Diabetologia
`https://doi.org/10.1007/s00125-024-06144-1
`
`ARTICLE
`
`Subcutaneously administered tirzepatide vs semaglutide
`for adults with type 2 diabetes: a systematic review and network
`meta‑analysis of randomised controlled trials
`
`Thomas Karagiannis1,2
`Panagiota Kakotrichi1
`Eleni Bekiari1,2
`
` · Athina Stamati3
` · Ioannis Avgerinos1,2
` · Konstantinos Malandris1
` ·
` · Aris Liakos1,2
` · Despoina Vasilakou1,2
` · Nikolaos Kakaletsis1
` · Apostolos Tsapas1,2,4
`
` ·
`
`Received: 9 December 2023 / Accepted: 16 February 2024
`© The Author(s) 2024
`
`Abstract
`Aims/hypothesis We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c.
`administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus.
`Methods We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks
`assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of
`0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible
`trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs.
`Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of
`≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal
`adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias,
`conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In
`Network Meta-Analysis (CINeMA) framework.
`Results A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the
`most efficacious treatment in reducing HbA1c (mean difference −21.61 mmol/mol [−1.96%]) followed by tirzepatide 10 mg (−20.19
`mmol/mol [−1.84%]), semaglutide 2.0 mg (−17.74 mmol/mol [−1.59%]), tirzepatide 5 mg (−17.60 mmol/mol [−1.60%]), semaglu-
`tide 1.0 mg (−15.25 mmol/mol [−1.39%]) and semaglutide 0.5 mg (−12.00 mmol/mol [−1.09%]). In between-drug comparisons, all
`tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo,
`tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg)
`to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to
`2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than
`semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with
`placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia.
`Conclusions/interpretation Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduc-
`tion compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide,
`increased gastrointestinal adverse events.
`Registration PROSPERO registration no. CRD42022382594
`
`Keywords GIP/GLP-1 receptor agonist · GLP-1 receptor agonist · Network meta-analysis · Semaglutide · Systematic
`review · Tirzepatide
`
`Abbreviations
`CINeMA
` Confidence In Network Meta-Analysis
`EMA
` European Medicines Agency
`
`FDA
`GIP
`GLP-1 RA
`MD
`
` US Food and Drug Administration
` Glucose-dependent insulinotropic peptide
` Glucagon-like peptide-1 receptor agonist
` Mean difference
`
`Extended author information available on the last page of the article
`
`Vol.:(0123456789)
`
`MPI EXHIBIT 1110 PAGE 1
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`

`

`
`
`Diabetologia
`
`Introduction
`
`Semaglutide, administered s.c., has shown superior efficacy
`compared with other glucose-lowering agents, including
`its oral formulation, in reducing HbA1c and in facilitating
`weight loss in individuals with type 2 diabetes [1, 2]. Ini-
`tially approved at doses of 0.5 mg and 1.0 mg once weekly,
`it has subsequently received authorisation for a 2.0 mg once-
`weekly dose for the management of type 2 diabetes. Tirze-
`patide, a novel agent belonging to the glucose-dependent
`insulinotropic peptide (GIP) and glucagon-like peptide-1
`receptor agonist (GLP-1 RA) class (dual GIP/GLP-1 RA),
`has also been approved by the US Food and Drug Adminis-
`tration (FDA) and the European Medicines Agency (EMA)
`for the treatment of type 2 diabetes. Data from RCTs have
`consistently shown the efficacy of tirzepatide in reducing
` HbA1c and body weight in people with type 2 diabetes [3].
`The ADA Standards of Care and the ADA/EASD con-
`sensus report recommend s.c. administered semaglutide and
`tirzepatide as the most efficacious medications for glycaemic
`control (alongside dulaglutide) and weight reduction [4, 5].
`However, direct comparison between s.c. tirzepatide and
`s.c. semaglutide in RCTs is scarce [6, 7], presenting a chal-
`lenge in drawing robust and precise conclusions regarding
`their comparative efficacy. To address this research gap, we
`
`conducted a network meta-analysis utilising both direct and
`indirect comparative data between the two medications [8].
`The aim of our systematic review and network meta-
`analysis was to compare the efficacy (in terms of glycaemic
`control and weight management) and safety (in terms of
`adverse events) of s.c. tirzepatide and s.c. semaglutide in
`people with type 2 diabetes based on data from RCTs.
`
`Methods
`
`The protocol of this systematic review and meta-
`analysis is registered in PROSPERO (registration no.
`CRD42022382594) [9]. We report our methods and results
`in accordance with the Preferred Reporting Items for Sys-
`tematic reviews and Meta-Analyses (PRISMA) statement for
`network meta-analyses [10].
`
`Eligibility criteria We included RCTs published in English
`that assessed s.c. tirzepatide at maintenance doses of 5 mg,
`10 mg or 15 mg once weekly, or s.c. semaglutide at main-
`tenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly for
`a minimum duration of 12 weeks. Eligible trials compared
`any of the specified doses of tirzepatide and semaglutide
`against each other, placebo or other glucose-lowering drugs.
`
`MPI EXHIBIT 1110 PAGE 2
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`

