established in 1812
`
`September 22, 2022
`
`vol. 387 no. 12
`
`Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes
`The GRADE Study Research Group*
`
`The members of the writing committee
`(David M. Nathan, M.D., John M. Lachin,
`Sc.D., Ashok Balasubramanyam, M.D.,
`Henry B. Burch, M.D., John B. Buse, M.D.,
`Nicole M. Butera, Ph.D., Robert M. Cohen,
`M.D., Jill P. Crandall, M.D., Steven E. Kahn,
`M.B., Ch.B., Heidi Krause‑Steinrauf, M.S.,
`Mary E. Larkin, R.N., Neda Rasouli, M.D.,
`Margaret Tiktin, D.N.P., Deborah J. Wexler,
`M.D., and Naji Younes, Ph.D.) assume
`responsibility for the overall content and
`integrity of this article.
`
`The affiliations of the members of the
`writing committee are listed in the Ap‑
`pendix. Dr. Lachin can be contacted at
` grademail@ bsc . gwu . edu or at the George
`Washington University Biostatistics Cen‑
`ter–GRADE Coordinating Center, 6110
`Executive Blvd., Ste. 750, Rockville, MD
`20852.
`
`*The members of the GRADE Study Re‑
`search Group are listed in the Supplemen‑
`tary Appendix, available at NEJM.org.
`
`N Engl J Med 2022;387:1063-74.
`DOI: 10.1056/NEJMoa2200433
`Copyright © 2022 Massachusetts Medical Society.
`
`CME
`at NEJM.org
`
`a bs tr ac t
`
`BACKGROUND
`The comparative effectiveness of glucose-lowering medications for use with metfor-
`min to maintain target glycated hemoglobin levels in persons with type 2 diabetes
`is uncertain.
`METHODS
`In this trial involving participants with type 2 diabetes of less than 10 years’ duration
`who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%,
`we compared the effectiveness of four commonly used glucose-lowering medica-
`tions. We randomly assigned participants to receive insulin glargine U-100 (here-
`after, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor
`agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary
`metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or
`higher that was subsequently confirmed, and the secondary metabolic outcome was
`a confirmed glycated hemoglobin level greater than 7.5%.
`RESULTS
`A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had
`received metformin for type 2 diabetes were followed for a mean of 5.0 years. The
`cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary
`metabolic outcome) differed significantly among the four groups (P<0.001 for a
`global test of differences across groups); the rates with glargine (26.5 per 100 par-
`ticipant-years) and liraglutide (26.1) were similar and lower than those with
`glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with
`respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome)
`paralleled those of the primary outcome. There were no material differences with
`respect to the primary outcome across prespecified subgroups defined according
`to sex, age, or race or ethnic group; however, among participants with higher
`baseline glycated hemoglobin levels there appeared to be an even greater benefit
`with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglyce-
`mia was rare but significantly more frequent with glimepiride (in 2.2% of the par-
`ticipants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Partici-
`pants who received liraglutide reported more frequent gastrointestinal side effects
`and lost more weight than those in the other treatment groups.
`CONCLUSIONS
`All four medications, when added to metformin, decreased glycated hemoglobin
`levels. However, glargine and liraglutide were significantly, albeit modestly, more
`effective in achieving and maintaining target glycated hemoglobin levels. (Funded
`by the National Institute of Diabetes and Digestive and Kidney Diseases and others;
`GRADE ClinicalTrials.gov number, NCT01794143.)
