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MRIGTEAIS RG N REGIMENS AND DRUGS THERAPIES: EMERGING

Diabetes Care Volume 43, October 2020 2509

Julio Rosenstock,1 Antonio Nino,2 Impact of a Weekly -Like Joseph Soffer,3 Lois Erskine,4 Andre Acusta,5 Jo Dole,3 Molly C. Carr,3 Jason Mallory,4 and 1 Receptor , Philip Home6 Albiglutide, on Glycemic Control and on Reducing Prandial Use in 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 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 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%) 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 (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 . 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, , , sodium– alized (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 (, lira- plementary Fig. 1). During insulin stan- glucose excursions .180 mg/dL (.10.0 glutide,,,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 () (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 1 glargine group. dose adjustment was warranted. Partici- RESEARCH DESIGN AND METHODS pants without the required self-monitoring Trial Design Trial Participants of plasma glucose (SMPG) measurements This 26-week, randomized, open-label, The complete inclusion/exclusion criteria were retrained on the requirement for parallel-group, active-control, multicen- are listed in the Supplemental Material. SMPG measurements. ter, treat-to-target study evaluated the Key eligibility criteria at screening were At randomization, participants in the efficacy and safety of a once-weekly age 18275 years, HbA1c $7.0% to #9.5% lispro 1 glargine group continued the single injection of albiglutide to replace ($53 to #80 mmol/mol), fasting C- dose of lispro from the standardization prandial insulin in participants with type peptide $0.8 ng/mL ($0.26 nmol/L), period but then adjusted it according to 2 diabetes experiencing inadequate gly- BMI #40.0 kg/m2, and current use of a dose titration algorithm (Supplemen- cemic control (HbA1c $7.0% to #9.5% a basal plus prandial insulin regimen tary Table 1). Participants in both groups care.diabetesjournals.org Rosenstock and Associates 2511

continued the glargine dose from stan- severe (requiring third-party intervention) The proportions of participants with dardization, again adjusting it according or documented (glucose ,70 mg/dL [,3.9 severe or documented symptomatic hy- to a common titration algorithm (Supple- mmol/L]) symptomatic hypoglycemia from poglycemia were compared between mentary Table 2). To manage the risk for randomization to week 26; and change groups using the nonparametric Cochran- severe hypoglycemia, study investigators from baseline in body weight and FPG at Mantel-Haenszel (CMH) test after ad- received training to instruct participants week 26. Prespecified hierarchical test- justment for baseline HbA1c,stratum, to detect, treat, and avoid hypoglycemia ing is described in Supplementary Material. age-group, metformin use, and region. with consistent nutritional intake and Clinical laboratory-measured plasma glu- The number of severe or documented frequent SMPG. Participants also used cose (Q2 Solutions; headquarters Morris- symptomatic hypoglycemic events was electronic diaries to assist patients’ sur- ville, NC, and central laboratory sites compared between groups using a Pois- veillance and monitoring of hypoglyce- Valencia, CA; San Juan Capistrano, CA; son regression model, which included mia and report hypoglycemic events that Cypress, CA; Little Rock, AK; Scotland, treatment effect and covariates (HbA1c, occurred between study visits. Study U.K.; and Singapore) was assayed as FPG age, metformin use, and region). investigators had access to information and fasting serum glucose (FSG) at screen- The safety population included all collected in participants’ electronic di- ing. At week 26, plasma glucose was those who received one or more doses aries. In addition, study investigators assayed as FSG, and FPG values were of randomized study . Safety received notification of extreme SMPG imputed by regression on the baseline data. results were summarized using descrip- measurements (i.e., SMPG #50 mg/dL Exploratory end points included the tive statistics. [#2.8 mmol/L] and SMPG between Treatment-Related Impact Measure for – Data and Resource Availability 50 and 60 mg/dL [2.8 3.3 mmol/L]), as Diabetes (TRIM-Diabetes) questionnaire Anonymized individual participant well as