`

`Diabetologia
`
`For a glucose-lowering drug to be included as a compara-
`tor, it was required to have been evaluated in at least one
`trial comparison against tirzepatide and one trial comparison
`against semaglutide. This approach was adopted to prevent
`unconnected networks, ensuring that each comparator served
`as a link for indirect comparisons between tirzepatide and
`semaglutide. We included trials recruiting adults with type
`2 diabetes regardless of their background glucose-lowering
`treatment, defined as the glucose-lowering therapy used both
`in the intervention and control arms after the randomisation.
`
`Information sources and searches We searched PubMed and
`Cochrane databases from inception until 11 November 2023.
`Our search strategy included both free-text and Medical Sub-
`ject Headings (MeSH) terms, utilising the keywords ‘tirze-
`patide,’ ‘ly3298176,’ ‘semaglutide’ and ‘nn9535’ (electronic
`supplementary material [ESM] Table 1).
`
`Study selection After deduplication, search results were
`screened at title and abstract level, and potentially eligible
`records were examined in full text with reasons for exclusion
`being recorded. Two independent reviewers performed the
`study selection process and any disagreements were resolved
`by a third reviewer. For the deduplication and the screening
`process we used the Systematic Review Accelerator (SRA)
`web application [11].
`
`Data collection Using predesigned forms, we extracted
`information on study characteristics, participants’ baseline
`characteristics and outcome data. Given the aggregated data
`format of the included RCTs in our meta-analysis, direct
`information on how sex or gender was determined in the
`individual studies was beyond the scope of our analysis. Our
`two primary outcomes were the change from baseline in
` HbA1c and in body weight. Secondary efficacy outcomes
`were the proportion of participants attaining an HbA1c target
`of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), and
`those achieving a minimum of 10% body weight loss. Safety
`outcomes included the incidence (no. of participants with
`at least one outcome event) of nausea, vomiting, diarrhoea,
`treatment discontinuation due to gastrointestinal events,
`severe adverse events and severe hypoglycaemia (a hypo-
`glycaemic event requiring assistance). Data were extracted
`from the intention-to-treat population, which included all
`randomly assigned participants who received at least one
`dose of the study medication. For eligible trials identified
`through our database searches, we utilised ClinicalTrials.
`gov, using their respective National Clinical Trial (NCT)
`identifiers, to retrieve additional information when outcome
`data were absent or incomplete in the published articles.
`Data extraction was conducted by two independent review-
`ers, with discrepancies resolved by a third reviewer.
`
`Risk‑of‑bias assessment We used version 2 of the Cochrane
`risk-of-bias tool for randomised trials (ROB 2) to assess the
`risk of bias for the two primary outcomes [12]. Following
`the tool’s algorithms, each trial’s overall risk of bias was
`classified as low if all domains were at low risk, and high if
`any domain was at high risk. If none of the domains were
`classified as high risk but one or more were deemed to have
`some concerns, the overall risk of bias for that trial was
`categorised as ‘of some concern’. This assessment was con-
`ducted independently by two reviewers, with a third reviewer
`resolving any disagreements. We evaluated the presence of
`small-study effect (publication bias) by means of compari-
`son-adjusted funnel plots [13].
`
`Data analysis We explored the transitivity assumption by
`comparing the distribution of potential effect modifiers
`(baseline HbA1c and body weight) across treatment compari-
`sons [14]. We conducted frequentist random-effects network
`meta-analyses and calculated mean differences (MDs) for the
`two primary outcomes and risk ratios for dichotomous out-
`comes, alongside 95% CIs [15]. We evaluated heterogeneity
`for the primary outcomes based on the agreement between
`CIs and prediction intervals in relation to the null effect and
`the clinically important effect on the opposite direction to
`the point estimate [16, 17]. We assumed a minimum reduc-
`tion in HbA1c of 5.5 mmol/mol (0.5%) and in body weight
`of 4.5 kg (5% of mean body weight value at baseline across
`all trials) as clinically important [18]. We addressed inco-
`herence (inconsistency) both locally by comparing directly
`with indirect evidence using the Separating Indirect from
`Direct Evidence (SIDE) method [19] and globally using the
`design-by-treatment interaction model [20]. Moreover, we
`used P-scores, ranging from 0 to 1, to rank treatments; these
`can be interpreted as the average degree of certainty for a
`treatment to be better than the other treatments in the net-
`work [21]. Statistical analyses were performed in R (R Core
`Team 2019, R Foundation for Statistical Computing, Vienna,
`Austria) using the R packages ‘meta’ and ‘netmeta’ [22], and
`in NMAstudio (version 2.0) web application [23, 24].
`
`Evaluation of confidence in findings We evaluated Confi-
`dence In Network Meta-Analysis (CINeMA) effect estimates
`for the primary outcomes utilising the CINeMA methodo-
`logical framework and application [17, 25]. The six domains
`evaluated were within-study bias (risk of bias), across-study
`bias (small-study effect/publication bias), indirectness,
`imprecision, heterogeneity and incoherence (inconsistency).
`We assigned judgements at three levels (no concerns, some
`concerns and major concerns) to each domain and summa-
`rised judgements across domains to an overall assessment
`ranging across very low, low, moderate or high level of con-
`fidence [17, 25].
`
`MPI EXHIBIT 1110 PAGE 3
`
`

