Abstract Body

Glucose variability (GV) has emerged as an important component of dysglycaemia.

GV is an independent risk factor for diabetic complications, macro- and micro-vascular. Both short- and long-term GV has also an important role in precipitating and accelerating hypoglycaemia and consequently adverse cardiovascular outcomes.

Methods

Currently several indices of GV are being proposed for its evaluation in clinical practice.

Results

To assess short term, within-day GV, the coefficient of variation might be a simple and useful tool for separating stable from labile glycaemic control with a cut-off value of 36%. In contrast, longer-term GV can be defined based on quarterly visit-to-visit measurements of HbA1c, fasting or post-prandial glucose.

Conclusions

Meanwhile, a number of therapeutic strategies, both non-pharmacological (continuous glucose monitoring and life style changes) and pharmacological (GLP-1 receptor agonists, SGLT-2 inhibitors, new long acting insulins and also their fixed combinations with GLP-1 receptor agonists) are available to address this challenging aspect of diabetes management.

Background and Aims / Part 1

There is a need for basal insulin preparations that could be administered on a weekly rather than a daily basis.

Methods / Part 2

Literature and internet review at http://clinicaltrials.gov.

Results / Part 3

Both glargine U-300 and degludec have longer duration of action than glargine U-100. Degludec appears to show lower variability than glargine U-300 although this remains a matter of debate. Both degludec and glargine U-300 facilitate reductions in HbA1c, fasting plasma glucose, and mean glucose while reducing variability of daily mean glucose and reducing risk of hypoglycemia compared with glargine U-100 in TID or T2D (clinical trials including BEGIN, DEVOTE, SWITCH1, SWITCH2, BRIGHT, CONCLUDE, and real world data).
PEGylated Lispro insulin has extended duration of action, excellent potency in lowering HbA1c and induces weight loss instead of weight gain. Unfortunately, it is associated with elevation of hepatic enzymes (ALA) and liver fat deposition. Accordingly, it is not being pursued further.
Four pharmaceutical laboratories have investigated insulin coupled to an Fc fragment of Immunoglobulin. Two compounds have reached Phase 2 testing with weekly administration. One compound, NCT03951805 or LAI287 (Icodec) administered QW has demonstrated excellent glycemic control in terms of A1C, comparable to or greater than that of glargine U-100 administered daily. The combination of this insulin-Fc with semaglutide has been evaluated in Phase 1 studies using weekly administration. A second form of insulin for QW administration, LY3209590, has just completed a Phase 2 trial using daily insulin degludec as comparator. Results are expected to be reported in the near future.

Conclusions / Part 4

Insulin NNC0148-0287 C and Insulin LY3209590 that utilize modifications of insulin by covalent attachment of Fc fragments of immunoglobulin increase the duration of action of insulin sufficiently to permit weekly administration. Active clinical trials are ongoing and Phase 2 results are strongly encouraging.

References
Insulin NNC0148-0287 C. National Clinical Trials database, clinicaltrials.gov NCT03951805
Insulin LY3209590. National Clinical Trials database, clinicaltrials.gov NCT03736785
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