episodes of severe hypoglycemia (23) and the Hypoglycemia Fear Survey data and study documents can be re- recorded in the electronic diary. (HFS)-II (24). Safety assessments included quested for further research from www fi Daytime hypoglycemia was de ned as AEs (25), clinical laboratory tests, vital .clinicalstudydatarequest.com. hypoglycemia events with an onset be- signs, electrocardiograms, and physical tween 0600 h and 0000 h (inclusive) and examinations. Potential events of pan- RESULTS nocturnal hypoglycemia was defined as creatitis were adjudicated by an inde- Participants hypoglycemic events with an onset be- pendent adjudication committee blinded In all, 402 participants were randomized tween 0001 h and 0559 h (inclusive). To to study treatment. to the albiglutide 1 glargine group and aid in the correct classification and treat- 412 to the lispro 1 glargine group, of ment of hypoglycemic events, patients Statistical Analyses whom 86% (87% albiglutide 1 glargine, were instructed to repeat SMPG mea- The planned sample size was 794 partic- 85% lispro 1 glargine) completed the surements #70 mg/dL (#3.9 mmol/L). ipants to test for noninferiority. Assuming study (Supplementary Fig. 3). The pro- All hypoglycemic events reported by awithdrawalrateof15%,;337 partic- portions of participants who withdrew participants were assessed and classified ipants in each treatment group were ex- and reasons for withdrawal were simi- by the investigator as severe (requiring pected to complete the 26-week study, lar between groups. Most participants third-party intervention), documented resulting in $90% power to reject the null (.86%) were compliant $80% of the symptomatic (typical symptoms and a hypothesis of inferiority for change from time to their randomized treatments plasma glucose concentration #70 mg/dL baseline in HbA1c (assuming a noninfer- (albiglutide 99.7% and glargine 91.9% in [#3.9 mmol/L]), asymptomatic (not ac- iority margin of 0.3% [3 mmol/mol], an the albiglutide 1 glargine group, lispro companied by typical symptoms but expected treatment group difference of 86.4% and glargine 88.0% in the lispro 1 plasma glucose concentration #70 mg/dL 0, and an SD of 1.2% [13 mmol/mol], with glargine group). Compliance was as- [#3.9mmol/L]),orprobablysymptomatic a one-sided significance level of 0.025). sessed for albiglutide, lispro, and glargine (event during which symptoms typical of The efficacy population consisted of all from the pens dispensed to and returned hypoglycemia were not accompanied by a participants randomized to study treat- by study participants. plasma glucose determination but were ment. The primary end point analysis One participant (albiglutide 1 glargine presumably caused by a plasma glucose used a mixed-effects model with re- group) was not treated and was excluded concentration #70 mg/dL [#3.9 mmol/ peated measures (MMRM), with HbA1c from the safety population. One partici- L]) and recorded as a nonserious or se- changes from baseline at all postbaseline pant in that group was dispensed lispro rious AE if appropriate. visits as dependent variables; treatment, instead of albiglutide but was included in region, age category, metformin use, visit the allocated efficacy population, while Study End Points week, treatment-by-week interaction, and being removed to the lispro safety pop- The primary efficacy end point was baseline HbA1c-by-week interaction as ulation. The numbers in the safety and change from baseline in HbA1c at 26 weeks. fixedeffects;baselineHbA1c as a contin- efficacy population therefore slightly dif- Secondary end points included the pro- uous covariate; and participant as a ran- fer accordingly. portionofparticipants inthe albiglutide 1 dom effect. Treatment effect estimates Baseline characteristics were similar glargine group who did not resume lis- of albiglutide were evaluated within this between groups (Table 1). The mean du- pro; total, basal, and prandial daily MMRM model as least squares (LS) means ration of diabetes was 15 years, mean insulin doses at week 26; number of contrasts relative to lispro. Analysis meth- HbA1c at screening 8.2% (66 mmol/mol), weekly insulin injections at weeks 4, 10, ods for secondary end points are provided and mean HbA1c at baseline 7.7% (60 18, and 26; percentage of participants with in Supplementary Table 3. mmol/mol) in both groups. 2512 Reduced Prandial Insulin in GLP-1RA Switch Trial Diabetes Care Volume 43, October 2020

