American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

Just a few years shy of a century ago, a group of Canadian researchers discovered a viable method of extracting insulin, filling a large and critical gap in the therapeutic treatment of diabetes (1). Since then, insulin and its associated delivery devices have become an integral part of the care and management of patients living with diabetes. Shortly after the first insulin injection was successfully delivered, vials of insulin became available commercially. At this time, large glass syringes were used to administer insulin, and each injection required sterilization of the syringe, as well as sharpening of the syringe needle with a pumice stone. Through the years, insulin syringes modernized, but it was not until the 1970s that an alternate delivery system—the insulin pump, used in continuous subcutaneous insulin infusion (CSII) regimens—became available. Fifteen years later, the first insulin pen was introduced to the marketplace, providing evidence that, as time progresses, there is no shortage of innovation in the diabetes arena.

The first two rapid-acting inhaled insulins on the market—Exubera in 2006 and Afrezza in 2014—represented yet another innovation milestone. In theory, inhaled insulin completely eliminated the psychological barriers associated with subcutaneous insulin delivery, such as needle phobia and incorrect injection technique. However, in October 2007, Pfizer withdrew Exubera from the market, and in January 2016, Sanofi withdrew from a $925 million marketing agreement with MannKind for Afrezza; both removals were due to poor sales volume. Although patients and providers have been searching for years for alternatives to injecting insulin, Exubera has already failed, and Afrezza’s destiny is uncertain.

In 2006, Exubera was the first inhaled insulin approved by the U.S. Food and Drug Administration (FDA). It showed noninferiority in efficacy with regard to A1C lowering in both type 1 diabetes (2) and type 2 diabetes (3) compared to mixed regular/NPH …

https://spectrum.diabetesjournals.org/content/diaspect/29/3/180.full.pdf

Commentary: Why Was Inhaled Insulin a Failure in the Market?

Afrezza® (insulin human) inhalation powder is a rapid-acting Technosphere® insulin (TI) administered via a breath-powered oral inhaler to patients with diabetes requiring prandial insulin TI, a dry powdered formulation of recombinant human insulin adsorbed onto a proprietary carrier, is designed to deliver insulin to the deep lung, at the level of the alveoli, where it is absorbed into the systemic circulation In a randomized, open-label, multinational, phase III trial (trial 171) in type 1 diabetes (T1DM) patients, prandial TI via the Gen2 inhaler provided noninferior glycated haemoglobin (HbA1c) lowering compared with prandial subcutaneous insulin aspart Although TI was associated with less HbA1c lowering, it provided significantly lower fasting plasma glucose levels and significantly less hypoglycaemia and bodyweight gain compared with insulin aspart In a randomized, double-blind, placebo-controlled, multinational, phase III trial (trial 175) in type 2 diabetes (T2DM) patients, prandial TI via the Gen2 inhaler provided superior HbA1c lowering compared with inhaled placebo Cough was the most commonly occurring non-hypoglycaemia adverse event across both studies In a pooled analysis of tolerability data from phase II and III studies, the most commonly occurring non-hypoglycaemia adverse events in T1DM and T2DM patients were cough and throat pain/irritation However, cough was generally mild, dry and decreased over time In addition, treatment with TI was associated with positive patient-reported outcomes Insulin human inhalation powder is an effective and generally well-tolerated agent for the prandial treatment of hyperglycaemia in T1DM and T2DM patients and may provide a solution to insulin initiation barriers such as injection phobia, concerns of bodyweight gain and concerns of hypoglycaemia

AFREZZA® (insulin human) Inhalation Powder: A Review in Diabetes Mellitus

Recent advances in the development of microparticles for pulmonary administration.

Background Since the discovery of insulin, it was the only drug available for the treatment of diabetes until the development of sulfonylureas and biguanides 50 years later. But even with the availability of oral glucose-lowering drugs, insulin supplementation was often needed to achieve good glucose control in type 2 diabetes. Insulin NPH became the basal insulin therapy of choice and adding NPH to metformin and/or sulfonylureas became the standard of care until basal insulin analogs were developed and new glucose-lowering drugs became available. Areas of uncertainty The advantages in cost-benefit of insulin analogs and their combination with new glucose-lowering drugs are still a matter of debate. There is no general agreement on how to avoid inertia by prescribing insulin therapy in type 2 diabetes when really needed, as reflected by the diversity of recommendations in the current clinical practice guidelines. Data sources When necessary for this review, a systematic search of the evidence was done in PubMed and Cochrane databases. Therapeutic advances Adding new oral glucose-lowering drugs to insulin such as DPP-4 inhibitors lead to a modest HbA1c reduction without weight gain and no increase in hypoglycemia. When SGLT-2 inhibitors are added instead, there is a slightly higher HbA1c reduction, but with body weight and blood pressure reduction. The downside is the increase in genital tract infections. GLP-1 receptor agonists have become the best alternative when basal insulin fails, particularly using fixed ratio combinations. Rapid-acting insulins via the inhaled route may also become an alternative for insulin supplementation and/or intensification. "Smart insulins" are under investigation and may become available for clinical use in the near future. Conclusions Aggressive weight loss strategies together with the new glucose-lowering drugs which do not cause hypoglycemia nor weight gain should limit the number of patients with type 2 diabetes needing insulin. Nevertheless, because of therapeutic inertia and the progressive nature of the disease, many need at least a basal insulin supplementation and insulin analogs are the best choice as they become more affordable. Fixed ratio combinations with GLP1 receptor agonists are a good choice for intensification of insulin therapy.

Insulin Therapy in Type 2 Diabetes.

OBJECTIVE To investigate the efficacy and safety of prandial Technosphere inhaled insulin (TI), an inhaled insulin with a distinct time action profile, in insulin-naive type 2 diabetes (T2D) inadequately controlled on oral antidiabetes agents (OADs).

RESEARCH DESIGN AND METHODS Subjects with T2D with HbA1c levels ≥7.5% (58.5 mmol/mol) and ≤10.0% (86.0 mmol/mol) on metformin alone or two or more OADs were randomized to add-on prandial TI ( n = 177) or prandial Technosphere inhaled placebo (TP) ( n = 176) to their OAD regimen in this double-blind, placebo-controlled trial. Primary end point was change in HbA1c at 24 weeks.

RESULTS TI significantly reduced HbA1c by −0.8% (−9.0 mmol/mol) from a baseline of 8.3% (66.8 mmol/mol) compared with TP −0.4% (−4.6 mmol/mol) (treatment difference −0.4% [95% CI −0.57, −0.23]; P < 0.0001). More TI-treated subjects achieved an HbA1c ≤7.0% (53.0 mmol/mol) (38% vs. 19%; P = 0.0005). Mean fasting plasma glucose was similarly reduced in both groups. Postprandial hyperglycemia, based on 7-point glucose profiles, was effectively controlled by TI. Mean weight change was 0.5 kg for TI and −1.1 kg for the TP group ( P < 0.0001). Mild, transient dry cough was the most common adverse event, occurring similarly in both groups (TI, 23.7%; TP, 19.9%) and led to discontinuation in only 1.1% of TI-treated and 3.4% of TP-treated subjects. There was a small decline in forced expiratory volume in 1 s in both groups, with a slightly larger decline in the group receiving TI (TI, −0.13 L; TP, −0.04 L). The difference resolved after treatment discontinuation.

CONCLUSIONS Prandial TI added to one or more OADs in inadequately controlled T2D is an effective treatment option. Mild, transient dry cough was the most common adverse event.

/pdf/inhaled-technosphere-insulin-versus-inhaled-technosphere-22l5eny0c7.pdf

Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naïve Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents

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Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naïve Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents