No Adjunctive Drug Candidates Promise
to Overcome Insulin Infusion Defects

Conventional treatment of T1D orbits around insulin replacement.  The textbook etiology of T1D is straightforward: autoimmune destruction of beta-cells leads to an absolute deficit of insulin, which results in glucose starvation and diabetic ketoacidosis.  The obvious solution is to infuse exogenous insulin in a manner that closely mimics endogenous secretions.

Thus, innovations since the discovery of insulin have focused on improving insulin therapy, including new insulin formulations, better delivery technologies, continuous glucose monitoring, and most recently AID.  In all cases, insulin remains the center of the T1D universe.  “(T)he existing dogma – that the clinical features of the disease were entirely due to lack of insulin – was not easily abandoned.” (2017) [1]

As we’ve pointed out, subcutaneous delivery of insulin faces pharmacokinetic and physiological barriers to closely mimicking beta-cell secretions.  With insulin development facing diminishing returns, non-insulin adjunctive drug therapies have been under consideration.

To date only two drugs have FDA approval as adjuncts to insulin for treating T1D:

  • Glucagon:  Lilly introduced glucagon in 1960 as a remedy for insulin induced hypoglycemia.  More recently several companies have been working on stable liquid formulations that could be used in dual hormone AID systems.  To quote a 2017 review:  “In direct comparison, dual-hormone systems have been shown to be superior to single-hormone systems in preventing hypoglycaemia and achieving target glucose concentrations in response to meals and exercise.” [2]  However, as we discuss in a subsequent section, glucagon is indicated for use after the onset of hypoglycemia and does not directly address the pharmaceutical limitations of insulin infusions that raise the risk of hypoglycemia.  In effect, glucagon is a band-aid to cover up the wound caused by insulin.

  • An amylin agonist:  Pramlintide has been shown to sharply reduce postprandial spikes in blood glucose. [3]  However, the benefit of this for HbA1c is modest at about 0.33% HbA1c. [4]  Nausea and additional injections have discouraged use, with the result that, after fourteen years of marketing, pramlintide has not become a major diabetes drug.

Other FDA-approved diabetes drugs have been proposed as candidates for T1D indications:

  • Metformin: A survey of 197 studies showed insulin-dose reductions, but no benefits for cardiovascular and other key clinical outcomes, including glycemic control. [5] [6]

  • GLP-1 agonists: A survey of 9 clinical trials showed only weight benefits, while gastrointestinal adverse events were common. [7] 22  A GLP-1 agonist was also tested for improving hypoglycemia unawareness in T1D; results were negative. [8] From a March 2020 report: [9] “Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes.”

  • DPP4 inhibitors: Studies demonstrated no increase nor decrease the risk of hypoglycemia, nor was there a decrease in HbA1c levels. 22 [10]

  • SGLT inhibitors: Studies have showed modest HbA1c improvements with increased risk of diabetic ketoacidosis. [11]  A recent study showed a reduction of time in hyperglycemia, but no change of time in hypoglycemia. [12]  In March 2019 Sanofi’s SGLTi indication for T1D received a Complete Response Letter (turn-down) by the FDA. [13]  In March 2020 the candidate sponsored by Lilly and Boehringer Ingelheim was also rejected by the FDA. [14] The European Medicines Agency approved an SGLTi only in overweight, obese T1D patients. [15]

  • Triple therapy: Investigators are testing whether the addition of dapagliflozin and semaglutide could improve HbA1c in T1D. [16]

It’s important to note that these candidates target glucose control mechanisms which are not directly linked to beta-cell failure.  Thus, they do not address the core defect of T1D.

To summarize, the situation for T1D patients is frustrating.  Progress toward normalizing HbA1c has stalled, further breakthroughs in insulin therapy are unlikely short of IP delivery, and other anti-diabetic drugs appear to be of limited value.  What’s needed now is a new disease model that reconsiders the pathophysiology of beta-cell destruction and looks beyond the obvious insulin deficiency.

As a first step in pursuing this hypothesis, we step back and reassess the basic insulincentric therapy model, and we ask might there be a basic flaw in the popular understanding of T1D pathophysiology?

Endnotes

[1]  Insulin and glucagon: partners for life; Endocrinology 158(4):696-701 2017.

[2]  Effect of artificial pancreas systems on glycaemic control in patients with T1D - a systematic review and meta-analysis of outpatient randomised controlled trials; The Lancet Diabetes & Endocrinology 5:501-12 2017.

[3]  Adocia announces positive topline results for the first clinical study of ADO09, a new co-formulation of pramlintide and a prandial insulin analog, in people with type 1 diabetes; Adocia Press Release April 9 2019.

[4]  SYMLIN (pramlintide acetate) Injection Prescribing Information.

[5]  The use of metformin in type 1 diabetes: a systematic review of efficacy;  Diabetologia 53:809-20 2010.

[6]  Adjuvant pharmacotherapies to insulin for the treatment of type 1 diabetes; Current Diabetes Reports 18:article79 2018.

[7]  GLP-1 agonists in type 1 diabetes mellitus; Annals of Pharmacotherapy  50:656-65 2016.

[8]  Effect of the GLP1-1 receptor agonist exenatide on impaired awareness of hypoglycemia in type 1 diabetes; a randomized controlled trial; J Clin Endocrinol Metab Epub ahead of print 2019.

[9]  Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial; Lancet Diabetes & Endocrinology Online March 2 2020 https://doi.org/10.1016/S2213-8587(20)30030-9.

[10]  The efficacy and safety of DPP4 inhibitors in patients with type 1 diabetes: a systematic review and meta-analysis; Diabetes Research and Clinical Practice 121:184-91 2016.

[11]  SGLT inhibitors for type 1 diabetes: an obvious choice or too good to be true?; Diabetes Care 41:2444-7 2018.

[12]  Glucose Variables in Type 1 Diabetes Studies With Dapagliflozin: Pooled Analysis of Continuous Glucose Monitoring Data From DEPICT-1 and -2; Diabetes Care (ePub ahead of print) 2019.

[13]  FDA knocks back diabetes drug from Sanofi, Lexicon; BiopharmaDive March 22, 2019.

[14]  US FDA issues complete response letter for empagliflozin 2.5 mg as adjunct to insulin for adults with type 1 diabetes; https://www.prnewswire.com/news-releases/us-fda-issues-complete-response-letter-for-empagliflozin-2-5-mg-as-adjunct-to-insulin-for-adults-with-type-1-diabetes-301027705.html March 20 2020.

[15]  First oral add-on treatment to insulin for treatment of certain patients with type 1 diabetes; European Medicines Agency 2019.

[16]  Triple therapy in T1DM;  ClinicalTrials.gov NCT03899402 2019.