6 1 Table 1—Baseline demographic and clinical characteristics 25.9 units for lispro glargine). Total Albiglutide 1 glargine Lispro 1 glargine insulin dose decreased in the albiglu- (n 5 402) (n 5 412) tide 1 glargine group (80.3 6 29.1 units at baseline and 69.0 6 33.2 units at week Age at randomization, mean 6 SD, years 58.0 6 9.4 58.1 6 9.5 26) and increased in the lispro 1 glargine Sex, n (%) group (82.9 6 32.1 units at baseline and Female 228 (56.7) 214 (51.9) 6 Male 174 (43.3) 198 (48.1) 130.4 61.1 units at week 26). Changes Race, n (%) in prescribed insulin dose with time are White 284 (70.6) 312 (75.7) shown in Fig. 1C and D. The difference Non-White 118 (29.4) 100 (24.3) (decrease) in change in LS mean adjusted Ethnicity, n (%) daily total prescribed insulin in the albi- Hispanic/Latino 159 (39.6) 152 (36.9) glutide 1 glargine versus the lispro 1 Not Hispanic/Latino 243 (60.4) 260 (63.1) glargine groups at week 26 was 261 units Weight, mean 6 SD, kg 87.8 6 17.3 89.8 6 17.8 and for prandial insulin 262 units (Table 2). BMI n 5 401 n 5 412 At week 26, the mean 6 SD number of Mean 6 SD, kg/m2 32.1 6 4.5 32.5 6 4.7 injections with albiglutide 1 glargine was 6 Baseline HbA1c, mean SD, % (mmol/mol), reduced from 29 to 13 per week (re- after lead-in insulin optimization 7.7 6 0.6 (60 6 7) 7.7 6 0.6 (60 6 7) duction of 216 6 8 per week) but was Current metformin use, n (%) unchanged at 28 per week in the lispro 1 Yes 269 (66.9) 280 (68.0) glargine group (Table 2 and Fig. 1E). At No 133 (33.1) 132 (32.0) study end, 62% of the 351 participants Baseline clinical FPG n 5 397 n 5 409 who completed the study in the albi- Mean 6 SD, mg/dL (mmol/L) 145 6 46 (8.1 6 2.6) 140 6 48 (7.8 6 2.7) glutide 1 glargine group required no Duration of diabetes n 5 399 n 5 413 Mean 6 SD, years 15.2 6 7.7 14.7 6 7.2 injections of lispro, 9% required one injection oflispro per day, 12% required two injections of lispro per day, and 16% required three injections of lispro per day. Blood Glucose Control reintroduction of lispro) through week At week 26, the LS mean 6 SD change 26. The remaining 184 participants (46%) Hypoglycemia and Body Weight from baseline in HbA1c was 21.04 6 include those who received lispro re- The proportion of participants with se- 0.04% (211 6 0.4 mmol/mol) (reduced introduction at any time or those for vere or documented symptomatic hypo- to 6.7 6 0.8% [49 6 8 mmol/mol]) in the whom data were not available to allow glycemia from baseline to week 26 was albiglutide 1 glargine group and 21.10 verification of absence of lispro reintro- lower in the albiglutide 1 glargine than 6 0.04% (212.0 6 0.4 mmol/mol) (re- duction through week 26. Overall, 291 par- the lispro 1 glargine group (57.2% vs. duced to 6.6 6 0.8% [48 6 8 mmol/mol]) ticipants (72%) did not require lispro 75.0%, respectively; odds ratio 0.43 in the lispro 1 glargine group (LS mean reintroduction through week 26 or were [95% CI 0.31–0.60]) (Table 3). The overall difference 0.06% [95% CI 20.05 to 0.17], able to decrease lispro dose without on-therapy event rate for severe, docu- 2 0.7 mmol/mol [95% CI 0.5 to 1.9]; worsening HbA1c at week 26, while mented symptomatic, or asymptomatic noninferiority P , 0.0001) (Table 2). 28% remained on the same or higher hypoglycemia (exposure adjusted) was Change in HbA1c over time was similar dose of lispro or had a lower dose of lispro 13.0 and 32.2 per person-year for the between groups (Fig. 1A). but worse HbA1c at week 26. There were albiglutide 1 glargine and lispro 1 glar- The proportion of participants achiev- no differences between individuals who gine groups (event rate ratio 0.43 [95% CI ing HbA1c ,7.0% (53 mmol/mol) was did or did not require the reintroduction 0.36–0.52]); for on-therapy severe hypo- similar between groups (61% and 62% at of lispro in terms of duration of diabe- glycemia, the event rate was 0.05 vs. 0.13 1 week 26 for the albiglutide glargine tes, age, weight, BMI, baseline HbA1c, per person-year and occurred in 2.3% and lispro 1 glargine groups, respec- andbaselinetotalinsulindose(datanot (albiglutide 1 glargine) and 5.3% (lis- tively) (Table 2). shown). pro 1 glargine) of participants (Table 3). The LS mean change from baseline in Mean prescribed daily prandial insulin On-therapy daytime severe hypoglyce- FPG was significantly greater in the albi- dose decreased from 38.7 6 19.0 units mic events were experienced by 1.5% of glutide 1 glargine than in the lispro 1 at baseline to 9.8 6 17.3 units at week participants in the albiglutide 1 glargine glargine group at week 26 (LS mean dif- 26 in the albiglutide 1 glargine group and group vs. 3.4% in the lispro 1 glargine ference 210 mg/dL [95% CI 216 to 25], increased from 41.3 6 21.6 units to 71.9 group, while 1.0% of participants in the 20.6 mmol/L [95% CI 20.9 to 20.3]) 6 40.1 units in the lispro 1 glargine albiglutide 1 glargine group experienced (Table 2). group. Daily basal insulin dose increased an on-therapy nocturnal severe hypogly- to a similar degree in both groups from cemic event vs. 1.5% in the lispro 1 and Injections baseline (41.6 6 17.3 units for albiglu- glargine group. The proportion of par- In the albiglutide 1 glargine group, 54% tide 1 glargine and 41.6 6 17.1 units for ticipants who experienced an on-therapy of participants (218 of 402) were able to lispro1glargine)toweek26(59.3624.1 documented symptomatic hypoglycemic totally replace lispro with albiglutide (no units for albiglutide 1 glargine and 58.6 event was 46.8% (daytime) and 25.3% care.diabetesjournals.org Rosenstock and Associates 2513

