Inhaled Insulin vs Rapid-acting Injections for Post-meal Glucose Control in Women With Gestational Diabetes

Gestational diabetes mellitus (GDM) affects up to 25% of births globally, and its rates continue to rise each year. Pregnancy is a dynamic time marked by rapid changes in physiology, anatomy, and metabolism that support the growth and development of the fetus. This period can also be vulnerable, as expectant mothers may experience shifts in body perception, food preferences, and physical fitness, which can lead to decreased self-esteem, depression, and anxiety. A diagnosis of GDM often catches women by surprise and may bring feelings of guilt and anxiety about the potential effects on their baby's health. For pregnant individuals unable to meet specific glucose targets through diet and exercise alone, insulin is recommended as the primary treatment. However, transitioning to insulin injections can provoke fear, stress, and discomfort-both emotionally and physically-for many patients. Consequently, some pregnant women opt for oral anti-diabetic medications like metformin or glyburide due to their apprehension about using insulin injections. Both of these drugs pass through the placenta and raise safety concerns, making them secondary choices according to the American Diabetes Association (ADA) and the American College of Obstetricians and Gynecologists (ACOG).

While GDM is typically managed with injectable insulin, inhalable insulin offers a potential alternative. Technosphere® Insulin inhalation powder (TI) is an ultra-rapid-acting insulin administered via oral inhalation using a breath-powered inhaler. It provides an alternative to injectable insulin for prandial glucose control. It consists of recombinant human insulin adsorbed onto fumaryl diketopiperazine (FDKP), a proprietary excipient that, at acidic pH, self-assembles into particles, and polysorbate 80. TI particles have a median diameter of approximately 2 to 2.5 μm, a size appropriate for inhalation into the lung. Following inhalation, Afrezza particles dissolve immediately at the physiologic pH of the lung, and insulin and FDKP are absorbed systemically. After administration of TI in adults, the maximum serum insulin concentration occurs in approximately 12 to 15 minutes (versus 45 to 60 minutes for RAA via subcutaneous route) and returns to near baseline levels in approximately 180 minutes (versus about 5 hours for RAA).

The United States Food and Drug Administration (FDA) approved TI Inhalation Powder and the Gen2 Inhaler (a dry powder device) as Afrezza® to improve blood sugar control in adults aged 18 years and older with diabetes on June 27, 2014. Inhaled TI has proven safe and effective in reducing postprandial (after-meal) hyperglycemia in individuals with Type 1 and Type 2 diabetes. It's important to note that TI units are not equivalent to injectable insulin units; TI's bioequivalent dose has been found to be about twice that of injectable rapid-acting insulin when prescribed for diabetes management.

All insulins, including TI, have a similar label wording with respect to use in pregnancy indicating that studies have not shown an association of insulin and birth defects and that there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. Insulin, whether subcutaneously administered or inhaled, has not been demonstrated to cross the placenta secondary to its large molecular weight. TI's inert excipient FDKP is not metabolized and is fully excreted from the body with the majority in urine and some in the feces (i.e. for the amount swallowed). Animal studies using subcutaneous administration of carrier particles at 21 times human dosing demonstrated no adverse fertility, teratogenicity, or other developmental outcomes (described in Afrezza label).

TI's optimal dosing, efficacy and risk for hypoglycemia in pregnancy is unknown. Outside of pregnancy, TI has been shown to cause less hypoglycemia than RAA insulin. The dose conversions of TI from RAA therapy have not been characterized in pregnancy to effectively administer across gestation with the dynamic metabolic changes, although insulin resistance is high in the 3rd trimester and dosing is expected to be at least as high as in patients with T2D (~2X SQ insulin dosing).

The goal of this investigator-initiated randomized crossover trial is to assess the efficacy of TI in lowering PP glycemia and the frequency of hypoglycemia compared with subcutaneous RAA insulin among pregnant individuals with GDM.