Beyond Insulin
Patients with Type 1 diabetes rely on insulin, but other medications are increasingly prescribed to help stabilize blood sugar levels, as well as secondary symptoms such as hypoglycemia. This journal scan will discuss the most recent literature on the efficacy and administration of supplemental treatments for Type 1 and 2 diabetes.
May 2021
Volume 10, Issue 2

Introduction

Illustration of figures on a seesaw

To a person with type 1 diabetes (T1D), insulin is necessary but not sufficient to maintain glucose homeostasis. Glycemic control is at the fulcrum with insulin treatment on one side and glucagon on the other; however, this leaves many patients with diabetes constantly teetering between hyperglycemia and hypoglycemia. In a self-report survey, no more than 25% of T1D patients felt that they were very successful at achieving time in range (TIR) goals. The Advanced Technologies & Treatments for Diabetes (ATTD) suggests that T1D patients try to achieve a TIR of 70%, with time above range (TAR; hyperglycemic state) less than 25% and time below range (TBR; hypoglycemic state) less than 4%.

Unfortunately, many patients and their families are fearful of the more severe effects of hypoglycemia and thus tend to become more tolerant of hyperglycemic states. Although low blood sugar can have immediate and severe consequences, the long-term effects of high blood sugar are also concerning. This leaves many patients with diabetes questioning how to get off this seesaw. 

Glucose monitors provide real-time data regarding blood glucose levels with programmable threshold alarms to warn people when they deviate from normal levels. Inhalable insulin provides accessible prandial insulin dosing, while keeping glucagon on hand for hypoglycemia also reduces guesswork for patients in the middle of an episode. Drugs that have previously been used to treat T2D circumnavigate insulin, and instead have tackled deviations in blood glucose through other mechanisms, are now being explored as supplementary treatments for T1D.

Sodium-glucose linked transporters (SGLTs) are responsible for nearly all renal glucose reabsorption. Drugs that inhibit this process, SGLT inhibitors, reduce blood glucose concentrations independent of pancreatic beta cell function.

Glucagon-like peptide-1 (GLP-1) induces insulin release from pancreatic beta cells; however, receptors found in the gastric mucosa, kidneys and hypothalamus point us to the other roles played by GLP-1, including muting post-prandial glucagon release, slowing gastric emptying and increasing feelings of satiety. FDA-approved drugs in both of these categories have helped T2D patients achieve A1C targets, improve glycemic control, lose weight and reduce total daily insulin doses. In addition, these drugs may provide benefits against cardiovascular and renal diseases.

C-peptide was originally thought of as an inert by-product of proinsulin cleavage. It was useful as a measure of residual insulin production in newly diagnosed T1D patients, but recent preclinical and clinical research suggests it has a role in mitigating the effects of long-term hyperglycemia. Studies suggest that C-peptide may help preserve vascular endothelial cells through antioxidant and anti-inflammatory mechanisms. Preservation of the microvasculature reduces cardiovascular and renal diseases as well as diabetic neuropathies and retinopathy.

A surprising number of T1D patients still have residual C-peptide production, due to an incomplete suppression of the beta cell function, even years after diagnosis. Davis et al. found that patients who were older at diagnosis (>18 yo) were more likely to have residual C-peptide, but those levels dropped in the years post diagnosis.

The importance of residual C-peptide, and in theory residual insulin production, is found in the ADJUNCT ONE and TWO studies. These are two of the largest studies investigating the effects of a GLP-1 agonist (liraglutide) in T1D patients. They found that in a subpopulation of T1D patients with residual C-peptide, A1C levels were lower and there were fewer incidents of hypoglycemia and hyperglycemic ketosis while on GLP-1 treatment. It is hypothesized that the best T1D candidates for GLP-1 treatments, then, are those with residual C-peptide levels.

There are new drugs on the distant horizon as well. Glucagon receptor antagonists have a low risk of hypoglycemia while lowering A1C levels in T2D patients. Most recently, small molecule glucokinase activators have some benefit in T1D, inducing mild reductions in A1C levels and decreasing the frequency of severe hypoglycemic events without apparent risk of ketosis.

In this journal scan, we take an in-depth look at various therapeutics that influence glycemic control. The majority of which are on the other side of the glycemic fulcrum from standard injected insulin. As many of the risks and comorbidities present in T2D are also in T1D and often with greater frequency, we consider how to facilitate FDA-approved T2D treatments towards treating T1D when beneficial.

First Article:
Chapter 1: Non-Insulin Injectable Medications
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