Table 2—Summary of efficacy end points

Albiglutide 1 glargine (n 5 402) Lispro 1 glargine (n 5 412)

HbA1c, % (mmol/mol) Participants, n 345 350 At screening* 8.2 6 0.6 (66 6 7) 8.2 6 0.6 (66 6 7) Baseline 7.8 6 0.6 (61 6 7) 7.7 6 0.6 (60 6 7) Week 26 6.7 6 0.8 (49 6 8) 6.6 6 0.8 (48 6 8) Change from baseline 21.10 6 0.8 (212 6 9) 21.12 6 0.8 (212 6 8) Model-adjusted change from baseline, mean 6 SE† 21.04 6 0.04 (211 6 0.4) 21.10 6 0.04 (212 6 0.4) LS mean difference (95% CI)‡ %-units 0.06 (20.05 to 0.17)*** mmol/mol 0.7 (–0.5 to 1.9) Clinical FPG, mg/dL (mmol/L)§ Participants, n 345 349 Baseline 144 6 46 (8.0 6 2.6) 139 6 48 (7.7 6 2.6) Week 26 105 6 36 (5.8 6 2.0) 114 6 41 (6.3 6 2.3) Change from baseline 239 6 51 (22.2 6 2.8) 225 6 52 (21.4 6 2.9) Model-adjusted change from baseline, mean 6 SE† 236 6 2.2 (22.0 6 0.1) 226 6 2.2 (21.5 6 0.1) LS mean difference (95% CI)‡ mg/dL 210 (215 to 25)††† mmol/L 20.6 (20.9 to 20.3) Total daily insulin dose, units| Participants, n 342 341 Baseline 80.3 6 29.1 82.9 6 32.1 Week 26 69.0 6 33.2 130.4 6 61.1 Model-adjusted total daily insulin dose, mean 6 SE† 70.4 6 2.2 131.2 6 2.1 LS mean difference (95% CI)‡ 260.8 (266.6 to 255.1)‡‡‡ Total daily basal insulin dose, units| Participants, n 342 341 Baseline 41.6 6 17.3 41.6 6 17.1 Week 26 59.3 6 24.1 58.6 6 25.9 Model-adjusted total daily insulin dose, mean 6 SE† 59.8 6 1.0 59.4 6 1.0 LS mean difference (95% CI)‡ 0.4 (22.3 to 3.0) Total daily prandial insulin (lispro) dose, units| Participants, n 342 341 Baseline 38.7 6 19.0 41.3 6 21.6 Week 26 9.8 6 17.3 71.9 6 40.1 Model-adjusted daily prandial insulin dose, mean 6 SE† 10.6 6 1.5 72.5 6 1.5 LS mean difference (95% CI)‡ 261.8 (265.9 to 257.8)‡‡‡ Total number of weekly injections Participants, n 342 341 Baseline 29 6 1.5 28 6 0.0 Week 26 13 6 7.8 28 6 0.0 Change from baseline 216 6 7.9 0.0 6 0.0 Body weight, kg Participants, n 349 352 Baseline 87.7 6 17.3 89.6 6 18.1 Week 26 85.7 6 17.5 92.0 6 18.6 Change from baseline 22.0 6 3.6 2.5 6 4.1 Model-adjusted change from baseline, mean 6 SE† 22.0 6 0.2 2.4 6 0.2 LS mean difference (95% CI)‡ 24.4 (24.9 to 23.8)‡‡‡ TRIM-Diabetes questionnaire total score¶ Participants, n 347 350 Baseline 72.3 6 14.1 73.5 6 12.5 Week 26 76.7 6 13.3 74.3 6 13.2 Change from baseline 4.4 6 12.3 0.7 6 11.1 Model-adjusted change from baseline, mean 6 SE† 4.3 6 0.6 1.1 6 0.6 LS mean difference (95% CI)‡ 3.2 (1.7–4.8)‡‡‡ HFS-II questionnaire worry subscale total score# Participants, n 348 349 Baseline 16.7 6 15.6 15.3 6 13.9 Week 26 14.2 6 14.3 16.0 6 13.4 Change from baseline 22.5 6 13.6 0.7 6 13.2 Model-adjusted change from baseline, mean 6 SE† 22.6 6 0.7 0.2 6 0.7 LS mean difference (95% CI)‡ 22.8 (24.5 to 21.1)§§§ Continued on p. 2514 2514 Reduced Prandial Insulin in GLP-1RA Switch Trial Diabetes Care Volume 43, October 2020

Table 2—Continued

Albiglutide 1 glargine (n 5 402) Lispro 1 glargine (n 5 412)

Achieving HbA1c ,7.0% at week 26 Participants, n (%) 244 (60.7) 255 (61.9) Odds ratio (95% CI)** 1.0 (0.7–1.3)

Achieving HbA1c ,7.0% without weight gain†† and severe or documented symptomatic hypoglycemia to week 26 Participants, n (%) 64 (15.9) 16 (3.9) Odds ratio (95% CI)** 3.8 (2.2–6.5)||| Data are means 6 SD unless otherwise indicated. Mean baseline value includes only those participants with both baseline and week 26 values. *At screening, n 5 389 in the albiglutide 1 glargine group and n 5 403 in the lispro 1 glargine group. †Based on MMRM model. ‡For the albiglutide 1 glargine vs. the lispro 1 glargine group. §FPG at week 26 is missing for all participants and is imputed with FSG at week 26. |Insulin dose at week 26 is defined as the prescribed insulin dose at week 25. ¶TRIM-Diabetes total and domain scores range from 0 to 100, with higher scores indicative of better experienced health state (less negative impact). #HFS-II worry subscale ranges from 0 to 72, with higher scores indicative of more worries about low blood glucose. **Differencefrom lispro 1 glarginegroup based on nonparametric CMHtest after adjustment for baseline HbA1c category, age category, region, and current use of metformin. ††No body weight gain is defined as #1 kg increase from baseline. ***P , 0.0001 (noninferiority), †††P 5 0.0004 (superiority), ‡‡‡P , 0.0001 (superiority), §§§P 5 0.0014 (superiority), |||P , 0.0001 with the nonparametric CMH test.