`

`
`
`Results
`
`Search results and study characteristics The search retrieved
`2798 records, of which 28 RCTs [6, 7, 26–51] with 23,622
`participants were included in the systematic review and
`network meta-analysis (ESM Fig. 1). Study and partici-
`pant characteristics are presented in Table 1. Only two tri-
`als directly compared tirzepatide with semaglutide, with
`one of these also including a placebo arm [6, 7]. Sixteen
`trials compared semaglutide with placebo, other GLP-1
`RAs, basal insulin, prandial insulin or varying doses of
`semaglutide. The remaining ten trials compared tirzepatide
`with placebo, GLP-1 RA (other than semaglutide), basal
`insulin, prandial insulin or varying doses of tirzepatide. All
`trials had a parallel-group design and 15 were open-label
`(Table 1). Most trials were multinational, except for five that
`recruited exclusively Japanese participants [39–41, 48, 49].
`The intervention duration ranged from 24 to 28 weeks in five
`trials and from 30 to 56 weeks in 21 trials. The remaining
`two trials, a trial with tirzepatide in people with obesity and
`type 2 diabetes (SURMOUNT-2) [50] and a cardiovascular
`outcomes trial with semaglutide (SUSTAIN 6) [31], had a
`duration of 72 and 104 weeks, respectively. The background
`glucose-lowering therapy, referring to the common treat-
`ment received by all trial groups post-randomisation, var-
`ied across the trials. However, the predominant background
`treatment was metformin, used either as monotherapy or
`in combination with other medications. Across all trials,
`10,442 participants (44.2%) were female, participants’ mean
` HbA1c at baseline was 66.6 mmol/mol (8.3%), mean body
`weight was 88.8 kg and mean age was 57.8 years (Table 1).
`The distribution of potential effect modifiers (HbA1c and
`body weight at baseline) was deemed sufficiently similar
`across all treatment comparisons to assume that a network
`meta-analysis was appropriate (ESM Figs 2 and 3).
`
`Overview of network Figure 1 shows the network of com-
`parisons used in the meta-analysis. Risk of bias for the
`change in HbA1c was assessed as low in all trials except for
`one that was at high risk of bias and one with some con-
`cerns (ESM Table 2). For the change in body weight, seven
`trials were at high risk of bias and one trial had some con-
`cerns; all other trials were at low risk of bias (ESM Table 3).
`Comparison-adjusted funnel plots did not suggest the pres-
`ence of small-study effect (ESM Figs 4 and 5). There was
`presence of heterogeneity in some comparisons, particularly
`those involving semaglutide 2.0 mg (ESM Tables 4 and 5).
`In terms of incoherence, the design-by-treatment interaction
`model did not identify global inconsistency in the analyses
`for both primary outcomes (ESM Tables 4 and 5), while
`local inconsistency was also low.
`
`Diabetologia
`
`Glycaemic efficacy Compared with placebo, tirzepatide
`15 mg was the most efficacious treatment in reducing HbA1c
`(MD [95% CI]: −21.61 mmol/mol [−23.26 to −19.97]
`[−1.96% (−2.11 to −1.82)]), followed by tirzepatide 10 mg
`(−20.19 mmol/mol [−21.89 to −18.48] [−1.84% (−1.99 to
`−1.69)]), semaglutide 2.0 mg (−17.74 mmol/mol [−22.03
`to −13.45] [−1.59% (−1.95 to −1.22)]), tirzepatide 5 mg
`(−17.60 mmol/mol [−19.36 to −15.84] [−1.60% (−1.75 to
`−1.44)]), semaglutide 1.0 mg (−15.25 mmol/mol [−16.73
`to −13.77] [−1.39% (−1.52 to −1.26)]) and semaglutide
`0.5 mg (−12.00 mmol/mol [−13.74 to −10.26] [−1.09%
`(−1.24 to −0.94)]) (Fig. 2 and ESM Fig. 6). In compari-
`sons between tirzepatide and semaglutide, when HbA1c was
`measured in mmol/mol, all tirzepatide doses were compa-
`rable with semaglutide 2.0 mg and superior to semaglutide
`1.0 mg and 0.5 mg (ESM Table 6). Specifically, effect esti-
`mates (MD [95% CI]) for tirzepatide 15 mg vs semaglutide
`2.0 mg, tirzepatide 10 mg vs semaglutide 1.0 mg, and tirze-
`patide 5 mg vs semaglutide 0.5 mg were, respectively, as
`follows: −3.87 mmol/mol (−8.22 to 0.48); −4.94 (−6.65
`to −3.23); and −5.60 mmol/mol (−7.60 to −3.60) (ESM
`Table 6). When HbA1c was measured in %, tirzepatide at
`doses of 15 mg, 10 mg and 5 mg demonstrated greater effi-
`cacy than semaglutide at doses of 2.0 mg (MD = −0.38%
`[95% CI −0.75% to −0.01%]), 1.0 mg (MD = −0.45% [95%
`CI −0.60% to −0.31%]) and 0.5 mg (MD = −0.51% [95% CI
`−0.68% to −0.33%]), respectively (ESM Table 7). The confi-
`dence in estimates for comparisons between tirzepatide and
`semaglutide was high to moderate, except for comparisons
`vs semaglutide 2.0 mg, where the confidence was generally
`low (ESM Table 8). Consistently with meta-analysis find-
`ings, tirzepatide 15 mg held the highest probability (P-score
`= 0.99) of being the most efficacious treatment in reducing
` HbA1c (ESM Fig. 7).
`Compared with placebo, semaglutide 2.0 mg (risk ratio
`= 7.73 [95% CI 5.62, 10.63]) and tirzepatide 15 mg (risk
`ratio = 7.01 [95% CI 5.73, 8.57]) were the most efficacious
`in achieving an HbA1c target of ≤48 mmol/mol (≤6.5%)
`(ESM Table 9). In between-drug comparisons, tirzepatide
`15 mg and 10 mg outperformed semaglutide 1.0 mg and
`0.5 mg and tirzepatide 5 mg was superior to semaglutide
`0.5 mg, while no differences were found between semaglu-
`tide 2.0 mg and any of the tirzepatide doses (ESM Table 9).
`Similarly, semaglutide 2.0 mg (risk ratio = 4.01 [95% CI
`3.24, 4.95]) and tirzepatide 15 mg (risk ratio = 3.70 [95%
`CI 3.26, 4.20]) were the most efficacious in achieving an
` HbA1c target of <53 mmol/mol (<7%) as compared with
`placebo (ESM Table 10). No differences were found when
`any of the tirzepatide doses were compared with semaglutide
`2.0 mg or 1.0 mg, while all tirzepatide doses were superior
`to semaglutide 0.5 mg (ESM Table 10).
`
`MPI EXHIBIT 1110 PAGE 4
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`