`
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`journal of medicine
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`

`

`A Quick Take
`is available at
`NEJM.org
`
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Type 2 diabetes affects more than 30
`
`million adults in the United States and
`more than 500 million worldwide, with
`an annual incidence in the United States of ap-
`proximately 1.5 million cases.1,2 Its major human
`and economic costs are caused primarily by the
`development of diabetes-specific complications,
`including retinopathy, nephropathy, and neuropa-
`thy, and a risk of cardiovascular disease that is
`two to five times as high as that among persons
`without diabetes.3 The long-term diabetes-specif-
`ic complications have been ameliorated by inter-
`ventions that decrease chronic glycemia, as mea-
`sured by glycated hemoglobin levels.4,5 A target
`glycated hemoglobin level of less than 7.0%
`(<53.0 mmol per mole) has been established by
`consensus for most persons with type 2 diabe-
`tes, with the goal of decreasing morbidity.6
`Virtually all recommendations for the man-
`agement of glycemia in persons with type 2 dia-
`betes have included metformin as the first medi-
`cation to be used, with a second medication
`added when needed to achieve or maintain a
`glycated hemoglobin level of less than 7.0%.7,8
`Unfortunately, there are few long-term compara-
`tor studies to guide the choice of a second glucose-
`lowering medication. The purpose of the Glycemia
`Reduction Approaches in Type 2 Diabetes: A Com-
`parative Effectiveness (GRADE) Study was to ex-
`amine the relative effectiveness of agents from
`four of the most commonly used classes of glu-
`cose-lowering medications, when added to met-
`formin, in achieving and maintaining target
`glycated hemoglobin levels in persons with re-
`cent-onset type 2 diabetes.9 Here, we report the
`major glycemic outcomes of this trial. In our
`accompanying article in this issue of the Journal,
`we report the effects of the randomly assigned
`interventions on prespecified secondary outcomes
`(microvascular complications and cardiovascular
`events and their risk factors).10
`
`Me thods
`
`Trial Design and Oversight
`This multicenter, parallel-group, comparative-
`effectiveness clinical trial was sponsored by the
`National Institute of Diabetes and Digestive and
`Kidney Diseases (NIDDK) of the National Insti-
`tutes of Health and designed by a subgroup of the
`investigators with NIDDK participation.9 Ran-
`
`domization was conducted with the use of a cen-
`tralized Web-based system and stratified accord-
`ing to trial site. The participants and clinic staff
`were aware of the treatment assignments; how-
`ever, the investigators at the laboratories and
`reading centers and the members of the adjudi-
`cation committee were unaware of the treatment
`assignments and the identity of each participant.
`All the data were collected and analyzed by the
`trial research group. The authors vouch for the
`accuracy and completeness of the data and for
`the fidelity of the trial to the protocol, available
`with the Supplementary Appendix with the full
`text of this article at NEJM.org. The authors wrote
`the manuscript and made the decision to submit
`it for publication. No confidentiality restrictions
`were imposed by the sponsors.
`The manufacturers contributed the trial med-
`ications under clinical-trial agreements with the
`NIDDK but had no role in the design, conduct,
`or analysis of the trial. An independent data and
`safety monitoring board appointed by the NIDDK
`oversaw the conduct of the trial. All participating
`centers obtained approval from local institutional
`review boards.
`
`Participants
`Participants with type 2 diabetes were recruited
`at 36 clinical centers (Section S1 in the Supple-
`mentary Appendix) with the goal of composing
`a cohort that was broadly representative of the
`population with type 2 diabetes in the United
`States according to race and ethnic group. Eligible
`participants had type 2 diabetes that had been
`diagnosed at or after the age of 30 years, with
`the exception of American Indians or Alaska Na-
`tives, in whom the age at diagnosis was at least
`20 years.9 At initial screening, the known dura-
`tion of diabetes was less than 10 years, and the
`participants had received at least 500 mg of met-
`formin per day without the use of other glucose-
`lowering medications for the previous 6 months
`and were willing to use injection therapy. During
`a run-in period of 6 to 14 weeks before random-
`ization, the metformin dose was increased to at
`least 1000 mg per day, with a target maximal
`dose (one that could be taken without unaccept-
`able side effects) of 2000 mg per day. Eligible par-
`ticipants had a glycated hemoglobin level of 6.8 to
`8.5% (50.8 to 69.4 mmol per mole) at the end of
`the run-in period.
`
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`

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`Outcomes of Glycemia Reduction in Type 2 Diabetes
`
`Treatments
`The four medications selected for the current
`trial had to be approved by the Food and Drug
`Administration (FDA) and had to be in common
`use in combination with metformin at the time
`of the trial launch in 2013. Immediate-release
`or extended-release formulations of metformin
`(Bristol Myers Squibb) were supplied to all the
`participants. The randomly assigned treatment
`doses were adjusted on the basis of their labeling.
