Ninety Years of Insulin: What’s Needed? What’s New?

Value-Based Care in Cardiometabolic Health August 2012, Vol 1, No 2
Mary Mosley

The introduction of insulin glar­gine in 2000 and of insulin detemir in 2004 responded to some of the problems associated with neutral protamine Hagedorn (NPH) insulin, introduced 90 years ago. Continuous subcutaneous insulin infusion (CSII) delivered through an insulin pump became the gold standard replacement of insulin for type 1 diabetes in 1978. Yet, improved basal insulins are needed, said Geremia B. Bolli, MD, University of Perugia, Italy, in a session providing an update on insulin therapy at the 2012 ADA annual meeting.

Dr Bolli said that NPH is not appropriate when beta-cell function is lost, as in the case of patients with type 1 diabetes, or worsens, as in patients with type 2 diabetes. Also, as body mass index decreases, NPH is less indicated because of the increased risk for hypoglycemia.

Insulin Glargine versus Detemir
The merits of insulin glargine, the first long-acting insulin analog, include its relatively peakless pharmacodynamic profile, solubility that makes its absorption more reproducible, and a steady-state duration of action beyond 24 hours. In patients with type 1 diabetes, glargine is noninferior to CSII, is superior to NPH because of less hypoglycemia, particularly nocturnal, and results in the achievement of a lower or similar hemoglobin (Hb) A1c. These improvements with insulin glargine “make intensive treatment in type 1 diabetes much safer,” said Dr Bolli.

Insulin detemir, by contrast, is soluble, and therefore its absorption is less variable than that of glargine, it is nearly as peakless as glargine, and it is protective against hypoglycemia; however, detemir’s duration of action is shorter than glargine’s, and detemir has a weaker efficacy in obesity.

Dr Bolli reviewed several studies that showed the benefits of these drugs; however, he noted that glargine and detemir have limitations.

For glargine, the duration of action is not sufficient, and the day-to-day variability is too great in approximately 20% of patients with type 1 diabetes. For detemir, the duration of action needs to be longer in the majority of patients with type 1 diabetes, and greater potency is needed in obese patients (primarily those with type 2 diabetes).

Novel Basal Insulins on the Horizon
Dr Bolli also reviewed 2 investigational basal insulins—insulin de­gludec and PEGylated insulin lispro (LY2605541).

Insulin degludec. Insulin degludec, a second-generation agent, has a sustained release, with an approximate 25-hour duration of action in patients with type 1 diabetes. Its pharmaco­kinetic profile predicts that degludec will have a sustained effect for more than 24 hours, low variability in subcutaneous absorption, and a low rate of hypoglycemia.

In one study, degludec had a 4-fold lower day-to-day variability in its glucose-lowering effect compared with insulin glargine; however, a crossover study is needed to confirm this observation, said Dr Bolli.

A noninferiority trial in patients with type 1 diabetes showed that degludec was noninferior to glargine at a similar dose, showing a 25% risk reduction in nocturnal hypoglycemia with degludec, translating to 1.5 fewer events per patient-year.

In a noninferiority trial in patients with type 2 diabetes, degludec, at a similar dose as glargine, produced a similar reduction in HbA1c at 1 year, with an 18% risk reduction in hypoglycemia and a 25% reduction in nocturnal hypoglycemia.

An interesting possibility with a long-acting insulin such as degludec, noted Dr Bolli, is the ability to vary the timing of the dosing, without excessive disruption of glucose control or diff­erences in HbA1c or nocturnal hypoglycemia, as shown in 2 studies.

PEGylated insulin lispro. PEGylated insulin lispro (LY2605541) has a prolonged duration of action because it delays insulin absorption and reduces clearance. In vitro studies have shown that this agent is safe.

In patients with type 1 diabetes, a short phase 2 study showed that LY2605541 was noninferior to glargine on daily mean blood glucose, HbA1c, and fasting plasma glucose (FPG) variability. Dr Bolli said that these results were obtained with a prandial dose of LY2605541 that was 24% lower than the glargine dose, which could be interpreted as a “better provision of basal insulin” with LY2605541.