`

`Diabetologia
`
`Mean age, years
`
`duration, years
`Mean diabetes
`
`weight, kg
`Mean body
`
`bA1c,
`Mean
`
`%
` H
`
`mmol/mol
`bA1c,
`Mean
`
` H
`
`Female sex,
`
`n
`
`randomised,
`Participants
`
`n
`
`study arm
`Study (trial registration no.)/
`Blinding statusBackground glucose-lower-
`Table 1 Study details and participant baseline characteristics of included arms in RCTs
`
`ing therapya
`
`30
`weeks
`duration,
`Study
`
`64.7
`64.6
`
`58.8
`58.5
`59.1
`
`56.2
`56.7
`56.5
`
`56.7
`56.4
`
`56.0
`54.8
`
`53.9
`52.7
`54.6
`
`14.1
`14.3
`
`13.3
`13.7
`12.9
`
`8.6
`9.3
`7.8
`
`9.4
`9.0
`
`6.7
`6.4
`
`4.1
`3.6
`4.8
`
`92.9
`91.8
`
`89.9
`92.5
`92.7
`
`92.6
`94.0
`93.7
`
`95.4
`96.2
`
`89.2
`89.9
`
`89.1
`96.9
`89.8
`
`8.7
`8.7
`
`8.4
`8.3
`8.4
`
`8.1
`8.3
`8.1
`
`8.3
`8.4
`
`8.0
`8.0
`
`8.0
`8.1
`8.1
`
`71.6
`71.6
`
`68.6
`67.3
`67.9
`
`65.4
`66.6
`65.4
`
`67.6
`67.9
`
`64.4
`64.1
`
`63.4
`65.3
`64.9
`
`304
`331
`
`62
`54
`58
`
`165
`178
`165
`
`177
`185
`
`204
`202
`
`59
`50
`68
`
`822
`826
`
`133
`131
`132
`
`360
`360
`362
`
`405
`404
`
`409
`409
`
`129
`130
`128
`
`medication
`with any glucose-lowering
`dual-combination therapy
`
`Double-blindNone, or monotherapy/
`
`104
`
`(83.3%)
`insulin+metformin
`therapy (16.7%) or basal
`Basal insulin mono-
`
`Double-blind
`
`30
`
`(52%)
`metformin+sulfonylurea
`therapy (48%) or
`Metformin mono-
`
`Open-label
`
`30
`
`(48.1%)/TZDs (2.3%)
`(96.5%)/sulfonylurea
`bination with metformin
`Monotherapy or dual com-
`
`Open-label
`
`(45%)
`(55%) or metformin+TZD
`
`Double-blindMetformin monotherapy
`
`56
`
`56
`
`Double-blindNone
`
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`
`(NCT01720446)
`SUSTAIN 6 [31]
` Placebo
` Semaglutide 1 mg
` Semaglutide 0.5 mg
`
`(NCT02305381)
`SUSTAIN 5 [30]
` Basal insulin (glargine)
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`
`(NCT02128932)
`SUSTAIN 4 [29]
`extended release)
` GLP-1 RA (exenatide
` Semaglutide 1.0 mg
`
`(NCT01885208)
`SUSTAIN 3 [28]
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`
`(NCT01930188)
`SUSTAIN 2 [27]
` Placebo
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`(NCT02054897)
`SUSTAIN 1 [26]
`
`MPI EXHIBIT 1110 PAGE 5
`
`

