INSULIN DEGLUDECBy ARSALAN MASOUD PGR NMW

Insulin degludec is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 40 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir), making it a once-daily basal insulin, that is one that provides a base insulin level, as opposed to the fast and short acting bolus insulins

MOLECULAR STRUCTUREInsulin degludec is a modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L-glutamyl spacer at the amino acid lysine at position B29.

PHARMACOLOGY

Mechanism of Action:Insulin degludec is an ultra-long acting insulin that, unlike insulin glargine, is active at a physiologic pH.The addition of hexadecanedioic acid to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation

Pharmacodynamics:Insulin degludec has an onset of action of 30–90 minutes (similar to insulin glargine and insulin detemir).There is no peak in activity, due to the slow release into systemic circulation. The duration of action of insulin degludec is reported as being longer than 24 hours.

EFFECTIVENESS AGAINST OTHER LONG ACTING INSULINS

Studies have shown that patients taking insulin degludec needed to take significantly smaller doses of basal insulin than those taking insulin glargine, while achieving similar blood glucose levels.

Insulin degludec also has the ability to be mixed with other insulins, thereby improving glycemic control. This cannot be done using current long-acting insulins

CLINICAL TRIAL DATA

TYPE 1 DIABETES MELLITUS

Insulin degludec was studied as an alternative to insulin glargine as part of a basal-bolus regimen in the BEGIN Basal-Bolus Type 1 trial.

629 patients with type 1 diabetes were randomized in a 3:1 ratio to either insulin degludec (n=472) or insulin glargine (n=157) in addition to mealtime insulin aspart.

Patients in the degludec treatment arm were switched from their basal insulin to insulin degludec in a 1:1 ratio, with a 20-30% dose reduction in patients receiving multiple basal doses per day.

After 52 weeks, patients treated with insulin degludec produced a similar reduction in HbA1c (0.40% vs. 0.39%) meeting the criteria for non-inferiority.

Adverse events were similar in the two treatment arms; however, rates of nocturnal hypoglycemia (between midnight and 6am) were 27% lower in patients treated with insulin degludec (3.91 vs. 5.22%,p=0.024).

The reduction in the incidence of hypoglycemia was seen as a therapeutic benefit, as hypoglycemia is often a dose limiting toxicity in insulin therapy

TYPE 2 DIABETES MELLITUS

In the BEGIN Basal-Bolus Type 2 trial, insulin degludec was studied as an alternative to insulin glargine in patients with type 2 diabetes mellitus.

995 patients were randomized to receive either insulin degludec (n=755) or insulin glargine (n=251), in addition to either mealtime insulin aspart, metformin, and/or pioglitazone.

Patients in this trial had an average HbA1c of 8.3-8.4%, and 49-50% were on a regimen consisting of basal-bolus insulin + oral antidiabetic medications.

After 52 weeks, insulin degludec was found to be noninferior to insulin glargine, providing a similar HbA1c lowering effect (-1.10 vs. -1.18%). Overall rates of hypoglycemia were significantly lower with insulin degludec (11.09 vs. 13.63%/yr, p=0.0359), including cases of nocturnal hypoglycemia (1.39 vs. 1.84%/yr, p=0.0399).[

COMPARISON STUDY

Nutr Metab Cardiovasc Dis. 2015 Jun 18. pii: S0939-4753(15)00151-9. doi: 10.1016/j.numecd.2015.06.005. [Epub ahead of print]

Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials.

Russell-Jones D1, Gall MA2, Niemeyer M3, Diamant M4, Del Prato S5.

ABSTRACT BACKGROUND AND AIMS: Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). METHODS AND RESULTS: Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy. CONCLUSION: This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D.

PATIENT FACTORS

Once daily, with flexibility in timing of administration. SmPC

states that a minimum of 8 hours between injections should always be ensured.

Similar tolerability to insulin glargine. Statistically significant reductions in nocturnal hypoglycaemia

of between 1.4 and 4 episodes per patient per year with insulin degludec compared with insulin glargine (2 RCTs up to 104 weeks).

ADVERSE EFFECTS

Hypersensitivity Hypoglycemia: occurs if the insulin dose is too high in relation to the

insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. Symptoms may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

Lipodystrophy: Injection site should be shuffled on regular basis Heart Failure: Combination with pioglitazone may precipitate Heart Failure. Diabetic Retinopathy: Bringing the glycemic level down abruptly may

aggravate diabetic retinopathy

INSULIN PEGLISPRO

BIOCHEMISTRY

Insulin Peglispro or LY2605541 The active component of LY2605541 is insulin lispro, a short-acting

insulin analog, which is covalently coupled to a single 20-kilodalton polyethylene glycol (PEG) moiety via an urethane bound to lysine B28 (Fig. 1) (4,5).

This results in a large hydrodynamic radius of the analog, delaying the absorption rate of insulin lispro by slowing diffusion rate and reducing renal filtration.

The PEGylation of insulin lispro also prolongs its half-life by increasing stability against proteolysis. The increase in molecular size appears to alter the tissue distribution of this insulin.

The hepatic sinusoidal endothelium with its wide fenestration may allow greater transport of LY2605541 to the liver than to muscles and fat, ensuring a preferential hepatic action.

STUDIES

Efficacy and safety of LY2605541 has been tested in two phase II studies. In a randomized 12-week open-label study in type 2 diabetic patients, once-daily basal insulin LY2605541 and insulin glargine were both administered in the morning.

At 12 weeks, fasting blood glucose was similar in the two groups, as was HbA1c. Intra- and interday blood glucose variability was reduced with LY2605541, which also induced a weight loss of −0.6 kg, compared with a weight gain of 0.3 kg in the insulin glargine group.

The incidence of total and nocturnal hypoglycemia did not differ between the two groups, although LY2605541-treated patients had a 48% reduction in nocturnal hypoglycemia after adjusting for run-in period of hypoglycemia. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglycerides increased in the LY2605541 group and were higher than during insulin glargine treatment.

The number of patients developing detectable antibodies against LY2605541 or insulin glargine did not differ between the groups. At week 12, mean insulin dose/kg was 1.5-fold greater with LY2605541 than with insulin glargine treatment

Efficacy and safety of LY2605541 has been tested in two phase II studies. In a randomized 12-week open-label study in type 2 diabetic patients, once-daily basal insulin LY2605541 and insulin glargine were both administered in the morning.

At 12 weeks, fasting blood glucose was similar in the two groups, as was HbA1c. Intra- and interday blood glucose variability was reduced with LY2605541, which also induced a weight loss of −0.6 kg, compared with a weight gain of 0.3 kg in the insulin glargine group.

The incidence of total and nocturnal hypoglycemia did not differ between the two groups, although LY2605541-treated patients had a 48% reduction in nocturnal hypoglycemia after adjusting for run-in period of hypoglycemia.

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglycerides increased in the LY2605541 group and were higher than during insulin glargine treatment. The number of patients developing detectable antibodies against LY2605541 or insulin glargine did not differ between the groups.

At week 12, mean insulin dose/kg was 1.5-fold greater with LY2605541 than with insulin glargine treatment

THANK YOU