In this study, patients lost weight with LY2605541 but gained weight with glargine. Although there was more hypoglycemia overall with the new insulin, the nocturnal hypoglycemia was reduced.

Other findings included an elevation in hepatic enzymes and triglycerides, an increase in low-density lipoprotein cholesterol (LDL-C), and a decrease in high-density lipoprotein cholesterol (HDL-C), although this value remained in the normal range.

Another study of patients with type 2 diabetes demonstrated that LY2605541 was noninferior to glargine on FPG and HbA1c after 12 weeks. The weight loss was consistent with that in the study in patients with type 1 diabetes. Hypoglycemia (including nocturnal) was reduced with LY2605541. Continuous glucose monitoring revealed that there was less time spent in hypoglycemia (24-hour, nocturnal) and lower blood glucose variability. The increase in hepatic enzymes with LY2605541 was within the normal range, triglycerides were higher, and LDL-C and HDL-C did not change.

Further work is needed to answer remaining questions about degludec and LY2605541, including questions on the day-to-day variability at doses relevant to clinical practice, titration, and protection against hypoglycemia.

Advantages and Benefits of Rapid-Acting Insulin Analogs vs Regular Insulin.

Bolus Insulin Analogs
The bolus (prandial) insulin analogs lispro, aspart, and glulisine address the limitations seen with regular human insulin. These analogs are more physiologically active in terms of their appearance and disappearance from the circulation than regular insulin, said Luigi F. Meneghini, MD, MBA, University of Miami, FL. Key advantages of rapid-acting insulins are listed in the Table.

Bolus Insulin in the Pipeline
An insulin formulated with a synthetic hyaluronidase, analog-rHuPH20, is under development. Combining a rapid-acting insulin with rHuPH20 results in higher insulin concentrations at 1 hour after injection and lower insulin concentrations at 2 hours after injection compared with rapid-acting insulin alone. The biologic activity of the rapid-acting insulin or the rapid-acting insulin analog is enhanced by rHuPH20, making it more physiologic, stated Dr Meneghini.

Inhaled insulin is currently under development. Technosphere-inhaled in­sulin is in phase 3 clinical trials. Compared with subcutaneous insulin, technosphere-inhaled insulin produced a slightly better clinically relevant improvement in HbA1c in patients with type 1 diabetes, according to a meta-analysis published in 2006.

A greater reduction in fasting FPG  was found with inhaled insulin, and no difference was seen in hypoglycemia or weight; however, one study of patients with type 2 diabetes showed less weight gain with inhaled insulin. Patient satisfaction was higher with inhaled insulin, and quality of life was improved in 2 studies.

However, pulmonary issues with inhaled insulin were found in the meta-analysis. Nonproductive cough is 3- to 4-fold higher with inhaled insulin but is not associated with changes in pulmonary function. The cough begins immediately after inhalation and tends to improve after the first month. First expiratory volume in 1 second (FEV1) progressively decreases for the first 6 months and then stabilizes, which is seen more in patients with type 1 diabetes. Diffusion capacity is slightly decreased, mostly in patients with type 1 diabetes, but this has been seen only in short-term studies.

A 52-week study in patients with uncontrolled type 2 diabetes showed a similar reduction in HbA1c with prandial inhaled insulin plus insulin glargine compared with twice-daily biaspart insulin. The inhaled insulin was associated with less weight gain, lower FPG, lower postprandial glucose excursions after a meal challenge, and less hypoglycemia.

In patients with type 1 diabetes, inhaled technosphere insulin plus glargine produced a similar HbA1c reduction at 1 year as aspart plus glargine. FPG was lower with techno­sphere-inhaled insulin. But fewer than 20% of patients reached an HbA1c level <7.0% with the inhaled insulin, which is a criticism of inhaled insulins, said Dr Meneghini.

Last modified: July 6, 2021
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