EMERGING THERAPIES: DRUGS AND REGIMENS Diabetes Care Volume 43, October 2020 2509 Julio Rosenstock,1 Antonio Nino,2 Impact of a Weekly Glucagon-Like Joseph Soffer,3 Lois Erskine,4 Andre Acusta,5 Jo Dole,3 Molly C. Carr,3 Jason Mallory,4 and Peptide 1 Receptor Agonist, Philip Home6 Albiglutide, on Glycemic Control and on Reducing Prandial Insulin Use in Type 2 Diabetes Inadequately Controlled on Multiple Insulin Therapy: A Randomized Trial Diabetes Care 2020;43:2509–2518 | https://doi.org/10.2337/dc19-2316 OBJECTIVE The principle of replacing prandial insulin lispro with a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) for type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. 1Dallas Diabetes Research Center at Medical City, RESEARCH DESIGN AND METHODS Dallas, TX 2Research and Development Immuno-Inflammation In this treat-to-target study, basal plus prandial insulin was optimized over 4 weeks Therapy Area Unit, GlaxoSmithKline, Collegeville, before participants were randomized (1:1) to albiglutide plus optimized basal PA 3 insulin glargine and lispro (dose reduced by 50% at randomization; subsequently, Research and Development Future Pipelines Dis- lispro injections were fully discontinued 4 weeks later) (n 5 402) or to continued covery, GlaxoSmithKline, Collegeville, PA 4Clinical Development, GlaxoSmithKline, King of optimized lispro plus optimized glargine (n 5 412). Prussia, PA 5Clinical Statistics, GlaxoSmithKline, Collegeville, PA RESULTS 6Newcastle University, Newcastle upon Tyne, U.K. Mean 6 SD HbA1c at baseline, 7.8 6 0.6% (61 6 7 mmol/mol) in the albiglutide 1 Corresponding author: Julio Rosenstock, glargine group and 7.7 6 0.6% (60 6 7 mmol/mol) in the lispro 1 glargine group, was [email protected] reducedatweek26to6.76 0.8% (49 6 8 mmol/mol) and 6.6 6 0.8% (48 6 8mmol/mol), Received 19 November 2019 and accepted 8 June respectively (least squares [LS] difference 0.06% [95% CI 20.05 to 0.17]; non- 2020 inferiority P < 0.0001). In the albiglutide 1 glargine group, 218 participants (54%) Clinical trial reg. no. NCT02229227, clinicaltrials .gov replaced all prandial insulin without reintroducing lispro up to week 26. Total daily This article contains supplementary material online prandial insulin dose was similar at baseline but was lower by 62 units/day (95% at https://doi.org/10.2337/figshare.12469121. CI265.9to257.8;P<0.0001) atweek26inthealbiglutide 1glarginegroup,and the M.C.C. is currently affiliated with Eli Lilly, Indian- total number of weekly injections was also reduced from 29 to 13 per week. Less apolis, IN. severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the J.M. is currently affiliated with Kriya Therapeu- albiglutide1glarginegroupwithmeaningfulweightdifferences(LSmean6SE22.0 tics, Durham, NC. 6 0.2 vs. 12.4 6 0.2 kg; P < 0.0001) vs. lispro 1 glargine. Gastrointestinal adverse This article is featured in a podcast available at events were higher with albiglutide 1 glargine (26% vs. 13%). https://www.diabetesjournals.org/content/ diabetes-core-update-podcasts. CONCLUSIONS © 2020 by the American Diabetes Association. A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, Readers may use this article as long as the work is properly cited, the use is educational and not for substantially reducing the number of prandial insulin injections; glycemic control profit, and the work is not altered. More infor- improved, with the added benefits of weight loss and less hypoglycemia in the GLP- mation is available at https://www.diabetesjournals 1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal plus .org/content/license. prandial insulin treatments and achieve better outcomes in type 2 diabetes. See accompanying article, p. 2333. 2510 Reduced Prandial Insulin in GLP-1RA Switch Trial Diabetes Care Volume 43, October 2020 Insulin remains the cornerstone therapy [$53 to #80 mmol/mol]) on a basal plus (three or more injections/day and #140 for longer-duration type 2 diabetes and prandial insulin regimen (three or more units/day) for $3 months. Patients re- b-cell failure (1). However, basal insulin injections/day and #140 units/day) with ceiving any antihyperglycemia medica- regimens that include prandial insulin or without metformin. Optimized basal tion other than metformin and insulin(e.g., can be difficult for most people to man- plus prandial insulin therapy (actively GLP-1RA, dipeptidyl peptidase-4 inhibitor, age and many fail to attain individu- titrated insulin glargine [Lantus; Sanofi, sulfonylurea, meglitinide, sodium–glucose alized glycated hemoglobin (HbA1c) Bridgewater, NJ] and insulin lispro [Hu- cotransporter 2 inhibitor, or thiazolidine- targets, despite increasing dosage and malog; Lilly, Indianapolis, IN]), based