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

Chapter 2: Pursuing Non-Insulin Oral Medications for Type 1 Diabetes

Medications used to treat patients with T2D can also help stabilize blood sugar for patients with T1D.

Rev Endocr Metab Disord. 2021;2:217-240

Currently, only insulin and amylin are approved for adult type 1 diabetes (T1D) and only insulin for pediatric T1D. The burden of daily insulin injections contributes to less than ideal glycemic control. It has been postulated that the ability to take oral medication would reduce the burden and improve the balance between hyperglycemia and hypoglycemia. Unfortunately, insulin is readily degraded by the gastrointestinal environment making it unsuitable for oral administration. However, the desire for an oral insulin persists, and so researchers continue to explore ways to make it happen.

For patients with type 2 diabetes (T2D) there are multiple oral non-insulin medications that help this group maintain glycemic control. Several have mechanisms of action independent of insulin production and might benefit those with T1D.

Type 2 Adjunct Oral Therapies in Consideration for the Treatment of Type 1

Metformin

Metformin is in the biguanide class of drugs. It reduces hepatic production of glucose, decreases its absorption in the intestine and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In T2D patients, metformin can be taken once daily as either a pill or solution.

Because T1D patients have little to no insulin release, it is unclear if metformin would benefit this group; however, as our modern day sedentary lifestyles continue, weight gain, obesity and emerging insulin resistance can be additional burdens on those with T1D. Two recent placebo controlled, double-blind trials investigated the use of metformin in T1D overweight patients. In adults (> 40 yo) at risk for cardiovascular disease due to weight or family history, the REMOVAL trial found that metformin decreased weight and lowered low-density lipoprotein (LDL) cholesterol. These effects were minimal, however, and there were no indications that participants had lower A1C levels or decreased their daily insulin dosage. In overweight adolescents with T1D, 3 months of metformin reduced insulin resistance, as indicated by a change in glucose infusion rates, and caused moderate weight loss. Like the adult study, there were no changes in A1C levels. Thus, metformin may have small benefits in people with T1D, especially if overweight. Metformin is not approved for T1D in the US. It is possible that it never will be due to the fact it is available as a generic drug. Furthermore, there is a known risk of lactic acidosis observed in T2D.

The incidence of metformin-associated lactic acidosis among all users is relatively rare, with less than 0.1 cases per 1,000 patient-years, but it can have a high mortality rate once present. The incidence of lactic acidosis increases with different comorbidities and lifestyles. In patients with T2D and chronic kidney disease (CKD), the incidence of lactic acidosis increased to 1.96 cases per 1,000 patient-years. Add metformin into the treatment regime of T2D patients with CKD and the number of cases per 1,000 patient-years was 2.01. Therefore the addition of metformin treatment only slightly increased risk in this type of patient.

As CKD progresses, the risks become significantly greater. In T2D patients with an estimate glomerular filtration rate (eGFR) of greater than 59mL/min/1.73 m, the hazard ratio for lactic acidosis is negligible, 0.86 (95% CI 0.54-1.27). When eGFR levels fall below this range, the hazard ratio jumps to 2.26 (95% CI 1.59-3.19) and continues to rise as eGFR falls. More research is needed to determine if T1D patients with good renal function would experience a similar incidence rate of metformin-associated lactic-acidosis.

SGLT Inhibitors

Sodium-glucose linked transporters (SGLT) are accountable for nearly all renal glucose reabsorption. Inhibiting SGLT reduces blood glucose concentrations independent of pancreatic beta-cell function. While SGLT-2 receptors are found mainly in the renal proximal tubules, the SGLT-1 receptors can also be found in the gastrointestinal tract. Blocking SGLT-1 receptors specifically delays intestinal glucose absorption and may extend the post-prandial effect of SGLT inhibition. Therapeutics designed to interact with sodium-glucose transport focus on inhibiting SGLT-2 or the combination of SGLT-1 and -2.

In T2D, SGLT inhibitors are usually taken once a day before the morning meal. This class of drug has been shown to help patients achieve A1C targets, improve glycemic control, lose weight and reduce total daily insulin doses. The hope is that SGLT inhibitors can contribute the same benefits to T1D patients, especially those that are challenged by weight or at greater risk for hypoglycemia. The cardiovascular and renal benefits are assumed to be true for T1D patients as well, but more testing is needed.

While the SGLT inhibitors clearly have some benefit, the FDA has not yet approved them for T1D use due to the risk of diabetic ketoacidosis (DKA). The use of SGLT inhibitors is associated with increase glucagon levels, which can lead to lipolysis and ketogenesis. The ideal T1D patient then should be willing to monitor ketone levels as well as blood glucose levels, but there is hope that eventually the DKA risk will diminish with better mitigation strategies.

DDP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) is an enzyme that degrades digestive hormones, glucagon-like peptide 1 (GLP4) and gastric inhibitory peptide (GIP) almost as fast as they can be released. These incretin hormones support the release of insulin, decrease glucagon release and slow gastric emptying. DPP-4 inhibitors are a class of drugs that prevent GLP4 and GIP degradation, prolonging their ability to function. In T2D, DPP-4 inhibitors are taken once daily in a pill form.

There have been several studies investigating the benefits of DPP-4 inhibitors in T1D in the past 15 years. In general, T1D study participants experienced some weight loss, mild decreases in A1C and possible changes in LDL, and some were also able to reduce daily insulin doses. All of the effects though have been minimal, likely due to its influence, or lack thereof, on T1D insulin release. This leaves us to question the true clinical benefit in this patient population.

In conclusion, until an oral insulin medication can be formulated, clinicians can look to medications that show promise in treating patients with T2D, especially those that work independent of insulin or beta-cell function, to supplement treatment for patients with T1D.

Commentary

Next Article:
Chapter 3: Emergency Glucagon Delivery for Hypoglycemia Treatment
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