REVIEW
`
`FEWER THAN HALF OF US ADULTS
`
`with type 2 diabetes reach a he-
`moglobin A1c (HbA1c) level of
`less than 7% despite several
`available therapies.1 Ineffective imple-
`mentation of existing pharmacothera-
`pies is a significant factor contribut-
`ing to suboptimal care.2 However,
`efficacy of available therapies, even
`when used appropriately, diminishes as
`the disease progresses because of a
`steady, relentless decline in pancre-
`atic beta cell function.3 Furthermore,
`current therapies for type 2 diabetes are
`often limited by adverse effects such as
`weight gain, edema, or hypoglycemia,
`and most do not target postprandial hy-
`perglycemia effectively. Therefore,
`therapies targeting the decline in pan-
`creatic beta cell function without caus-
`ing weight gain and with minimal ad-
`verse effects are desirable.
`Recently, improved understanding of
`the incretin effect on the pathophysi-
`ology of type 2 diabetes has led to de-
`velopment of new hypoglycemic agents.
`The incretin effect is the augmenta-
`tion of glucose-stimulated insulin se-
`cretion by intestinally derived pep-
`tides, which are released in the presence
`of glucose or nutrients in the gut.4 The
`theory evolved from the observation
`that an oral glucose load was more ef-
`fective at releasing insulin compared
`with the same amount of glucose given
`intravenously.5 The actions of incre-
`
`Author Affiliations: Division of Endocrinology, Dia-
`betes and Metabolism (Drs Amori and Pittas) and In-
`stitute for Clinical Research and Health Policy Studies
`(Dr Lau), Tufts-New England Medical Center, Bos-
`ton, Massachusetts.
`
`Corresponding Author: Anastassios G. Pittas, MD, MSc,
`Division of Endocrinology, Diabetes and Metabo-
`lism, Tufts-New England Medical Center, 750 Wash-
`ington St, #268, Boston, MA 02111 (apittas
`@tufts-nemc.org).
`
`194 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted)
`
`©2007 American Medical Association. All rights reserved.
`
`Efficacy and Safety of Incretin Therapy
`in Type 2 Diabetes
`Systematic Review and Meta-analysis
`Renee E. Amori, MD
`Joseph Lau, MD
`Anastassios G. Pittas, MD, MSc
`
`Context Pharmacotherapies that augment the incretin pathway have recently be-
`come available, but their role in the management of type 2 diabetes is not well defined.
`Objective To assess the efficacy and safety of incretin-based therapy in adults with
`type 2 diabetes based on randomized controlled trials published in peer-reviewed jour-
`nals or as abstracts.
`Data Sources We searched MEDLINE (1966–May 20, 2007) and the Cochrane Cen-
`tral Register of Controlled Trials (second quarter, 2007) for English-language random-
`ized controlled trials involving an incretin mimetic (glucagonlike peptide 1 [GLP-1] ana-
`logue) or enhancer (dipeptidyl peptidase 4 [DPP4] inhibitor). We also searched prescribing
`information, relevant Web sites, reference lists and citation sections of recovered ar-
`ticles, and abstracts presented at recent conferences.
`Study Selection Randomized controlled trials were selected if they were at least
`12 weeks in duration, compared incretin therapy with placebo or other diabetes medi-
`cation, and reported hemoglobin A1c data in nonpregnant adults with type 2 diabetes.
`Data Extraction Two reviewers independently assessed trials for inclusion and ex-
`tracted data. Differences were resolved by consensus. Meta-analyses were con-
`ducted for several efficacy and safety outcomes.
`Results Of 355 potentially relevant articles identified, 51 were retrieved for detailed
`evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A1c com-
`pared with placebo (weighted mean difference, −0.97% [95% confidence interval {CI},
`−1.13% to −0.81%] for GLP-1 analogues and −0.74% [95% CI, −0.85% to −0.62%]
`for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagon-
`like peptide 1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and
`insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide
`1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0-4.2]
`for nausea and 3.2 [95% CI, 2.5-4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors
`had an increased risk of infection (risk ratio, 1.2 [95% CI, 1.0-1.4] for nasopharyngitis
`and 1.5 [95% CI, 1.0-2.2] for urinary tract infection) and headache (risk ratio, 1.4
`[95% CI, 1.1-1.7]). All but 3 trials had a 30-week or shorter duration; thus, long-term
`efficacy and safety could not be evaluated.
`Conclusions Incretin therapy offers an alternative option to currently available hy-
`poglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy
`and a favorable weight-change profile. Careful postmarketing surveillance for ad-
`verse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-
`term studies and in clinical practice are required to determine the role of this new class
`among current pharmacotherapies for type 2 diabetes.
`JAMA. 2007;298(2):194-206
`
`www.jama.com
`
`MPI EXHIBIT 1132 PAGE 1
`
`

`

`EFFICACY AND SAFETY OF INCRETIN THERAPY IN TYPE 2 DIABETES
`
`tins depend on glucose concentration,
`and their function ceases when serum
`glucose level is less than 55 mg/dL (to
`convert to millimoles per liter, multi-
`ply by 0.0555).4,6 The incretin effect is
`composed primarily of 2 peptides, glu-
`cose-dependent insulinotropic poly-
`peptide (GIP) and glucagonlike pep-
`tide 1 (GLP-1). Incretins are rapidly
`inactivated by the enzyme dipeptidyl
`peptidase 4 (DPP4), resulting in a very
`short half-life (minutes). The incretin
`pathway appears to be attenuated in
`type 2 diabetes, making the pathway a
`target for development of new phar-
`macologic agents.7,8
`In April 2005, the US Food and Drug
`Administration approved the first incre-
`tin mimetic, exenatide, a GLP-1 recep-
`tor analogue resistant to DPP4 degrada-
`tion, as adjunctive therapy for patients
`with type 2 diabetes. Because GLP-1 ana-
`logues require injection, considerable ef-
`fort has been devoted to creating an oral
`agent targeting the incretin pathway. In-
`hibition of DPP4 extends the half-life of
`native incretins, thereby prolonging their
`effects. In October 2006, the Food and
`Drug Administration approved the first
`oral incretin enhancer, sitagliptin, a se-
`lective DPP4 inhibitor, for use as mono-
`therapy or in combination with metfor-
`min or thiazolidinedione. Additional
`incretin-based agents are in late-stage de-
`velopment.8
`The present meta-analysis assesses
`the efficacy and safety of incretin-
`based therapy (GLP-1 analogues and
`DPP4 inhibitors) in nonpregnant adults
`with type 2 diabetes based on pub-
`lished and unpublished randomized
`controlled trials.
`
`METHODS
`We followed the QUOROM (Quality of
`Reporting of Meta-analyses) guide-
`lines for reporting our meta-analysis
`methods and results.9
`
`Data Sources and Searches
`We conducted a search of MEDLINE
`(1966–May 20, 2007) and the Coch-
`rane Central Register of Controlled
`Trials (second quarter, 2007) for En-
`glish-language randomized controlled
`
`trials of incretin therapy (GLP-1 ana-
`logues and DPP4 inhibitors) in non-
`pregnant adults with type 2 diabetes.
`We used the following search terms:
`diabetes, blood glucose, hyperglycemia,
`glucose, glycohemoglobin, hemoglobin
`A1c, incretin, glucagon like peptide,
`enteroglucagon, GLP-1, GIP, exenatide,
`liraglutide, dipeptidyl peptidase, DPP,
`LAF237, MK-0431, sitagliptin, vilda-
`gliptin, saxagliptin, human, and clini-
`cal trial. We searched for additional
`trials in the prescribing information
`documents of approved medications, at
`relevant Web sites (eg, http://www
`.clinicalstudyresults.org and http://www
`.clinicaltrials.gov), and in personal ref-
`erence lists and citation sections of
`recovered articles. We also searched ab-
`stracts presented at the American Dia-
`betes Association and the European As-
`sociation Study of Diabetes conferences
`for 2005-2006. We included abstracts
`with data that had not been published
`in peer-reviewed journals because in
`our search of the relevant literature, we
`did not find any differences between
`trial results that were originally de-
`scribed in abstracts and those from the
`same trials that were subsequently pub-
`lished in peer-reviewed journals.
`
`Study Selection
`Two reviewers (R.E.A. and A.G.P.) in-
`dependently screened abstracts accord-
`ing to the inclusion criteria. An ab-
`stract was judged relevant if it reported
`original data from controlled trials in
`patients with type 2 diabetes with HbA1c
`outcomes for an incretin-based vs a
`non–incretin-based comparator group
`(placebo or hypoglycemic agent). We
`excluded studies of less than 12 weeks’
`duration because such studies would
`give an inadequate assessment of
`change in glycemic efficacy, as HbA1c
`reflects glycemia during the previous
`3 months.10 Full-text articles were re-
`trieved and reviewed if a decision on
`inclusion could not be made solely
`based on the abstract. Any discrepan-
`cies were resolved by consensus be-
`tween the 2 independent reviewers or
`in group conference via referencing the
`original article.
`
`Data Extraction
`and Quality Assessment
`Participant baseline characteristics of
`the included studies were extracted and
`are described in TABLE 1. For glyce-
`mic efficacy, we extracted data on
`change from baseline in HbA1c, fasting
`plasma glucose, and postprandial gly-
`cemia after a mixed-meal test and pro-
`portion of patients achieving HbA1c of
`less than 7%. When available, we also
`extracted data on change in body weight
`and lipid profile. To evaluate safety, we
`extracted data on hypoglycemia (se-
`vere or nonsevere) and all reported ad-
`verse events. We also extracted data on
`level of circulating antibodies to incre-
`tin analogue. For hypoglycemia, we
`combined and present data on the total
`number of patients per treatment group
`who reported at least 1 episode of hy-
`poglycemia. Differences in baseline
`characteristics between groups, descrip-
`tion of allocation concealment, inten-
`tion-to-treat analysis, and dropout rate
`were used to evaluate study quality.
`
`Data Synthesis and Analysis
`The primary measure for glycemic ef-
`ficacy was the treatment group differ-
`ence in HbA1c change from baseline.
`Treatment group difference in fasting
`plasma glucose and the proportion of
`participants reaching an HbA1c of less
`than 7% were secondary glycemic ef-
`ficacy outcomes. For safety, we exam-
`ined number of participants reporting
`hypoglycemia and other adverse ef-
`fects. Because these 2 classes of medi-
`cations are relatively new, to assess
`safety, we analyzed all reported ad-
`verse events.
`For continuous variables (HbA1c,
`fasting plasma glucose, weight), we cal-
`culated weighted mean differences and
`95% confidence intervals (CIs) for
`change from baseline in incretin vs
`comparator (placebo or hypoglycemic
`agent) groups. For dichotomous vari-
`ables (percentages achieving HbA1c
`⬍7% and percentages with hypoglyce-
`mia and adverse events), we calcu-
`lated the risk ratios and 95% CIs for in-
`cretin vs comparator groups. If data
`from more than 2 trials were available,
`
`©2007 American Medical Association. All rights reserved.
`
`(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 195
`
`MPI EXHIBIT 1132 PAGE 2
`
`

`

`EFFICACY AND SAFETY OF INCRETIN THERAPY IN TYPE 2 DIABETES
`
`Table 1. Characteristics of Randomized Controlled Trials of Glucagonlike Peptide 1 Analogues and Dipeptidyl Peptidase 4 Inhibitors Included
`in the Systematic Review
`
`Study
`Duration,
`wk
`
`No. of
`Participantsb
`
`Mean
`Age, y/
`Women, %/
`White, %
`
`Duration
`of
`Diabetes,
`y
`
`Baseline
`HbA1c
`Level,
`%
`
`Incretin-Based
`Therapyc
`
`Controlc
`
`Allocation
`Concealment
`Described?