`The treatments included the following: insu-
`lin glargine U-100 (hereafter, glargine) (Sanofi),
`administered daily at an initial dose of up to 20 U
`and adjusted according to glucose levels moni-
`tored by the participant and to avoid hypoglyce-
`mia; the sulfonylurea glimepiride (Sanofi), in-
`creased from 1 to 2 mg to a maximum of 8 mg per
`day, administered in divided doses and adjusted
`according to glucose levels monitored by the par-
`ticipant and to avoid hypoglycemia; the glucagon-
`like peptide-1 (GLP-1) receptor agonist liraglu-
`tide (Novo Nordisk) initiated at a dose of 0.6 mg,
`with escalation to a maximum dose of 1.8 mg
`daily, depending on gastrointestinal side effects;
`and the dipeptidyl peptidase 4 inhibitor sitagliptin
`(Merck) at a dose of 100 mg, with the dose ad-
`justed according to kidney function.
`The assigned treatment was continued until
`the participant had a confirmed glycated hemo-
`globin level greater than 7.5% (>58.5 mmol per
`mole) (the secondary metabolic outcome) (Fig. S1
`in the Supplementary Appendix). At that time,
`glargine was added to the three assigned nonin-
`sulin treatments. In participants assigned to re-
`ceive glargine who had a secondary outcome event
`and those in the other three treatment groups who
`had a tertiary outcome event, described below,
`treatment was intensified by adding prandial
`rapid-acting insulin aspart to the glargine regi-
`men, and the randomly assigned medications, with
`the exception of glargine, were discontinued.
`Thiazolidinediones were not included in the
`trial because of safety concerns present at the
`time of trial planning; these concerns included
`bone loss, fluid retention, and a risk of bladder
`cancer with pioglitazone.11 Sodium–glucose co-
`transporter 2 (SGLT2) inhibitors were not in-
`cluded because they had not been approved by
`the FDA in the United States during the plan-
`ning and launch of this trial, and there was no
`clinical experience with them.
`
`During the trial, consensus recommendations
`on the preferential use of GLP-1 receptor agonists
`and SGLT2 inhibitors in persons with prevalent
`cardiovascular disease or kidney disease were is-
`sued by the American Diabetes Association and
`the European Association for the Study of Diabe-
`tes.12,13 These recommendations were communi-
`cated to participants with cardiovascular disease
`or kidney disease and to their health care pro-
`viders. Any glucose-lowering medications other
`than those included as part of the trial were
`prescribed by the participants’ own health care
`providers.
`
`Outcomes and Assessments
`The participants were evaluated quarterly. The
`primary outcome was primary metabolic failure
`of the randomly assigned treatment, defined as
`confirmation (usually at the next quarterly visit)
`of a glycated hemoglobin level of 7.0% or high-
`er.9 A participant could first have a primary-
`outcome event at 6 months, with confirmation
`at 9 months, unless the glycated hemoglobin
`level was greater than 9.0% (>74.9 mmol per mole),
`in which case the outcome event could occur at
`3 months with confirmation at 3 to 6 weeks
`thereafter. The secondary metabolic outcome was
`a confirmed glycated hemoglobin level greater
`than 7.5% after the primary outcome. The pro-
`tocol stipulated initiation of glargine in the three
`noninsulin treatment groups and intensification
`of insulin therapy in the original glargine treat-
`ment group after a secondary-outcome event.9
`The tertiary metabolic outcome was a confirmed
`glycated hemoglobin level greater than 7.5% af-
`ter the secondary outcome, regardless of wheth-
`er glargine was initiated in the three noninsulin
`treatment groups and insulin therapy was inten-
`sified in the original glargine treatment group.
`All laboratory measurements were performed in
`the GRADE Central Biochemical Laboratory (Sec-
`tion S3).
`In the comparisons of the four treatments,
`other important trial outcomes included the fol-
`lowing: serious adverse events; targeted adverse
`events (severe hypoglycemia warranting treatment,
`as well as pancreatitis and pancreatic and other
`cancers, with the exception of nonmelanoma skin
`cancer) adjudicated by committee9; and effects
`on microvascular complications and cardiovascu-
`lar disease and risk factors for these conditions.
