• Insulin

• Insulin
• Endocrinology
• Diabetes & Metabolic Syndrome

Luigi Meneghini, MD, University of Miami, Miami, Florida, USA, presented evidence supporting the efforts to develop longer-acting insulin therapy.

The importance of insulin therapy and associated glycemic control is incontestable. Prior to the discovery of insulin in the early 1920s, the life expectancy of a 10-year-old diagnosed with type 1 diabetes was only 2.6 years. In the early years following the introduction of insulin, the life expectancy of a 10-year-old patient with diabetes had increased to 24.3 years and had leapt to 55 years 2 decades later [Joslin EP. Diabetic Manual for the Doctor and Patient, 9th Ed. 1957].

Establishing glycemic control early in the course of diabetes reduces vascular complications later in life [UKPDS Group. Lancet 1998; Gerstein HC et al. N Engl J Med 2008; Duckworth W et al. N Engl J Med 2009; ACCORD Study Group. N Engl J Med 2010]. However, insulin therapy does have limitations. One is the risk of hypoglycemia. Hypoglycemia, which most often occurs in individuals with diabetes who require insulin, accounted for >95% of all endocrine-related emergency hospitalizations in people aged >65 years in the United States from 2007 through 2009 [Budnitz DS et al. N Engl J Med 2011]. The frequency of severe episodes of hypoglycemia rises with duration of both type 1 and type 2 diabetes [UK Hypoglycemia Study Group. Diabetologia 2007; Amiel SA et al. Diab Med 2008]. There is also increasing awareness of asymptomatic hypoglycemia, especially occurring during the night, as evidenced by data collected through continuous glucose monitoring [Hay LC et al. Diab Tech Ther 2003].

Longer-acting (≥24 hours) insulin could be useful especially when accompanied by minimal-to-no peak effect and predictable day-to-day glucose response. Insulin detemir and insulin glargine have shown promise towards these goals, although the peak effect has only been reduced but not eliminated, compared with neutral protamine Hagedorn (NPH) insulin [Heise T et al. Diabetes 2004]. Nocturnal hypoglycemia is reduced with insulin glargine and insulin detemir, compared with NPH insulin [Riddle MC et al. Diab Care 2003; Philis-Tsimikas A et al. Clin Ther 2006].

In seeking to extend the benefits of basal insulin, studies have focused on larger molecules that have a longer duration of action, such as the multihexameric insulin degludec. Insulin degludec attains steady state with 2 to 3 days of once-daily dosing. Compared with insulin glargine, insulin degludec maintains a more sustained serum concentration over time, a longer mean half-life (Table 1).

Compound LY2605541 (pegylated lispro insulin) is another large molecule that is delayed in absorption and clearance, which prolongs its action.

These ultra long-acting insulin preparations have been compared with insulin glargine with regards to efficacy and risk of hypoglycemia. While there is comparable reduction in HbA1C between these longer-acting basal analogs and insulin glargine, there is also a consistent reduction in the risk of nocturnal hypoglycemia associated with the use of these new ultra-long basal insulin preparations [Rodbard HW et al. Diabet Med 2013; Bergenstal RM et al. Diabetes Care 2012].

Because these longer-acting insulin preparations take ∼3 to 4 dosing injections to reach steady state, adjusting the basal insulin dose on a weekly basis to achieve desired fasting plasma glucose targets should allay any potential concerns over stacking of the insulin.

Long-term cardiovascular trials planned for some of these longer-acting basal insulin preparations should be able to address any remaining issues regarding the cardiovascular safety of these novel insulin molecules.

• © 2013 MD Conference Express®