David Rodbard, United States of America
Presenter Of 3 Presentations
MISSED PRANDIAL INSULIN BOLUSES REDUCE TIME IN RANGE (TIR) AND INCREASE TIME ABOVE RANGE (TAR): NEW METHODS OF ANALYSIS
Background and Aims
Insulin nonadherence leads to poor glycaemic control. Several methods have been proposed for identifying missed and suboptimal meal-related insulin bolus. To improve the analysis of results from clinical studies, we compared a new method based on the Mean Amplitude of Glycaemic Excursion (MAGE) concept (Method 1) and Kovatchev-Breton method (Method 2).
Method 1 uses Baghurst’s algorithm for MAGE to identify prandial glucose peaks utilising upstrokes which exceed a prespecified amplitude rather than the standard deviation of continuous glucose monitoring (CGM). Method 2 uses a >70 mg/dL increase within 2 hours of glucose increase. Missed bolus dose was defined as no injection within 2 hours prior to onset of the glucose excursion. The methods were compared using data from a 12-week study with two 21-day periods (period 1: masked CGM, 68 subjects; period 2: real-time CGM, 65 subjects; using Dexcom G5) in subjects with type 1 diabetes or type 2 diabetes using a basal-bolus regimen with prandial insulin lispro U-100 injected using a connected pen.
In both periods, days with no missed bolus had lower mean glucose, higher TIR and lower TAR compared to days with ≥1 missed bolus (Table).
Methods 1 and 2 have excellent concurrence; both identify the effects of missed bolus on TIR and TAR. This study highlights the utility of connected insulin pens to identify suboptimal diabetes self-management and points to the need for development of consensus in the clinical community about the reporting of insulin dosing metrics.
Insulin - A century of progress leading to the ultra long-acting insulin analogs
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.
Insulin NNC0148-0287 C. National Clinical Trials database, clinicaltrials.gov NCT03951805
Insulin LY3209590. National Clinical Trials database, clinicaltrials.gov NCT03736785
Lane W, ... JAMA 2017 318(1):33-44
Wysham C, ... JAMA 2017 318(1):45-56
Rosenstock J, ... Diabetes Care. 2018 Oct;41(10):2147-215414.
Sullivan SD, ... DOM 2019; 21(9): 2123-2132.
Philis-Tsimikas A et al. Diabetologia 2020 Jan 27. doi: 10:1007/s00125-019-05080-9
Rodbard HW, Rodbard D. American Journal of Therapeutics 2020 (Jan).
Little S, ... Diabetes Technol. Therapeutics 2011;1 3 Suppl 1:S53-64.
Lepore M, ... Diabetes. 2000 Dec;49(12):2142-8.
Heise T, ... Diabetes. 2004 Jun;53(6):1614-20.
Porcellati F, ... Dia Care 2007;30:2447-2452
Russell-Jones D, ... Nutr Metab Cardiovasc Dis. 2015 Oct;25(10):898-905.
Reinhard H.A, ... Diabetes Care 2015;38:637-643
Heise T, ... Diabetes Obes Metab. 2017 Jul; 19(7): 1032–1039
Bergenstal RM, ... Diabetes Care. 2017 Apr;40(4):554-560.