptin has been studied the most for use in type 1 diabetes. Only a few small studies have been done but they have shown improvements in glycemic control, postprandial glucose and reductions in insulin dosage. There is also a potential beta-cell preserving effect that has been seen in animals but still requires further study in humans.

 

Glucagon-like peptide-1 agonists

Studies using GLP-1 agonists have suggested that these agents may reduce A1C levels, fasting and postprandial glucose levels, insulin mealtime doses, and body weight without an increased risk of hypoglycaemia.  Currently, liraglutide is indicated for the treatment of obesity in Canada, under the tradename ‘Saxenda’. However, it is not currently approved for use with insulin, however studies have investigated this combination.

The largest studies, ADJUNCT-ONE and ADJUNCT-TWO demonstrate modest benefits when liraglutide is added to insulin therapy. The decrease in A1C was approximately 0.2% and not clinically significant.

The limitations of cost, increased injections, an increase in hypoglycaemia and hyperglycemia with ketosis, and the lack of information regarding long-term complication reduction suggest that their widespread use for type 1 diabetes is not likely to become standard management at this time.

 

SGLT2 Inhibitors

Several studies have been done or are underway to review the role of SGLT2 inhibitors as add-on medication for type 1 diabetes. Reduction in A1C, as well as bolus and total daily insulin, and weight loss were demonstrated in some studies. However, there has been an increased incidence of diabetic ketoacidosis with the use of SGLT2 inhibitors, and some instances have occurred in the absence of hyperglycemia. Careful monitoring of ketones is therefore recommended, especially when used in those with type 1 diabetes.

 

Conclusion

There is currently not enough information to recommend regular use of non-insulin medications for individuals with type 1 diabetes. The risk of hypoglycaemia and ketoacidosis as well as the added dosing and cost may limit their use until more evidence shows that they can reduce insulin dosing and limit weight gain. Time will tell!

 

REFERENCES

 

  1. Cleland SJ, Fisher BM, Colhoun HM, et al. Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks? Diabetologia 2013;56(7):1462-1470.
  2. Harris KB, Boland CL. Adjunctive role of glucagon-like peptide-1 receptor agonists in the management of type 1 diabetes mellitus. Pharmacotherapy 2016;36:1011-20.
  3. Ahren B, Hirsch IB, Piever TR, et al. Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes: the ADJUNCT TWO randomized trial. Diabetes Care 2016;39:1693-701.
  4. Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care 2016;39:1702-10.
  5. Munir KM, Davis SN. The treatment of type 1 diabetes mellitus with agents approved for type 2 diabetes mellitus. Expert Opin Pharmacother 2015;16(15):2331-2341.
  6. Bacha F, Kllinepeter BS. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type1 diabetes. Pediatr Diabetes 2016;17:545-588.