`
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`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Statistical Analysis
`The analyses were conducted in accordance with
`the intention-to-treat principle. We estimated that
`a sample of 5000 participants, with an assumed
`hazard rate of 0.0875 per year for the primary
`outcome, would provide the trial with 90% power,
`corrected for six pairwise tests at the 0.05 level, to
`detect a 25% reduction in the risk of treatment
`failure among the groups. Kaplan–Meier plots
`were used to capture the cumulative incidence of
`outcomes according to the time from random-
`ization to the visit at which an event was first
`reported and subsequently confirmed. We used
`a Cox proportional-hazards model to assess dif-
`ferences among the treatment groups, and the
`results are described with hazard ratios and ro-
`bust confidence limits.14 Differences in the out-
`comes were also reported as the restricted mean
`survival time,15 or time to event, over 4 years of
`follow-up (when 85.8% of the trial cohort was
`followed). Additional analyses compared each
`treatment group with the other three combined
`with the use of hazard ratios and confidence
`intervals.16
`For the primary outcome, a global log-rank
`test was used to test for any differences among
`the four groups, and additional tests were used
`to assess pairwise differences between groups.
`The closed-testing procedure provided protected
`P values for the six pairwise comparisons17 and
`for the comparison of each treatment group with
`the other three combined.16 The results of all
`other analyses were expressed as hazard ratios,
`estimates of effects (risk reductions), or mean
`values, all with accompanying 95% confidence
`intervals, or as simple percentages. The widths
`of the confidence intervals have not been adjusted
`for multiple testing, and any inferences drawn
`may not be reproducible; therefore, P values are
`not reported.
`Prespecified subgroup analyses included base-
`line factors as categories (age <45, 45 to 59, and
`≥60 years; sex; and race or ethnic group) or strata
`in thirds (body-mass index [BMI; the weight in
`kilograms divided by the square of the height in
`meters], duration of diabetes, and glycated he-
`moglobin levels). Sensitivity analyses were con-
`ducted to assess the effect of coronavirus disease
`2019 (Covid-19) and adherence to trial medications
`(“per-protocol analysis”). Details are provided in
`Figures S2 and S3.
`
`R esults
`
`Baseline Characteristics of the Participants
`The first participant underwent randomization
`in July 2013, and the last participant underwent
`randomization in August 2017 (Fig. S4). The base-
`line characteristics of the 5047 participants, which
`were reported previously18 and are shown in Table
`S1, included a mean (±SD) age of 57.2±10.0 years.
`A total of 63.6% were men, which reflected the
`inclusion of 10 Veterans Affairs medical centers
`as trial sites, and 41.5% of the participants were
`at least 60 years of age. A total of 65.7% of the
`participants identified as White, 19.8% as Black,
`and 3.6% as Asian. Ethnic group was also reported
`by the participants: 18.6% identified as Hispanic
`or Latinx, 2.7% as American Indian or Alaska
`Native, and 0.6% as Native Hawaiian or Pacific
`Islander.
`The mean duration of diabetes as reported by
`the participants was 4.2±2.7 years. The daily met-
`formin dose was 1576±525 mg at initial screening
`and 1944±205 mg at randomization, and 92.3%
`of the participants received 2000 mg per day. The
`mean BMI was 34.3±6.8, and the mean glycated
`hemoglobin level was 7.5±0.5% (58.3±5.3 mmol
`per mole). There were no substantial differences
`in any baseline demographic characteristic or
`findings on physical examinations or laboratory
`measurements among the four treatment groups.
`The baseline characteristics of the recruited cohort
`resembled those in the U.S. population who had
`type 2 diabetes that was being treated with met-
`formin, who were of a similar age, and who had
`a similar duration of diabetes and a similar
`glycated hemoglobin range (Table S2).
`
`Participant Retention and Adherence to Trial
`Visits and Assigned Medications
`At the end of the trial in April 2021, the mean
`duration of follow-up was 5.0 years (range, 0 to
`7.6), and 85.8% of the participants had been fol-
`lowed for at least 4 years. Retention and adher-
`ence were high; 94% of the participants com-
`pleted a final visit, and they adhered to a mean
`of 92% of their expected trial visits (Table 1). A
`total of 27 of 5047 participants (0.5%) were lost
`to follow-up, and 153 died during the trial. Dur-
`ing the Covid-19 pandemic, which overlapped with
`the trial closeout period, many visits were con-
`ducted by telephone and data on the glycated
`
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`

`Outcomes of Glycemia Reduction in Type 2 Diabetes
`
`Table 1. Protocol Completion and Adherence in the Treatment Groups during the Trial.