`
`Data
`Analysis
`
`Dropout
`Rate, %
`
`Study Qualityd
`
`Sourcea
`Exenatide
`Buse et al,11
`2004
`
`DeFronzo
`et al,12
`2005
`
`Kendall
`et al,13
`2005
`
`Heine et al,14
`2005f
`
`Nauck et al,15
`2007f
`
`Zinman
`et al,16
`2007
`
`30
`
`30
`
`30
`
`26
`
`52
`
`16
`
`377
`
`55/40/63
`
`336
`
`53/43/76
`
`734
`
`55/42/68
`
`551
`
`59/44/80
`
`505
`
`59/49/NR
`
`233
`
`56/45/84
`
`53/40/60
`
`6
`
`6
`
`9
`
`10
`
`10
`
`8
`
`5
`
`Sulfonylurea ⫹
`placebo injection
`(subcutaneous
`twice daily)
`Metformin ⫹
`placebo injection
`(subcutaneous
`twice daily)
`Sulfonylurea/
`metformin ⫹
`placebo injection
`(subcutaneous
`twice daily)
`
`No
`
`No
`
`No
`
`Yes
`
`Yes
`
`ITT
`
`ITT
`
`ITT
`
`APT
`
`APT
`
`Yes
`
`ITT
`
`31
`
`19
`
`19
`
`15
`
`16
`
`22
`
`8.6
`
`8.5
`
`Sulfonylurea ⫹
`exenatide, 10 µg
`Sulfonylurea ⫹
`exenatide, 5 µge
`8.2 Metformin ⫹
`exenatide, 10 µg
`Metformin ⫹
`exenatide, 5 µge
`Sulfonylurea/
`metformin ⫹
`exenatide, 5 µge
`Sulfonylurea/
`metformin ⫹
`exenatide, 10 µg
`Sulfonylurea/
`metformin ⫹
`exenatide, 10 µg
`Sulfonylurea/
`metformin ⫹
`exenatide, 10 µg
`
`8.2
`
`8.6
`
`7.9
`
`Thiazolidinedione
`(pioglitazone or
`rosiglitazone)/
`metformin ⫹
`exenatide, 10 µg
`
`Sulfonylurea/
`metformin ⫹
`insulin glargine
`Sulfonylurea/
`metformin ⫹
`biphasic aspart
`insulin
`Thiazolidinedione
`(pioglitazone or
`rosiglitazone)/
`metformin ⫹
`placebo injection
`(subcutaneous
`twice daily)
`Metformin/diet ⫹
`placebo injection
`(subcutaneous
`once/wk)
`
`8.5 Metformin/diet ⫹
`exenatide
`(subcutaneous
`once/wk), 2.0 mg
`Metformin/diet ⫹
`exenatide
`(subcutaneous
`once/wk),
`0.8 mge
`
`7.4
`
`7.0
`
`Liraglutide, 0.75 mg
`Liraglutide, 0.6 mge
`
`Liraglutide, 0.75 mg
`Liraglutide, 0.6 mge
`
`Placebo injection
`(subcutaneous
`twice daily)
`Metformin
`
`No
`
`ITT
`
`4
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`ITT
`
`13
`
`Completers
`
`15
`
`APT
`
`12
`
`APT
`
`11
`
`APT
`
`14
`
`APT
`
`13
`
`(continued)
`
`Placebo
`
`Placebo
`
`Placebo
`
`Metformin ⫹
`placebo
`
`7.9
`
`Sitagliptin, 50 mg
`twice daily
`Sitagliptin, 5 mg
`twice dailye
`Sitagliptin, 12.5 mg
`twice dailye
`Sitagliptin, 25 mg
`twice dailye
`Sitagliptin, 100 mg
`once daily
`Sitagliptin, 200 mg
`once dailye
`Sitagliptin, 100 mg
`once daily
`Sitagliptin, 200 mg
`once dailye
`8.0 Metformin ⫹
`sitagliptin, 100
`mg once daily
`
`8.1
`
`8.0
`
`Kim et al,17
`2007
`
`15
`
`45
`
`Liraglutide
`Madsbad
`et al,18
`2004
`Feinglos et
`al,19 2005
`Sitagliptin
`Scott et al,20
`2007
`
`Raz et al,21
`2006
`
`Ascher
`et al,22
`2006
`
`Charbonnel
`et al,23
`2006
`
`12
`
`12
`
`12
`
`18
`
`24
`
`24
`
`193
`
`58/33/100
`
`210
`
`54/60/78
`
`743
`
`55/45/65
`
`521
`
`55/46/68
`
`741
`
`54/46/51
`
`701
`
`55/43/64
`
`4
`
`5
`
`5
`
`5
`
`4
`
`6
`
`196 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted)
`
`©2007 American Medical Association. All rights reserved.