`

`5.6
`
`9.2
`9.8
`
`6.7
`6.3
`
`13.4
`13.4
`
`8.9
`9.6
`
`9.6
`9.8
`
`7.3
`7.3
`7.7
`
`88.8
`
`100.1
`98.6
`
`76.1
`77.6
`
`88.1
`87.6
`
`97.2
`96.6
`
`93.8
`89.6
`
`94.5
`95.5
`96.4
`
`7.8
`
`8.9
`8.8
`
`8.1
`8.1
`
`8.5
`8.6
`
`8.3
`8.2
`
`8.1
`8.0
`
`8.2
`8.2
`8.3
`
`61.8b
`
`73.4
`73.1
`
`65.0b
`65.0b
`
`69.8
`70.3
`
`67.2b
`66.1b
`
`64.5
`64.1
`
`65.9
`66.2
`67.5
`
`Mean age, years
`
`duration, years
`Mean diabetes
`
`weight, kg
`Mean body
`
`
`
`13.6
`
`91.9
`
`8.7
`
`bA1c,
`Mean
`
`%
` H
`
`71.6
`mmol/mol
`bA1c,
`Mean
`
` H
`
`Diabetologia
`
`56.8
`
`57.9
`58.2
`
`53.0
`53.0
`
`61.5
`60.8
`
`58.9
`60.1
`
`56.6
`57.5
`
`56.0
`55.0
`56.0
`
`64.6
`
`21
`
`201
`197
`
`136
`128
`
`425
`429
`
`120
`130
`
`64
`62
`
`267
`139
`132
`
`660
`
`Female sex,
`
`n
`
`69
`
`480
`481
`
`290
`288
`
`874
`874
`
`287
`290
`
`151
`151
`
`598
`300
`301
`
`Metformin monotherapy
`
`Open-label
`
`1649
`
`randomised,
`Participants
`
`n
`
`Blinding statusBackground glucose-lower-
`
`ing therapya
`
`monotherapy (82.9%)
`None (17.1%) or metformin
`
`Open-label
`
`26
`
`(53%)
`metformin+sulfonylurea
`therapy (47%) or
`Double-blindMetformin mono-
`
`Double-blindMetformin
`
`Metformin+insulin glargine
`
`Open-label
`
` Semaglutide 1.0 mg
`(NCT01923181)
`Davies et al [38]
` Semaglutide 2.0 mg
` Semaglutide 1.0 mg
`
`40
`
`30
`
`52
`
`(NCT03989232)
`SUSTAIN FORTE [37]
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`(NCT03061214)
`SUSTAIN CHINA [36]
` Prandial insulin (aspart)
` Semaglutide 1.0 mg
`(NCT03689374)
`SUSTAIN 11 [35]
` GLP-1 RA (liraglutide)
` Semaglutide 1.0 mg
`
`Open-label
`
`30
`
`(NCT03191396)
`SUSTAIN 10 [34]
` Placebo
` Semaglutide 1.0 mg
`
`inhibitor (24.6%)
`nylurea (46.8%)/SGLT2
`metformin (94.8%)/sulfo-
`or any combination of
`Metformin monotherapy
`
`sulfonylurea (12.9%)
`with metformin (71.5%)/
`tion of SGLT2 inhibitor
`apy (15.6%) or combina-
`SGLT2 inhibitor monother-
`
`Double-blind
`
`30
`
`40
`
`(NCT03086330)
`SUSTAIN 9 [33]
` GLP-1 RA (dulaglutide)
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`(NCT02648204)
`SUSTAIN 7 [32]
` Placebo
`
`weeks
`duration,
`Study
`
`study arm
`Study (trial registration no.)/
`Table 1 (continued)
`
`MPI EXHIBIT 1110 PAGE 6
`
`

`

`56.9
`55.9
`57.2
`56.3
`
`53.6
`52.9
`55.8
`54.1
`
`60.9
`62.1
`
`58.1
`58.8
`
`62.7
`61.5
`
`8.3
`8.7
`8.4
`9.1
`
`4.5
`4.8
`4.9
`4.6
`
`NR
`NR
`
`7.8
`8.0
`
`11.1
`13.4
`
`93.7
`93.8
`94.8
`92.5
`
`84.8
`85.4
`86.2
`87.0
`
`78.7
`79.8
`
`70.8
`67.8
`
`72.7
`72.3
`
`8.3
`8.3
`8.3
`8.3
`
`8.1
`7.9
`7.9
`8.0
`
`7.8
`7.9
`
`8.0
`8.2
`
`6.5
`6.4
`
`66.7
`66.8
`67.2
`67.5
`
`64.5
`62.3
`62.9
`63.6
`
`62.0
`63.0
`
`63.9b
`66.1b
`
`47.5
`46.4
`
`Diabetologia
`
`58.9
`
`6.7
`
`93.8
`
`Mean age, years
`
`duration, years
`Mean diabetes
`
`weight, kg
`Mean body
`
`8.0
`
`bA1c,
`Mean
`
`%
` H
`
`63.9b
`mmol/mol
`bA1c,
`Mean
`
` H
`
`244
`256
`231
`265
`
`59
`58
`49
`65
`
`25
`18
`
`27
`24
`
`5
`1
`
`31
`
`Female sex,
`
`n
`
`469
`470
`469
`470
`
`115
`121
`121
`121
`
`50
`50
`
`102
`103
`
`16
`16
`
`71
`
`randomised,
`Participants
`
`n
`
`Metformin monotherapy
`
`Open-label
`
`40
`
`Double-blindNone (54%) or previous oral
`
`medication use (46%)
`
`combination therapy)d
`either as monotherapy or
`pants received metformin
`tions (87.7% of partici-
`glucose-lowering medica-
`tion or any combination of
`glucose-lowering medica-
`Monotherapy with any
`
`Open-label
`
`None
`
`Open-label
`
`40
`
`24
`
`30
`
`insulin glargine (12.5%)c
`formin/SGLT2 inhibitor/
`any combination of met-
`monotherapy (75%), or
`None (12.5%), metformin
`
` Semaglutide 1.0 mg
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`(NCT03987919)
`SURPASS-2 [6]
` Placebo
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`(NCT03954834)
`SURPASS-1 [42]
`dulaglutide)
` GLP-1 RA (liraglutide or
` Semaglutide 0.5 mg
`
`(jRCTs1011200008)
`Takahashi et al [41]
` Semaglutide 1.0 mg
` Semaglutide 0.5 mg
`(NCT02254291)
`Seino et al [40]
` GLP-1 RA (dulaglutide)
` Semaglutide 0.5 mg
`
`Open-label
`
`26
`
`(UMIN000040044)
`Iijima et al [39]
` Placebo
`
`Blinding statusBackground glucose-lower-
`
`ing therapya
`
`weeks
`duration,
`Study
`
`study arm
`Study (trial registration no.)/
`Table 1 (continued)
`
`MPI EXHIBIT 1110 PAGE 7
`
`