`
`Variable
`
`Glargine
`(N = 1263)
`
`Glimepiride
`(N = 1254)
`
`Liraglutide
`(N = 1262)
`
`Sitagliptin
`(N = 1268)
`
`Retention — no./total no. (%)*
`
`1138/1221 (93.2)
`
`1142/1211 (94.3)
`
`1156/1235 (93.6)
`
`1144/1227 (93.2)
`
`Overall adherence to trial visits — %†
`
`Mean follow‑up — yr‡§
`
`Discontinuation of metformin — no. (%)
`
`Use of nontrial, glucose‑lowering medications
`outside the protocol, discontinuation
`of assigned trial treatment outside the
`protocol, or both — no. (%)¶
`
`<1 yr after randomization
`
`1 to <2 yr after randomization
`
`≥2 yr after randomization
`
`Duration of assigned trial treatment in
`accordance with the protocol — yr§¶‖
`
`Percentage of trial time during which participant
`received originally assigned treatment in
`accordance with the protocol §¶‖**
`
`Discontinuation of assigned trial treatment
`outside the protocol — no. (%)¶
`
`Maximum dose of assigned treatment
`received††‡‡
`
`Use of nontrial glucose‑lowering medication
`outside the protocol — no. (%)
`
`91.4
`
`4.9±1.4
`
`105 (8.3)
`
`332 (26.3)
`
`65 (5.1)
`
`51 (4.0)
`
`216 (17.1)
`
`4.3±1.8
`
`92.9
`
`5.0±1.3
`
`98 (7.8)
`
`92.3
`
`5.0±1.3
`
`88 (7.0)
`
`92.8
`
`5.0±1.3
`
`97 (7.6)
`
`426 (34.0)
`
`368 (29.2)
`
`347 (27.4)
`
`61 (4.9)
`
`65 (5.2)
`
`300 (23.9)
`
`4.2±1.7
`
`150 (11.9)
`
`51 (4.0)
`
`167 (13.2)
`
`4.1±2.0
`
`60 (4.7)
`
`60 (4.7)
`
`227 (17.9)
`
`4.3±1.7
`
`83.7±28.9
`
`82.0±28.7
`
`79.1±34.6
`
`84.0±27.7
`
`172 (13.6)
`
`294 (23.4)
`
`289 (22.9)
`
`236 (18.6)
`
`51.4±39.7 U
`
`5.4±2.8 mg
`
`1.6±0.5 mg
`
`98.4±12.2 mg
`
`176 (13.9)
`
`208 (16.6)
`
`136 (10.8)
`
`193 (15.2)
`
`*
`
` Retention was defined as completion of the trial closeout visit. The denominators in this row sum to 4894 (i.e., participants who were not
`known to have died before the end of the trial).
` Visit adherence was calculated for each participant as 100% multiplied by the number of trial visits attended, divided by the maximum number
`of trial visits according to either the expected closeout trial visit date in participants who survived to the end of the trial or the date of death.
` The duration of follow‑up was calculated as the date of last trial contact minus the date of randomization.
` Plus–minus values are means ±SE.
` Participants were considered to have received assigned treatment if treatment was discontinued in accordance with the trial protocol
`(e.g., the randomized medication was discontinued because the participant had a tertiary outcome event, as stated in the protocol).
` The duration shown is the time from randomization to the date of first discontinuation of trial treatment, use of nontrial glucose‑lowering
`medication, or both in participants who discontinued trial treatment, used nontrial glucose‑lowering medication during the trial, or both,
`or the time from randomization to the date of the last trial contact in those who did not discontinue trial treatment, did not use nontrial
`glucose‑lowering medication during the trial, or both.
`** The denominator for this percentage is the time from randomization to expected closeout visit date in participants who survived to the
`end of the trial, or the time from randomization to death, calculated for each participant.
`†† Shown is the mean maximum dose of randomly assigned medication taken at any time during the trial.
`‡‡ Plus–minus values are means ±SD.