`
`MPI EXHIBIT 1132 PAGE 3
`
`

`

`EFFICACY AND SAFETY OF INCRETIN THERAPY IN TYPE 2 DIABETES
`
`we combined data from trials within a
`class (GLP-1 analogues or DPP4 in-
`hibitors) and explored heterogeneity
`between comparable trials with pre-
`specified subgroup analyses by type of
`comparator group (placebo vs hypo-
`glycemic agent), duration of interven-
`tion (12 vs ⬎12 weeks), and available
`formulation within each class. For dose-
`dependent outcomes, such as glyce-
`
`mic efficacy (HbA1c, percentage achiev-
`ing HbA1c ⬎7%), weight change, and
`hypoglycemia, only data from the ap-
`proved maximum dose entered the
`meta-analyses (10 µg twice daily for ex-
`enatide and 100 mg/d for sitagliptin).
`For nonapproved medications, the
`highest dose was used (0.75 mg/d for
`liraglutide, 2.0 mg once weekly for ex-
`enatide given subcutaneously, and 100
`
`mg/d for vildagliptin). For adverse-
`event outcomes, we included data from
`all available doses to increase the sta-
`tistical power to detect differences be-
`tween treatment groups of uncom-
`mon events.
`For postprandial glycemia, lipid pro-
`file, and antibody development, we did
`not perform meta-analyses because of
`the diverse methods used to assess out-
`
`Table 1. Characteristics of Randomized Controlled Trials of Glucagonlike Peptide 1 Analogues and Dipeptidyl Peptidase 4 Inhibitors Included
`in the Systematic Review (cont)
`
`Study
`Duration,
`wk
`
`No. of
`Participantsb
`
`Mean
`Age, y/
`Women, %/
`White, %
`
`Duration
`of
`Diabetes,
`y
`
`Baseline
`HbA1c
`Level,
`%
`
`Incretin-Based
`Therapyc
`
`Controlc
`
`Allocation
`Concealment
`Described?
`
`Data
`Analysis
`
`Dropout
`Rate, %
`
`Study Qualityd
`
`Sourcea
`Sitagliptin
`Rosenstock
`et al,24
`2006
`Nauck et al,25
`2007f
`
`Nonaka et
`al,26 2006g
`Hanefeld et
`al,27 2005g
`
`24
`
`52
`
`12
`
`12
`
`353
`
`56/44/73
`
`1172
`
`57/41/74
`
`151
`
`555
`
`55/49/NR
`
`56/48/NR
`
`6
`
`6
`
`4
`
`4
`
`12
`
`107
`
`57/32/99
`
`6
`
`8.1
`
`7.6
`
`7.7
`
`Pioglitazone ⫹
`sitagliptin, 100
`mg once daily
`7.7 Metformin ⫹
`sitagliptin, 100
`mg once daily
`Sitagliptin, 100 mg
`once daily
`Sitagliptin, 100 mg
`once daily
`Sitagliptin 50 mg
`twice dailye
`Sitagliptin, 25 mg
`once dailye
`Sitagliptin, 50 mg
`once dailye
`
`Pioglitazone ⫹
`placebo
`
`Metformin ⫹
`glipizide
`
`Placebo
`
`Placebo
`
`No
`
`No
`
`No
`
`No
`
`APT
`
`APT
`
`APT
`
`APT
`
`13
`
`32
`
`NR
`
`NR
`
`Vildagliptin
`Ahren et al,28
`2004
`
`Ristic et al,29
`2005
`
`12
`
`279
`
`56/46/80
`
`3
`
`Pratley et al,30
`2006
`Pi-Sunyer
`et al,31
`2007
`
`12
`
`24
`
`100
`
`354
`
`56/57/47
`
`51/45/54
`
`Dejager et al,32
`2007
`
`24
`
`632
`
`54/53/73
`
`Garber et al,33
`2007
`
`24
`
`463
`
`54/50/80
`
`4
`
`2
`
`2
`
`5
`
`Metformin ⫹
`placebo
`
`Placebo
`
`Placebo
`
`Placebo
`
`No
`
`No
`
`No
`
`No
`
`ITT
`
`ITT
`
`ITT
`
`APT
`
`10
`
`NR
`
`9
`
`23
`
`Placebo
`
`No
`
`ITT
`
`19
`
`Pioglitazone ⫹
`placebo
`
`No
`
`APT
`
`19
`
`7.7
`
`8.0
`
`8.4
`
`7.8 Metformin ⫹