`

`
`
`Diabetologia
`
`55.6
`54.3
`53.5
`53.1
`
`59.0
`58.2
`59.6
`58.0
`
`60.0
`61.0
`60.0
`62.0
`
`63.8
`63.7
`63.7
`62.9
`
`57.5
`57.5
`57.4
`57.2
`
`7.6
`7.6
`7.9
`7.4
`
`14.0
`13.4
`13.9
`13.4
`
`12.9
`13.7
`12.6
`14.1
`
`10.7
`10.4
`10.6
`9.8
`
`8.1
`8.5
`8.4
`8.5
`
`77.0
`76.2
`76.3
`77.7
`
`90.3
`91.2
`89.1
`91.7
`
`94.1
`96.3
`94.5
`95.8
`
`90.2
`90.0
`90.6
`90.3
`
`94.2
`94.9
`94.3
`95.4
`
`8.7
`8.7
`8.7
`8.8
`
`8.8
`8.7
`8.8
`8.9
`
`8.4
`8.2
`8.4
`8.3
`
`8.5
`8.5
`8.6
`8.5
`
`8.1
`8.2
`8.2
`8.2
`
`71.5
`71.4
`71.7
`72.4
`
`72.7
`72.0
`72.5
`73.7
`
`68.0
`66.5
`67.9
`67.2
`
`69.4
`69.6
`70.4
`69.6
`
`65.4
`66.3
`66.0
`65.8
`
`102
`100
`102
`96
`
`396
`133
`149
`144
`
`54
`55
`47
`55
`
`364
`135
`119
`131
`
`147
`165
`165
`158
`
`220
`229
`228
`230
`
`708
`236
`238
`243
`
`120
`120
`119
`116
`
`1000
`338
`328
`329
`
`359
`358
`360
`358
`
`(47.5%)
`metformin+sulfonylurea
`therapy (52.5%) or
`Metformin mono-
`
`Open-label
`
`40
`
`Metformin+insulin glargine
`
`Open-label
`
`52
`
`tion with metformin (83%)
`apy (17%) or in combina-
`Insulin glargine monother-
`
`Double-blind
`
`40
`
`SGLT2 inhibitor (25%)
`(95%)/sulfonylurea (54%)/
`combination of metformin
`Monotherapy with or any
`
`Open-label
`
`52
`
` Basal insulin (glargine)
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`
`[47] (NCT04093752)
`SURPASS-AP-COMBO
` Prandial insulin (lispro)
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`(NCT04537923)
`SURPASS-6 [46]
` Placebo
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`
`(NCT04039503)
`SURPASS-5 [45]
` Basal insulin (glargine)
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`
`(NCT03730662)
`SURPASS-4 [44]
` Basal insulin (degludec)
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`
`Mean age, years
`
`duration, years
`Mean diabetes
`
`weight, kg
`Mean body
`
`bA1c,
`Mean
`
`%
` H
`
`mmol/mol
`bA1c,
`Mean
`
` H
`
`Female sex,
`
`n
`
`randomised,
`Participants
`
`n
`
`Blinding statusBackground glucose-lower-
`
`ing therapya
`
`tor (32%)
`metformin+SGLT2 inhibi-
`therapy (68%) or
`Metformin mono-
`
`Open-label
`
`52
`weeks
`duration,
`Study
`
`(NCT038882970)
`SURPASS-3 [43]
`
`study arm
`Study (trial registration no.)/
`Table 1 (continued)
`
`MPI EXHIBIT 1110 PAGE 8
`
`