`
`†
`
`‡
`§
`¶
`
`‖
`
`hemoglobin level were collected with the use of
`a validated mail-in kit.19 As a result, 89% of all
`expected visits were completed during the final
`year of the trial (May 1, 2020, through April 30,
`2021).
`No differences were observed across the four
`treatment groups with respect to the retention of
`participants or adherence to trial visits (Table 1).
`Slight differences were observed with respect to
`metformin use, with 8% of the participants over-
`all discontinuing metformin during study follow-
`
`up. There were differences in adherence to
`randomly assigned medications, with a higher
`frequency of discontinuation in the glimepiride
`and liraglutide groups (23% of the participants
`in each group) than in the sitagliptin (19%) and
`glargine (14%) groups. In the liraglutide and si-
`tagliptin groups, most participants received the
`maximum doses of their assigned treatment; the
`mean daily maximum doses in the glimepiride
`and glargine groups were 5.4 mg and 51.4 U,
`respectively (Table 1 and Table S3). The percent-
`
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`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`age of participants who received nontrial glu-
`cose-lowering medications was highest in the
`glimepiride group (17%) and the sitagliptin group
`(15%), with less use of nontrial glucose-lowering
`medications in the liraglutide (11%) and glargine
`(14%) groups (Table S4).
`
`Efficacy
`Table 2 shows the numbers of participants in
`each treatment group with a glycated hemoglo-
`bin level of 7.0% or higher (the primary meta-
`bolic outcome), a glycated hemoglobin level great-
`er than 7.5% (the secondary metabolic outcome),
`and the corresponding rates, as well as the pair-
`wise hazard ratios among the treatment groups,
`hazard ratios for each treatment as compared
`with the other treatments combined, and the re-
`stricted mean survival time (time to event). De-
`tails regarding the tertiary-outcome results are
`provided in Table S5.
`Over the mean 5-year follow-up, 71% of the
`cohort had a primary metabolic outcome event,
`with the highest frequency in the sitagliptin group
`(77%), intermediate frequency in the glimepiride
`group (72%), and the lowest frequency in the lira-
`glutide (68%) and glargine (67%) groups (Table 2).
`The between-group differences in the Kaplan–
`Meier estimates of the cumulative incidence of a
`primary-outcome event were significant (P<0.001
`by the log-rank test) (Fig. 1A). During the first
`year of the trial, 55% of the participants in the
`sitagliptin group had a primary metabolic out-
`come event, as compared with fewer than 40%
`in the other groups. The differences in cumula-
`tive incidences over the first 4 years of the trial
`translated into 697 mean days to a primary
`metabolic outcome event in the sitagliptin group
`and 809, 861, and 882 days in the glimepiride,
`glargine, and liraglutide groups, respectively.
`The six pairwise comparisons among the
`groups (Table 2) showed that the risk of a pri-
`mary-outcome event was significantly lower
`with glargine than with sitagliptin (hazard ratio,
`0.71, or a 29% risk reduction) and than with
`glimepiride (0.89, or an 11% risk reduction),
`with P values of less than or equal to 0.001 and
`0.02, respectively, protected with the use of a
`closed testing procedure. The difference between
`the glargine and liraglutide groups was not sig-
`nificant. The risk of a primary-outcome event
`was 41% higher in the sitagliptin group than in
`the glargine group (hazard ratio in the sitagliptin
`
`group as compared with the glargine group,
`1.41, which was obtained by inverting the haz-
`ard ratio in the glargine group as compared with
`the sitagliptin group [0.71]), 45% higher than in
`the liraglutide group, and 26% higher than in the
`glimepiride group (P≤0.001 for all comparisons)
`(Table 2). The glimepiride group had a signifi-
`cantly lower risk of a primary-outcome event than
`the sitagliptin group and a higher risk than the
`glargine and liraglutide groups.