on dione) within 30 days before screening intensification with basal insulin plus mul- predefined treat-to-target titration algo- were excluded. Additional criteria at ran- tiple prandial insulin injections (2–4). Crit- rithms, served as the active control domization were HbA1c $7.0% to #9.0% ical limitations of prandial insulin include (18–22). (GlaxoSmithKline has made the ($53 to #75 mmol/mol) and fasting lack of adherence to such complex regi- decision to discontinue commercial sale plasma glucose (FPG) ,280 mg/dL (15.5 mens, increased risk of hypoglycemia, of albiglutide effective July 2018. The mmol/L) 1 week earlier. weight gain, erratic pre- and postprandial decision was not related to any known glucose control, and fear amongusers and safety concerns.) Dosing and Dose Titration physicians about these unintended effects The protocol was approved by the in- The albiglutide (Tanzeum; GlaxoSmith- (2,3,5,6). Accordingly, less complex ther- dependent ethics committee or institu- Kline, Research Triangle Park, NC) start- apeutic approaches are needed to im- tional review board for every study site. ing dose (subcutaneous injection) was prove glycemic control in people using Written informed consent was obtained 30 mg weekly and was uptitrated at week insulin while avoiding these shortcomings from all study participants. The trial was 4 to 50 mg weekly for the remaining and enhancing adherence (3,4). conducted in accordance with the Dec- treatment period. Albiglutide is a glucagon-like peptide laration of Helsinki/International Con- In the albiglutide 1 glargine group, 1 receptor agonist (GLP-1RA) that was ference on Harmonization good clinical the lispro doses at randomization were indicated as an adjunct to diet and ex- practice guidelines. halved and at week 4 lispro injections ercise to improve glycemic control in The study included four periods: screen- were completely discontinued. Lispro could adults with type 2 diabetes at the time ing (2 weeks), insulin standardization be systematically reintroduced by inves- this study was conducted (7,8). In people (4 weeks), treatment (26 weeks), and tigators after week 8 in participants who failing to achieve glycemic targets with posttreatment follow-up (4 weeks) (Sup- had self-measured postprandial plasma basal insulin, GLP-1RAs (exenatide, lira- plementary Fig. 1). During insulin stan- glucose excursions .180 mg/dL (.10.0 glutide,lixisenatide,dulaglutide,semaglu- dardization, participants transitioned mmol/L), based on mean measurements tide) (9–15) have been shown to be better from their current basal plus prandial (taken before lunch, dinner, or bedtime) than placebo and similar (albiglutide, ex- insulin regimen to once-daily glargine from the last three available days (at least enatide) (16,17) or better (liraglutide) (18) and thrice-daily lispro to reduce any two consecutive) in the week before the than basal plus prandial insulin at reduc- confounding variability associated with next study visit or telephone contact, us- ing HbA1c, without weight gain and gen- other insulin combinations. In this phase, ing a standardized, stepwise titration al- erally with less hypoglycemia but with glargine and lispro were actively adjusted gorithm (Supplementary Fig.2).Themean higher frequency of gastrointestinal ad- to glycemic targets as close to normal as of measurements (taken before lunch, verse events (AEs) that tend to subside possible without untoward hypoglyce- dinner, or bedtime) from the last three over time. mia in accordance with local product available days (at least two consecutive) No large randomized controlled stud- labeling and standards of care. in the week before each study visit/ ies have previously explored, as in the At randomization, study participants telephone contact was used to calculate current study, the efficacy and safety of were stratified by screening HbA1c postprandial glucose (MyGlucoHealth substituting prandial insulin with a weekly (,8.0% vs. $8.0% [,64 vs. $64 wireless meter and test strips; Entra GLP-1RA in people with type 2 diabetes mmol/mol]), age (,65 vs. $65 years), Health Systems, El Cajon, CA). If mea- with inadequately controlled blood glu- and current background metformin (yes/ surements from 3 days (at least two con- cose levels despite intensive basal plus no). Participants were randomized 1:1 to secutive) were not available, the dose prandial insulin therapy (three or more the albiglutide 1 glargine group (with adjustment was delayed until the next injections/day). lispro reduced by 50% at randomization scheduled study visit/telephone contact followed by full discontinuation at week unless, in the investigator’s judgment, a 4) or lispro