`vildagliptin, 50
`mg once daily
`Vildagliptin, 100 mg
`once daily
`Vildagliptin, 25 mg
`twice dailye
`Vildagliptin, 25 mg
`once dailye
`Vildagliptin, 50 mg
`once dailye
`Vildagliptin, 25 mg
`twice daily
`Vildagliptin, 100 mg
`once daily
`Vildagliptin, 50 mg
`once dailye
`Vildagliptin, 50 mg
`twice dailye
`Vildagliptin, 100 mg
`once daily
`Vildagliptin, 50 mg
`once dailye
`Vildagliptin, 50 mg
`twice dailye
`Pioglitazone ⫹
`vildagliptin, 50
`mg twice daily
`Pioglitazone ⫹
`vildagliptin, 50
`mg once dailye
`
`8.4
`
`8.7
`
`©2007 American Medical Association. All rights reserved.
`
`(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 197
`
`(continued)
`
`MPI EXHIBIT 1132 PAGE 4
`
`

`

`EFFICACY AND SAFETY OF INCRETIN THERAPY IN TYPE 2 DIABETES
`
`comes and/or because of insufficiently
`reported data. For all meta-analyses, we
`used a random-effects model that
`weighs studies by the inverse of the
`within-study and between-studies vari-
`ances.40 Most studies reported differ-
`ences in the mean changes and the cor-
`responding 95% CIs (or standard
`errors) between comparison groups.
`For studies that reported only the mean
`changes and the corresponding stan-
`dard errors of the mean change, we cal-
`culated the differences and the stan-
`dard errors of the differences between
`comparison groups using these data.
`We used the I2 statistic to quantify the
`degree of heterogeneity among trials in
`
`each meta-analysis.41 Event rates of
`single groups across studies (eg, hypo-
`glycemia, adverse events) were calcu-
`lated using a random-effects model to
`combine the logits of the event rates
`then transforming back to the rates
`(percentages).
`
`RESULTS
`Search Results
`and Study Characteristics
`Search results are summarized in
`FIGURE 1. The characteristics of the 29
`included trials (articles and abstracts)
`are summarized in Table 1. Only 3 of
`the 29 studies had durations of longer
`than 30 weeks.
`
`There were 8 published trials
`(n = 3139; age range, 19-78 years) in
`which a GLP-1 analogue was added to
`existing inadequate therapy (lifestyle or
`oral hypoglycemic therapy) and com-
`pared with a double-blind injectable
`placebo,11-13,16,18 metformin,19 or open-
`label subcutaneous insulin (glargine or
`biphasic aspart).14,15 There was also 1
`small study (n=45) with a long-acting
`formulation of a GLP-1 analogue.17
`There were 13 published double-
`blind trials (n=4780; age range, 18-80
`years) in which a placebo was com-
`pared with a DPP4 inhibitor given
`as monotherapy20-22,29-32 or as add-
`on therapy to oral hypoglycemic
`
`Table 1. Characteristics of Randomized Controlled Trials of Glucagonlike Peptide 1 Analogues and Dipeptidyl Peptidase 4 Inhibitors Included
`in the Systematic Review (cont)
`
`Study
`Duration,
`wk
`
`No. of
`Participantsb
`
`Mean
`Age, y/
`Women, %/
`White, %
`
`Duration
`of
`Diabetes,
`y
`
`Baseline
`HbA1c
`Level,
`%
`
`Incretin-Based
`Therapyc
`
`Controlc
`
`Allocation
`Concealment
`Described?