`The rates of secondary-outcome events (Ta-
`ble 2) and tertiary-outcome events followed a
`pattern that was similar to that for the primary
`outcome, with lower rates in the glargine and
`liraglutide groups, an intermediate rate in the
`glimepiride group, and the highest rate in the
`sitagliptin group. The Kaplan–Meier analyses of
`the cumulative incidences of the secondary-out-
`come events (Fig. 1B) and tertiary-outcome events
`(Fig. 1C) also resembled those of the primary-
`outcome events. A secondary-outcome event oc-
`curred in 55% of the participants in the sitagliptin
`group over a mean follow-up of 5 years, followed
`by glimepiride (in 50%), liraglutide (in 46%), and
`glargine (in 39%). The percentage of partici-
`pants with a tertiary-outcome event increased
`slowly after the first year, reaching 27% at 4 years
`(Fig. 1C), with small differences among the
`groups and with the highest risk of a tertiary-
`outcome event in the glimepiride and sitagliptin
`groups and slightly lower risks in the glargine
`and liraglutide groups.
`The mean glycated hemoglobin levels reached
`a nadir at 6 months in the glargine group and at
`3 months in the other groups, with subsequent
`increases thereafter (Fig. 1D). At year 4, the ab-
`solute differences were small (Fig. S5), with mean
`glycated hemoglobin levels of 7.1% in the glargine
`and liraglutide groups as compared with 7.2% in
`the sitagliptin group and 7.3% in the glimepiride
`group.
`
`Subgroup Analyses
`Prespecified subgroup analyses were performed
`to identify potential heterogeneity of the effects
`of the interventions. Table S6 describes the inci-
`dences of the primary and secondary metabolic
`outcome events in the treatment groups within
`subgroups. The risk of a primary-outcome event
`appeared to differ (increase) among the groups
`according to the increasing strata of baseline gly-
`cated hemoglobin level (Fig. 2). Even among par-
`
`1068
`
`n engl j med 387;12 nejm.org September 22, 2022
`
`
`
`
`
`MPI EXHIBIT 1124 PAGE 6
`
`

`

`Outcomes of Glycemia Reduction in Type 2 Diabetes
`
`Table 2. Primary and Secondary Metabolic Outcomes.*
`
`Glargine
`(N = 1263)
`
`Glimepiride
`(N = 1254)
`
`Liraglutide
`(N = 1262)
`
`Sitagliptin
`(N = 1268)
`
`908 (72.4)
`
`30.4
`(28.4–32.4)
`
`0.89
`(0.81–0.98)‡
`
`—
`
`—
`
`1.01
`(0.93–1.09)
`
`809
`(780–838)
`
`633 (50.5)
`
`14.8
`(13.6–16.0)
`
`0.73
`(0.65–0.82)
`
`—
`
`—
`
`1.09
`(1.00–1.20)
`
`1115
`(1090–1141)
`
`860 (68.2)
`
`26.1
`(24.4–27.9)
`
`1.02
`(0.93–1.12)
`
`1.15
`(1.04–1.27)¶
`
`—
`
`0.84
`(0.78–0.91)§
`
`882
`(853–911)
`
`583 (46.2)
`
`13.0
`(12.0–14.1)
`
`0.83
`(0.73–0.93)
`
`1.13
`(1.01–1.27)
`
`—
`
`0.92
`(0.84–1.01)
`
`981 (77.4)
`
`38.1
`(35.8–40.6)
`
`0.71
`(0.64–0.78)§
`
`0.79
`(0.72–0.88)§
`
`0.69
`(0.63–0.76)§
`
`1.37
`(1.27–1.48)§
`
`697
`(667–726)
`
`697 (55.0)
`
`17.5
`(16.3–18.9)
`
`0.61
`(0.54–0.69)
`
`0.84
`(0.75–0.93)
`
`0.74
`(0.66–0.83)
`
`1.38
`(1.26–1.51)
`
`1154
`(1129–1179)
`
`1030
`(1002–1058)
`
`Outcome
`
`Primary metabolic outcome†
`
`Participants — no. (%)
`
`Rate/100 participant‑yr (95% CI)
`
`Pairwise hazard ratios (95% CI)
`
`Glargine
`
`Glimepiride
`
`Liraglutide
`
`852 (67.4)
`
`26.5
`(24.8–28.4)
`
`—
`
`—
`
`—
`
`Hazard ratio in the treatment group as
`compared with all other treatments
`combined (95% CI)
`
`0.87
`(0.80–0.94)§
`
`Restricted mean survival time over 4 yr of
`follow‑up (95% CI) — days
`
`861
`(831–891)
`
`Secondary metabolic outcome‖
`
`Participants — no. (%)
`
`Rate/100 participant‑yr (95% CI)
`
`Pairwise hazard ratios (95% CI)
`
`Glargine
`
`Glimepiride
`
`Liraglutide
`
`498 (39.4)
`
`10.7
`(9.8–11.7)
`
`—
`
`—
`
`—
`
`Hazard ratio in the treatment group as
`compared with all other treatments
`combined (95% CI)
`
`0.72
`(0.65–0.79)
`
`Restricted mean survival time over 4 yr of
`follow‑up (95% CI) — days
`
`1188
`(1163–1212)
`
`* Shown are the numbers of participants with primary and secondary metabolic outcome events according to randomized treatment group
`(intention‑to‑treat) with overall rates and hazard ratios. Calculations for the tertiary outcome are provided in Table S5. CI denotes confi‑
`dence interval.