`

`63.7
`61.1
`
`58.7
`56.6
`56.0
`56.5
`57.9
`
`54.7
`53.6
`54.3
`
`57.5
`56.0
`56.2
`56.8
`
`56.5
`56.9
`57.7
`
`12.7
`10.2
`
`9.3
`8.6
`8.5
`7.9
`8.9
`
`18.1
`17.5
`17.6
`
`5.0
`5.1
`5.1
`4.5
`
`8.5
`9.1
`8.5
`
`92.7
`94.2
`
`89.8
`91.5
`89.1
`92.7
`92.8
`
`101.7
`99.6
`100.9
`
`76.5
`78.9
`78.9
`78.5
`
`78.3
`76.6
`77.7
`
`7.7
`7.8
`
`8.1
`8.0
`8.2
`8.2
`8.2
`
`8.0
`8.1
`8.0
`
`8.2
`8.2
`8.2
`8.2
`
`8.6
`8.6
`8.5
`
`60.7
`62.1
`
`65.0
`63.9
`65.0
`66.1
`66.1
`
`63.7
`64.7
`64.0
`
`65.6
`66.1
`66.0
`65.9
`
`70.0
`70.2
`69.7
`
`10
`14
`
`30
`22
`31
`21
`21
`
`159
`159
`158
`
`42
`28
`39
`46
`
`44
`34
`29
`
`44
`45
`
`54
`51
`53
`51
`55
`
`315
`311
`312
`
`159
`160
`158
`159
`
`148
`147
`148
`
`Diabetologia
`
`Mean age, years
`
`duration, years
`Mean diabetes
`
`weight, kg
`Mean body
`
`bA1c,
`Mean
`
`%
` H
`
`mmol/mol
`bA1c,
`Mean
`
` H
`
`Female sex,
`
`n
`
`randomised,
`Participants
`
`n
`
`Blinding statusBackground glucose-lower-
`
`ing therapya
`
`52
`weeks
`duration,
`Study
`
`(NCT03861039)
`SURPASS J-COMBO [48]
`
`study arm
`Study (trial registration no.)/
`Table 1 (continued)
`
`cation
`one additional oral medi-
`Double-blindMetformin with or without
`
`Double-blindNone (9.8%) or metformin
`
`monotherapy (90.2%)
`
`(1%)
`α-glucosidase inhibitor
`(20%), TZD (4%), or
`(27%), SGLT2 inhibitor
`formin (89%), sulfonylurea
`or any combination of met-
`Double-blindNone or monotherapy with
`
`28
`
`26
`
`72
`
`Double-blindNone
`
`52
`
`SGLT2 inhibitor (14%)
`(14%), glinide (14%) or
`inhibitor (14%), TZD
`(14%), α-glucosidase
`lurea (30%), metformin
`Monotherapy with sulfony-
`
`Open-label
`
` Semaglutide 1.0 mg
` Tirzepatide 15 mg
`
`(NCT03951753)
`Heise et al [7]
` GLP-1 RA (dulaglutide)
` Placebo
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`(NCT03131687)
`Frias et al [51]
` Placebo
` Tirzepatide 15 mg
` Tirzepatide 10 mg
`
`(NCT04657003)
`SURMOUNT-2 [50]
` GLP-1 RA (dulaglutide)
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`(NCT03861052)
`SURPASS J-MONO [49]
` Tirzepatide 15 mg
` Tirzepatide 10 mg
` Tirzepatide 5 mg
`
`MPI EXHIBIT 1110 PAGE 9
`
`

`

`Diabetologia
`
`60.4
`
`11.0
`
`98.8
`
`7.9
`
`Mean age, years
`
`duration, years
`Mean diabetes
`
`weight, kg
`Mean body
`
`bA1c,
`Mean
`
`%
` H
`
`
`
`NR, not reported; SGLT2, sodium–glucose cotransporter 2; TZD, thiazolidinedione
`the comparator continued treatment with liraglutide or dulaglutide
`d All participants received GLP-1 RA (liraglutide or dulaglutide) before randomisation. After randomisation, participants in the intervention arm switched to semaglutide, while participants in
`tor arm switched from liraglutide to dulaglutide
`c All participants received liraglutide before randomisation. After randomisation, participants in the intervention arm switched from liraglutide to semaglutide, while participants in the compara-
`b Data were converted to mmol/mol units from values reported in percentage units using the formula: mmol/mol value = (10.93 × percentage value) − 23.5
`a Defined as the glucose-lowering treatment received by all trial groups post-randomisation
` Placebo
`
`62.9
`mmol/mol
`bA1c,
`Mean
`
` H
`
`7
`
`28
`
`Female sex,
`
`n
`
`randomised,
`Participants
`
`n
`
`Blinding statusBackground glucose-lower-
`
`ing therapya
`
`weeks
`duration,
`Study
`
`study arm
`Study (trial registration no.)/
`Table 1 (continued)
`
`MPI EXHIBIT 1110 PAGE 10
`
`