(nocturnal) in the albiglutide 1 glargine difference 22.8 [95% CI 24.5 to 21.1] in albiglutide 1 glargine group and con- group and 70.9% (daytime) and 36.8% favor of the albiglutide 1 glargine group gestive cardiac failure in the lispro 1 (nocturnal) in the lispro 1 glargine (Table 2). glargine group. group. The proportion of patients who No new safety signals were apparent experienced blood glucose levels ,56 Safety and Tolerability following review of clinical laboratory mg/dL (3.1 mmol/L) was 35.3% in the The incidence of on-therapy AEs (exclud- tests, vital signs, electrocardiograms, and albiglutide 1 glargine group and 57.9% ing hypoglycemia events) was 65% for physical examinations. in the lispro 1 glargine group. albiglutide 1 glargine and 62% for lis- Body weight changes from baseline at pro 1 glargine. Gastrointestinal events CONCLUSIONS week 26 differed in direction between (26%vs. 13%) and injection-site reactions To our knowledge, this is the first large the albiglutide 1 glargine and lispro 1 (2% vs. 0.2%) were more common in the randomized controlled trial using a treat- glargine groups (LS mean 6 SE 22.0 6 albiglutide1glarginegroup(Supplemen- to-target design to examine the impact 0.2 kg vs. 12.4 6 0.2 kg; difference 24.4 tary Table 5). There was one event of of substitution of a weekly GLP-1RA for kg [95% CI 24.9 to 23.8]) (Table 2 and acute in the albiglutide 1 prandial insulin on glucose control in Fig. 1F). glargine group (confirmed by an inde- type 2 diabetes insufficiently controlled The proportion of participants achiev- pendent adjudication committee). with multiple daily insulin therapy. Many ing HbA1c ,7.0% (53 mmol/mol) without The incidence of on-therapy AEs (ex- randomized, controlled, insulin treat-to- weight gain and without severe or docu- cluding hypoglycemia events) reported target studies have achieved average mented symptomatic hypoglycemia at by investigators to be drug related was HbA1c of ;7.0% (53 mmol/mol) (26); week 26 was significantly higher (odds higher in the albiglutide 1 glargine group however, such glucose control is usually ratio 3.8 [95% CI 2.2–6.5]) in the albiglu- (22.0%) vs. the lispro 1 glargine group not achieved in the clinical practice set- tide 1 glargine (15.9%) vs. the lispro 1 (5.1%), mainly due to gastrointestinal ting, as no structured support system is glargine (3.9%) group (Table 2). AEs (16.5% albiglutide 1 glargine vs. available similar to the structured setting 0.5% lispro 1 glargine). of a randomized controlled trial. Recent Patient-Related Outcomes The incidence of on-therapy serious basal-prandial insulin clinical trials, with Participants in the albiglutide 1 glargine AEs was 5.8% for albiglutide 1 glargine longer-acting basal insulin analogs, re- group had improved (higher) TRIM- and 7.5% for lispro 1 glargine, includ- sulted in average HbA1c in the 7.0% and Diabetes questionnaire scores at week ing 0% (albiglutide 1 glargine) and 1.5% 7.2% (53 and 55 mmol/mol) range, but at 26 (LS mean difference 3.2 [95% CI (lispro 1 glargine) serious AEs of se- the expense of major efforts and signif- 1.7–4.8]) vs. the lispro 1 glargine group vere hypoglycemia. Fourteen participants icant hypoglycemia, mostly daytime and (Table 2). Improvements were seen for (3.5%) in the albiglutide 1 glargine group attributed to fast-acting prandial insulin all five domains of the TRIM-Diabetes and 9 (2.2%) in the lispro 1 glargine group (20,21). In our study, active intervention questionnaire (treatment burden, daily had an on-therapy AE leading to discon- of the weekly GLP-1RA albiglutide added life, diabetes management, compliance, tinuation of study treatment/study with- to optimized basal insulin achieved very and psychological health) in the albiglu- drawal. The predominant reasons were good glycemic control (mean HbA1c of tide 1 glargine group (Supplementary (albiglutide 1 glargine) and hy- 6.7% [49 mmol/mol]) in individuals with Table 4); however, differences compared poglycemia (lispro 1 glargine). Other long-standing diabetes (14–15 years) with the lispro 1 glargine group were only reasons included vomiting, cholecystitis, similar to what was achieved with opti- significant for the diabetes management diarrhea, abdominal pain, acute kidney mized basal insulin in the control arm domain and the compliance domains. injury, decreased appetite, fatigue, hyper- (mean HbA1c of 6.6% [48 mmol/mol]). In Similarly, HFS-IIscores improved(LS mean sensitivity, malaise, and pancreatitis in the the albiglutide 1 glargine arm, glycemic care.diabetesjournals.org Rosenstock and Associates 2515