`† For the primary outcome, P values were obtained from closed testing of pairwise group differences corrected for six pairwise comparisons.
`Confidence limits corrected for six pairwise tests were obtained by inverting the closed‑testing z‑test value and then computing corrected
`95% confidence intervals. P<0.001 from a test of the log hazard ratios for treatment failure among the four treatment groups, with the use
`of a Cox proportional‑hazards model, with treatment group as the only predictor variable.
`‡ P≤0.05 for the specified comparison of two treatment groups.
`§ P≤0.001 for the specified comparison of two treatment groups.
`¶ P≤0.01 for the specified comparison of two treatment groups.
`‖ For the secondary outcome, confidence intervals obtained from the Cox proportional‑hazards model are not corrected for multiple compari‑
`sons among groups.
`
`ticipants in the lowest third of baseline glycated
`hemoglobin levels (6.8 to 7.2% [50.8 to 55.2 mmol
`per mole]), a glycated hemoglobin level of less
`than 7.0% was not achieved or maintained in
`approximately 60%.
`The hazard ratio in the glargine group as
`
`compared with the sitagliptin group differed
`among the strata of glycated hemoglobin levels.
`The risk reductions with glargine increased among
`participants from the lower to highest strata of
`baseline glycated hemoglobin levels, from 17%
`(95% confidence interval [CI], 3 to 29) to 32%
`
`n engl j med 387;12 nejm.org September 22, 2022
`
`1069
`
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`
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`
`MPI EXHIBIT 1124 PAGE 7
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Sitagliptin
`
`Glimepiride
`
`Liraglutide
`
`Glargine
`
`2244
`
`127
`
`B SecondaryMetabolicOutcome
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`CumulativeIncidence(%)
`
`No.ContributingDataoverTime
`5047
`
`P<0.001 by log-rank test
`
`A PrimaryMetabolicOutcome
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`CumulativeIncidence(%)
`
`No.ContributingDataoverTime
`5047
`
`1202
`
`66
`
`0
`
`1
`
`2
`3
`4
`5
`YearssinceRandomization
`
`6
`
`0
`
`1
`
`2
`3
`4
`5
`YearssinceRandomization
`
`6
`
`D MeanGlycatedHemoglobinLevel
`7.6
`
`0
`
`1
`2
`YearssinceRandomization
`
`3
`
`4
`
`7.4
`
`7.2
`
`7.0
`
`6.8
`
`6.6
`
`6.4
`
`0.0
`
`MeanLevel(%)
`
`3028
`
`211
`
`C TertiaryMetabolicOutcome
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`CumulativeIncidence(%)
`
`No.ContributingDataoverTime
`5047
`
`0
`
`1
`
`2
`3
`4
`5
`YearssinceRandomization
`
`6
`
`Figure 1. Kaplan–Meier Analysis of Outcome Events and Mean Glycated Hemoglobin Levels.
`Shown are the cumulative incidences of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) (Panel A), a gly‑
`cated hemoglobin level of greater than 7.5% (the secondary metabolic outcome) (Panel B), and a confirmed glycated hemoglobin level
`greater than 7.5% after the secondary outcome (the tertiary metabolic outcome) (Panel C), as well as the mean glycated hemoglobin levels
`(Panel D). In Panels A through C, the shaded bars along the x axis indicate the numbe