`
`Data
`Analysis
`
`Dropout
`Rate, %
`
`Study Qualityd
`
`Sourcea
`Vildagliptin
`Rosenstock et
`al,34 2007f
`Bosi et al,35
`2007
`
`Rosenstock et
`al,36 2007h
`Fonseca et
`al,37 2007
`
`Schweizer et
`al,38 2007f
`Mimori et al,39
`2006g
`
`24
`
`24
`
`24
`
`24
`
`52
`
`12
`
`786
`
`544
`
`315
`
`296
`
`780
`
`219
`
`54/42/80
`
`54/43/74
`
`52/36/42
`
`59/49/71
`
`2
`
`6
`
`2
`
`15
`
`53/46/68
`
`1
`
`59/NR/NR
`
`NR
`
`Rosiglitazone, 8 mg
`once daily
`Metformin ⫹
`placebo
`
`Pioglitazone, 30 mg
`once daily
`Unspecified insulin
`therapy ⫹
`placebo
`
`Metformin, 1000 mg
`twice daily
`Placebo
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`APT
`
`APT
`
`APT
`
`APT
`
`APT
`
`NR
`
`14
`
`15
`
`15
`
`19
`
`27
`
`NR
`
`8.7
`
`Vildagliptin, 50 mg
`twice daily
`8.4 Metformin ⫹
`vildagliptin, 50
`mg twice daily
`Metformin ⫹
`vildagliptin, 50
`mg once dailye
`Vildagliptin, 100 mg
`once daily
`Unspecified insulin
`therapy ⫹
`vildagliptin, 50
`mg twice daily
`Vildagliptin, 50 mg
`twice daily
`Vildagliptin, 50 mg
`twice daily
`Vildagliptin, 10 mg
`twice dailye
`Vildagliptin, 25 mg
`twice dailye
`
`8.7
`
`8.4
`
`8.7
`
`7.4
`
`Abbreviations: HbA1c, hemoglobin A1c; NR, not reported.
`aAll studies were multinational except Buse et al,11 Defronzo et al,12 and Kendall et al.13 Women who were pregnant or breastfeeding or those with reproductive potential who were not
`using contraceptives were excluded.
`bThe total number of participants randomized to all groups is different from the number of participants used in meta-analyses of glycemic efficacy, weight change, and hypoglycemia
`outcomes because most articles reported a modified ITT analysis (“all patients treated”) that did not include all randomized participants and because only the highest available dose
`entered these meta-analyses.
`cPlus sign indicates that the study medication (active or control) was added to existing therapy. Neither glucagonlike peptide 1 analogues nor dipeptidyl peptidase 4 inhibitors were titrated
`according to study-specific glucose goals. Exenatide or placebo injection was given subcutaneously twice daily approximately 15 minutes before a meal, titrated to the higher dose after
`an acclimation period, unless otherwise specified. Liraglutide or placebo injection was given subcutaneously once daily approximately 15 minutes before breakfast. When not specified,
`sulfonylurea drug was glyburide, glipizide, or glibenclamide.
`dFew studies reported whether they tested for balanced baseline characteristics between comparison groups. No differences were noted in the most important characteristics (age,
`weight, HbA1c, and duration of diabetes) except in the studies by Buse et al,11 Defronzo et al,12 Madsbad et al,18 and Dejager et al,32 in which small differences were noted between
`groups at baseline. Intention-to-treat (ITT) analyses were defined as those in which all randomized patients who received at least 1 dose of study treatment were included in the analysis;
`“all patients treated” (APT) analyses were defined as those in which all randomized patients who received at least 1 dose of study treatment and who had both a baseline and at least
`1 postbaseline measurement were included; “completers” analyses were defined as those in which participants with complete data at the last follow-up visit were included.
`eStudy groups with lower doses or nonapproved doses were used in meta-analyses for adverse events only.
`fNoninferiority trials.
`gData were available from abstracts only.
`hStudy had 2 additional groups (vildagliptin, 100 mg daily, combined with pioglitazone, 30 mg daily; and vildagliptin, 50 mg daily, combined with pioglitazone, 15 mg daily), which were
`not used in the meta-analyses.