Figure 1—HbA1c, FPG, insulin dose, number of injections, and body weight by study visit (full analysis population). A: Mean HbA1c by study visit from screening to week 26. B: Mean FPG by study visit to week 26. C: Model-adjusted prandial insulin dose by study visit to week 26. D: Model-adjusted basal insulin dose by study visit to week 26. E: Mean number of total injections per week by study visit to week 26. F: Model-adjusted change from baseline in body weight (kg) by study visit to week 26. C, albiglutide 1 glargine; ,, lispro 1 glargine. control was achieved without increase of insulin dose (only 28% were on the same over 26 weeks, but both the odds ratio hypoglycemia risk, with the added ben- or higher dose). for risk of one hypoglycemic event and efit of weight loss, and with decreases in In addition, FPG was lower in the the hypoglycemia event rate were more prandial injections and doses and total albiglutide 1 glargine arm compared than halved (Table 3) with the albiglutide prescribed insulin dose, while basal in- with the lispro 1 glargine arm, despite substitution. sulin requirements were unchanged. nearly identical mean glargine dose in In support of these findings, HFS-II More than 50% of participants did not both arms, consistent with observations scores suggested that switching to a need reintroduction of lispro, and the that long-acting GLP-1RAs can impact GLP-1RA allowed uptitration of basal average injection number per week was both prandial and fasting glucose levels. insulin without increasing concerns re- more than halved. Even in those 46% Unsurprisingly, considering the larger garding hypoglycemia. The TRIM-Diabetes of participants who had to reintroduce doses of prandial insulin, hypoglycemia questionnaire also showed differences be- lispro during the study, many achieved was a significant problem in the lispro 1 tween the two treatment groups. As glu- HbA1c ,7.0% (53 mmol/mol) with a lower glargine group, affecting 75% of people cose control and trial input were similar, 2516 Reduced Prandial Insulin in GLP-1RA Switch Trial Diabetes Care Volume 43, October 2020

Table 3—Hypoglycemia earlier stages of diabetes after oral agent Albiglutide 1 Lispro 1 failure when only basal insulin would glargine glargine normally be used (26,27). Limitations of our study include the Hypoglycemia (full analysis population) incidence fl to week 26 possibility that the study results re ect n 402 412 the specific titration algorithms used and Documented symptomatic or severe would differ with less consistent titration Participants, n (%) 230 (57.2) 309 (75.0) protocols used in clinical practice, which Odds ratio (95% CI)* 0.43 is mainly relevant to the findings for the (0.31–0.60)*** lispro 1 glargine arm. Further, patients On-therapy hypoglycemia (safety population) in the lispro 1 glargine arm may have exposure-adjusted incidence rate been more likely to self-monitor blood n 400 413 Asymptomatic glucose, which could in turn result in a Participants, n (%) 230 (57.5) 293 (70.9) greater likelihood that hypoglycemic Events/person-year† 6.6 12.6 events, particularly asymptomatic events, Documented symptomatic were detected in these individuals. The Participants, n (%) 203 (50.8) 299 (72.4) patient-reported outcomes measures Events/person-year† 6.3 19.5 were not administered to blinded study Severe groups, limiting their interpretation. Our Participants, n (%) 9 (2.3) 22 (5.3) Events/person-year† 0.05 0.13 study was 26 weeks in duration, and it is All‡ possible that the benefits of the GLP-1RA Participants, n (%) 290 (72.5) 359 (86.9) will be gradually lost and a full insulin Events/person-year† 13.0 32.2 replacement regimen again be needed. Rate ratio (95% CI)§ 0.43 Our study provides a systematic eval- – ††† (0.36 0.52) uation of a novel treatment approach for On-therapy hypoglycemic event by blood the management of patients with type 2 | glucose level diabetes. These findings, together with n 400 413 ,56 mg/dL (,3.1 mmol/L), n (%) 141 (35.3) 239 (57.9) other data in the literature, provide $56 mg/dL ($3.1 mmol/L), n (%) 160 (40.0) 121 (29.3) scientific evidence for a role for GLP- Missing data, n (%) 4 (1.0) 1 (0.2) 1RAs as a replacement for prandial in- *Difference from lispro 1 glargine group based on nonparametric CMH test after adjustment for sulin in patients with type 2 diabetes baseline HbA1c category, age category, region, and current use of metformin. †Exposure-adjusted requiring multiple daily insulin injections event rate (number of on-therapy severe or documented symptomatic hypoglycemic or to achieve glycemic control and may fi asymptomatic events divided by person-years), where person-years is de ned as the cumulative warrant reassessment of current treat- study treatment exposure duration (in years) for all participants in the treatment group during the treatment period being summarized. ‡Severe, documented symptomatic, or asymptomatic ment guidelines. Such an approach might hypoglycemiaevent.§RatioofLSincidencerate(albiglutide/insulinlispro)fromrepeated-measure be of particular interest in older individ- Poisson regression model with offset forthe person-year. The model includes treatment effect and uals for whom individualized HbA1c tar- interval as factors and HbA1c stratum, age category (,65 vs. $65 years), current use of metformin (yes vs. no), and region as covariates. The P value is from a two-sided t test for the difference in gets are less stringent, hypoglycemia risk rates. |Participants with more than one hypoglycemic event are only counted once in the worst is greater, and simplification of complex category. ***P , 0.0001 with the nonparametric CMH test; †††P 5 0.0001 with repeated- treatment regimens is more pressing, measures Poisson regression. and so, conceivably, the percentage of people not requiring prandial insulin in- jections could be even greater. Further, this likely reflects effects of the reduction people with type 2 diabetes uncontrolled although no head-to-head studies have in injections, decreased hypoglycemia, with glargine (17). Addition of liraglutide been done with albiglutide versus dula- and/or the better body weight trajectory to a multiple daily injection insulin reg- glutide or , data from the (mean difference of 4.4 kg) on patient imen achieved a mean HbA1c of 7.4% literature have shown HbA1c reductions health-related quality of life. (57 mmol/mol), higher than in our study with albiglutide in the 0.8%–0.9% range While other larger studies have not (6.7% [49 mmol/mol]), with no formal (17,30,31),while studies with dulaglutide addressed switching from prandial in- reduction in insulin dose (12). and semaglutide achieved HbA1c reduc- sulin, the efficacy of GLP-1RAs in com- Other studies of GLP-1RA plus insu- tions in the 1.1%–1.8% range and with bination with basal insulin has been lin combinations earlier in the course of greater weight loss in most studies examined. As examples, exenatide and type 2 diabetes, including the fixed-ratio (14,15,32–34). Therefore, although the semaglutide improved glucose control studies (27,28), confirm the synergy of idea is purely speculative, it is conceivable, when added to a basal insulin regimen, this approach, with noted advantage for based on available data, that other weekly with the added benefitofweightre- hypoglycemia and body weight change GLP-1RAs (i.e., dulaglutide, semaglutide) duction(11,14).IntheHARMONY6study, (29). Indeed, HbA1c of the same magni- might have a greater effect than albiglutide albiglutide added to basal insulin glargine tude has been achieved in people on for reducing HbA1c and body weight when was noninferior to the active control of insulin starting fixed-ratio formulations replacing prandial insulin in patients with prandial insulin added to glargine in of basal insulin and a GLP-1RA but at type 2 diabetes on multiple daily insulin care.diabetesjournals.org Rosenstock and Associates 2517