`

`Diabetologia
`
`Placebo
`
`GLP−1 RA
`
`Prandial insulin
`
`Basal insulin
`
`Semaglutide 0.5 mg
`
`Tirzepatide 5 mg
`
`Semaglutide 1.0 mg
`
`Tirzepatide 15 mg
`
`Semaglutide 2.0 mg
`
`Tirzepatide 10 mg
`
`Fig. 1 Network plot for change in HbA1c. Each circle indicates a
`treatment node. Lines connecting two nodes represent direct compari-
`sons between two treatments. The size of the nodes is proportional to
`
`the number of trials evaluating each treatment; the thickness of the
`lines is proportional to the number of trials directly comparing the
`two connected treatments
`
`Body weight In comparisons vs placebo, tirzepatide was
`the most efficacious medication for lowering body weight,
`resulting in reductions ranging from 9.57 kg (95% CI 8.36,
`10.78) with tirzepatide 15 mg to 5.27 kg (95% CI 3.98, 6.56)
`with tirzepatide 5 mg (Fig. 3). Semaglutide showed a less
`pronounced effect, with reductions ranging from 4.97 kg
`(95% CI 1.68, 8.26) with semaglutide 2.0 mg to 2.52 kg
`(95% CI 1.26, 3.78) with semaglutide 0.5 mg (Fig. 3). In
`between-drug comparisons, tirzepatide at doses of 15 mg,
`10 mg and 5 mg demonstrated greater efficacy than sema-
`glutide at doses of 2.0 mg (MD = −4.60 kg [95% CI −7.94,
`−1.26]), 1.0 mg (MD = −3.53 kg [95% CI −4.80, −2.25])
`and 0.5 mg (MD = −2.75 kg [95% CI −4.23, −1.28]),
`respectively (ESM Table 11). The confidence in estimates
`
`for comparisons between tirzepatide and semaglutide was
`high to moderate, except for comparisons vs semaglutide
`2.0 mg, where the confidence was low (ESM Table 12). Tirze-
`patide 15 mg was ranked highest (P-score = 1.00) among all
`treatments in terms of weight reduction (ESM Fig. 8).
`All doses of tirzepatide and semaglutide were superior to
`placebo in achieving at least a 10% body weight reduction,
`with tirzepatide 15 mg (risk ratio = 10.51 [95% CI 7.55,
`14.64]) and tirzepatide 10 mg (risk ratio = 8.84 [95% CI
`6.35, 12.32]) being the most efficacious treatments (ESM
`Table 13). In between-drug comparisons, tirzepatide at both
`the 15 mg and 10 mg doses outperformed all doses of sema-
`glutide, while tirzepatide at the 5 mg dose was more effica-
`cious than semaglutide 0.5 mg (ESM Table 13).
`
`Fig. 2 Network meta-analysis
`results for the change in HbA1c
`(mmol/mol) compared with
`placebo
`
`Treatment
`
`MD (95% CI)
`
`Tirzepatide 15 mg
`
`Tirzepatide 10 mg
`
`Semaglutide 2.0 mg
`
`Tirzepatide 5 mg
`
`Semaglutide 1.0 mg
`
`Semaglutide 0.5 mg
`
`Prandial insulin
`
`Basal insulin
`
`GLP−1 RA
`
`−21.61 (−23.26, −19.97)
`
`−20.19 (−21.89, −18.48)
`
`−17.74 (−22.03, −13.45)
`
`−17.60 (−19.36, −15.84)
`
`−15.25 (−16.73, −13.77)
`
`−12.00 (−13.74, −10.26)
`
`−9.65 (−12.51, −6.79)
`
`−7.86 (−10.03, −5.69)
`
`−7.81 ( −9.81, −5.82)
`
`−30 −20 −10
`
`0
`
`10
`
`20
`
`30
`
`Favours treatment Favours placebo
`
`MPI EXHIBIT 1110 PAGE 11
`
`

`

`
`
`Fig. 3 Network meta-analysis
`results for the change in body
`weight (kg) compared with
`placebo
`
`Treatment
`
`MD (95% CI)
`
`Diabetologia
`
`Tirzepatide 15 mg
`
`Tirzepatide 10 mg
`
`Tirzepatide 5 mg
`
`Semaglutide 2.0 mg
`
`Semaglutide 1.0 mg
`
`Semaglutide 0.5 mg
`
`GLP−1 RA
`
`Basal insulin
`
`Prandial insulin
`
`−9.57 (−10.78, −8.36)
`
`−7.70 (−8.94, −6.46)
`
`−5.27 (−6.56, −3.98)
`
`−4.97 (−8.26, −1.68)
`
`−4.17 (−5.26, −3.09)
`
`−2.52 (−3.78, −1.26)
`
`−0.53 (−1.97, 0.92)
`
`2.86 (1.24, 4.49)
`
`3.85 (1.68, 6.02)
`
`Gastrointestinal adverse events Compared with placebo,
`all doses of tirzepatide and semaglutide demonstrated an
`increase in the risk for nausea (ESM Fig. 9), vomiting (ESM
`Fig. 10) and diarrhoea (ESM Fig. 11). Specifically, the risk
`ratios for nausea ranged from 2.07 to 3.51 across different
`doses of tirzepatide, and from 2.45 to 2.84 for semaglutide
`(ESM Table 14). For vomiting, the risk ratios ranged from
`2.39 to 4.36 with tirzepatide, and from 2.33 to 3.62 with
`semaglutide (ESM Table 15). For diarrhoea, the risk ratios
`ranged from 1.81 to 2.18 with tirzepatide, and from 1.66
`to 1.80 with semaglutide (ESM Table 16). In comp