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Edelman SV, Weyer C. Unresolved challenges ADD-ON). Diabetes Obes Metab 2014;16:636–644 LLC and funded by GlaxoSmithKline. The authors with insulintherapy in type 1 and type 2diabetes: 19. Abrahamson MJ, Peters A. Intensification of thank John Cook, formerly of GlaxoSmithKline, potential benefit of replacing , a second insulin therapy in patients with type 2 diabetes for his assistance with early drafts of the beta-cell hormone. Diabetes Technol Ther 2002; mellitus: an algorithm for basal-bolus therapy. manuscript. 4:175–189 Ann Med 2012;44:836–846 Duality of Interest. This study (NCT02229227) 7. GlaxoSmithKiline. Highlights of prescribing in- 20. Garber AJ, King AB, Del Prato S, et al.; was funded by GlaxoSmithKline (GSK). J.R. has formation: Tanzeum (albiglutide) for injection, NN1250-3582 (BEGIN BB T2D) Trial Investigators. participated in advisory panels for Boehringer for subcutaneous use [Internet], 2014. Research Insulin degludec, an ultra-longacting basal in- Ingelheim Pharmaceuticals, Intarcia Therapeutics, Triangle Park, NC, GlaxoSmithKline. Available sulin, versus insulin glargine in basal-bolus treat- Applied Therapeutics, Janssen Pharmaceuticals, from https://www.accessdata.fda.gov/drugsatfda_ ment with mealtime insulin aspart in type 2 Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, docs/label/2017/125431s019lbl.pdf. Accessed diabetes (BEGIN Basal-Bolus Type 2): a phase 3, and Oramed Pharmaceuticals and has received re- 10 February 2020 randomised, open-label, treat-to-target non-in- search support from GSK, Janssen Pharmaceuticals, 8. GlaxoSmithKline.Eperzan:summaryofproduct feriority trial. Lancet 2012;379:1498–1507 Pfizer, Intarcia Therapeutics, Genentech, Merck characteristics [Internet], 2014. County Cork, Ireland, 21. Riddle MC, Rosenstock J, Vlajnic A, Gao L. & Co., Eli Lilly and Company, Novo Nordisk, GalxoSmithKline. Available from https://www.ema Randomized, 1-year comparison of three ways to Sanofi, and Oramed Pharmaceuticals. A.N., .europa.eu/en/documents/product-information/ initiate and advance insulin for type 2 diabetes: J.S., L.E., A.A., and J.D. are employees of and eperzan-epar-product-information_en.pdf. Accessed twice-daily premixed insulin versus basal insulin own stock in GSK. M.C.C. and J.M. were employ- 10 February 2020 with either basal-plus one prandial insulin or ees of GSK during the time of the study. P.H., or 9. Ahmann A, Rodbard HW, Rosenstock J, et al.; basal-bolus up to three prandial injections. Di- institutions with which he is associated, has NN2211-3917 Study Group. Efficacy and safety abetes Obes Metab 2014;16:396–402 received funding from the manufacturer of albi- of liraglutide versus placebo added to basal 22. Rosenstock J, Ahmann AJ, Colon G, Scism- glutide, GSK, and from AntriaBio, AstraZeneca, insulin analogues (with or without metformin) in Bacon J, Jiang H, Martin S. Advancing insulin Biocon, Boehringer Ingelheim, Eli Lilly and Com- patients with type 2 diabetes: a randomized, therapy in type 2 diabetes previously treated pany, Hanmi, Janssen, Merck Sharp & Dohme (a placebo-controlled trial. Diabetes Obes Metab with glargine plus oral agents: prandial premixed subsidiary of Merck & Co.), Novo Nordisk, and 2015;17:1056–1064 (insulin lispro protamine suspension/lispro) ver- Sanofi. No other potential conflicts of interest 10. Buse JB, Bergenstal RM, Glass LC, et al. Use sus basal/bolus (glargine/lispro) therapy. Diabe- relevant to this article were reported. of twice-daily exenatide in basal insulin-treated tes Care 2008;31:20–25 Author Contributions. J.R., A.N., J.S., A.A., and patients with type 2 diabetes: a randomized, con- 23. Brod M, Hammer M, Christensen T, Lessard J.M. contributed to the conception or design of the trolled trial. Ann Intern Med 2011;154:103–112 S, Bushnell DM. Understanding and assessing the study and the data analysis or interpretation of the 11. Guja C, Fr´ıas JP, Somogyi A, et al. Effect of impact of treatment in diabetes: the Treatment- study. L.E., J.D., and P.H. contributed to the data exenatide QW or placebo, both added to titrated Related Impact Measures for Diabetes and De- analysis or interpretation of the study. M.C.C. insulin glargine, in uncontrolled type 2 diabetes: vices(TRIM-DiabetesandTRIM-DiabetesDevice). contributed to the conception or design of the the DURATION-7 randomized study. Diabetes Health Qual Life Outcomes 2009;7:83 study. All authors commented critically and ap- Obes Metab 2018;20:1602–1614 24. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek proved the final draft for submission. J.R. and A.A. 12. Lind M, Hirsch IB, Tuomilehto J, et al. Lir- G, Butterfield J. Fear of hypoglycemia: quantifica- are the guarantors of this work and, as such, had aglutide in people treated for type 2 diabetes tion, validation, and utilization. Diabetes Care 1987; full access to all the data in the study and take with multiple daily insulin injections: randomised 10:617–621 responsibility for the integrity of the data and the clinicaltrial (MDILiraglutide trial).BMJ2015;351: 25. European Medicines Agency. Assessment re- accuracy of the data analysis. h5364 port for GLP-1-based therapies [Internet], 2013. 2518 Reduced Prandial Insulin in GLP-1RA Switch Trial Diabetes Care Volume 43, October 2020

Available from http://www.ema.europa.eu/docs/ 29. Lind M, Hirsch IB, Tuomilehto J, Dahlqvist S, controlled on , with or without met- en_GB/document_library/Report/2013/08/ Torffvit O, Pehrsson NG. Design and methods formin. Diabetes Obes Metab 2014;16:1257– WC500147026.pdf. Accessed 15 May 2018 of a randomised double-blind trial of adding 1264 26. Garber AJ. Treat-to-target trials: uses, in- liraglutide to control HbA1c in patients with 32. Ahren´ B, Masmiquel L, Kumar H, et al. Efficacy terpretation and review of concepts. Diabetes type 2 diabetes with impaired glycaemic control and safety of once-weekly semaglutide versus once- Obes Metab 2014;16:193–205 treatedwithmultipledailyinsulininjections daily as an add-on to metformin, thia- 27. Gough SC, Bode B, Woo V, et al.; NN9068- (MDI-Liraglutide trial). Prim Care Diabetes zolidinediones, or both, in patients with type 2 3697 (DUAL-I) trial investigators. Efficacy and 2015;9:15–22 diabetes (SUSTAIN 2): a 56-week, double-blind, safety of a fixed-ratio combination of insulin de- 30. AhrenB,JohnsonSL,StewartM,etal.;´ phase 3a, randomised trial. Lancet Diabetes Endo- gludec and liraglutide (IDegLira) compared with its HARMONY 3 Study Group. HARMONY 3: 104- crinol 2017;5:341–354 components given alone: results of a phase 3, open- week randomized, double-blind, placebo- and 33. Pratley RE, Aroda VR, Lingvay I, et al.; SUS- label, randomised, 26-week, treat-to-target trial in active-controlled trial assessing the efficacy and TAIN 7 investigators. Semaglutide versus dula- insulin-naive patients with type 2 diabetes. Lancet safety of albiglutide compared with placebo, glutideonceweeklyinpatientswithtype2 Diabetes Endocrinol 2014;2:885–893 sitagliptin, and in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, 28. Rosenstock J, Diamant M, Aroda VR, et al.; diabetes taking metformin. Diabetes Care 2014;37: phase 3b trial. Lancet Diabetes Endocrinol 2018; LixiLan PoC Study Group. Efficacy and safety of 2141–2148 6:275–286 LixiLan, a titratable fixed-ratio combination of 31. Reusch J, Stewart MW, Perkins CM, et al. 34. Wysham C, Blevins T, Arakaki R, et al. Efficacy lixisenatide and insulin glargine, versus insulin Efficacy and safety of once-weekly glucagon-like and safety of dulaglutide added onto pioglita- glargine in type 2 diabetes inadequately con- peptide 1 receptor agonist albiglutide (HARMONY zone and metformin versus exenatide in type 2 trolled on metformin monotherapy: the LixiLan 1 trial): 52-week primary endpoint results from a diabetes in a randomized controlled trial proof-of-concept randomized trial. Diabetes Care randomized, double-blind, placebo-controlled tri- (AWARD-1). Diabetes Care 2014;37:2159– 2016;39:1579–1586 al in patients with type 2 diabetes mellitus not 2167