`
`198 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted)
`
`©2007 American Medical Association. All rights reserved.
`
`MPI EXHIBIT 1132 PAGE 5
`
`

`

`EFFICACY AND SAFETY OF INCRETIN THERAPY IN TYPE 2 DIABETES
`
`agents23,24,28,33,35 or insulin.37 Four
`published trials (n = 3053) directly
`compared a DPP4 inhibitor with a
`hypoglycemic agent, including glipiz-
`ide titrated to glycemic goals,25 metfor-
`min,38 or a thiazolidenedione.34,36 There
`were 3 abstracts concerning a DPP4
`inhibitor (n=925), with data contribut-
`ing only to certain meta-analyses.26,27,39
`
`Methodological Quality
`All studies included a control group (pla-
`cebo or hypoglycemic agent) in a
`double-blind design, except the stud-
`ies involving insulin, which were open-
`label.14,15 Eligibility criteria were clearly
`reported in all trials. Concealment allo-
`cation was clearly described in only 3
`studies.14-16 Few studies reported
`whether they tested for balanced base-
`line characteristics (eg, age, weight,
`HbA1c, and duration of diabetes) be-
`tween comparison groups. We noted
`small baseline differences in only 3 stud-
`ies.11,12,18 Participant withdrawal was ap-
`proximately 19% in the GLP-1 ana-
`logue studies (19% with exenatide and
`12% with liraglutide) and 18% in the
`DPP4 inhibitor studies (20% with sita-
`gliptin and 16% with vildagliptin). With-
`drawals were primarily due to loss of gly-
`cemic efficacy in the placebo groups and
`gastrointestinal adverse effects in the ex-
`enatide treatment groups. All studies
`
`were funded by pharmaceutical compa-
`nies; the role of the sponsor was clearly
`disclosed in only 2 studies.14,16
`
`Incretin Mimetics
`(GLP-1 Analogues)
`Glycemic Outcomes. Hemoglobin A1C.
`Combining data from studies compar-
`ing GLP-1 analogues with placebo in-
`jection showed a statistically signifi-
`cant difference in HbA 1 c decline
`from baseline favoring incretin
`therapy (weighted mean difference,
`−0.97%; 95% CI, −1.13% to −0.81%)
`(FIGURE 2).11-13,16-18 There was no dif-
`ference in HbA1c in open-label nonin-
`feriority studies between exenatide and
`insulin glargine or biphasic aspart.14,15
`Liraglutide showed similar HbA1c
`efficacy compared with open-label
`glimepiride titrated to glycemic goals18
`or double-blind, maximum-dose
`metformin.19
`Patients receiving exenatide were more
`likely to achieve an HbA1c of less than 7%
`compared with patients receiving pla-
`cebo (45% vs 10%, respectively; risk ra-
`tio, 4.2; 95% CI, 3.2-5.5),11-13,16 but there
`was no difference between exenatide and
`insulin in noninferiority trials (39% vs
`35%, respectively; risk ratio, 1.1; 95% CI,
`0.8-1.5) (TABLE 2).14,15
`Fasting and Postprandial Glycemia.
`Fasting plasma glucose was reduced
`
`with a GLP-1 analogue compared
`with placebo injection (weighted
`mean difference, −27 mg/dL; 95% CI,
`−33 to −21 mg/dL) (Table 2).11-13,16-18
`In the open-label studies comparing
`exenatide vs insulin glargine or bipha-
`sic aspart, postprandial glycemia was
`reduced more with exenatide,14,15
`while there was no difference in fast-
`ing plasma glucose (weighted mean
`difference, 13 mg/dL; 95% CI, −16 to
`41 mg/dL). In mixed-meal testing,
`
`Figure 1. Study Design
`
`355 Potentially relevant articles identified
`
`304 Excluded based on review of abstract
`
`51 Full-text manuscripts or conference
`abstracts retrieved for detailed evaluation
`
`22 Manuscripts or abstracts excluded
`based on detailed evaluation
`11 Study duration <12 wk
`3 No study participants with
`type 2 diabetes
`2 No incretin given
`1 Continuation of previously
`reported studies
`1 Duplicate study
`1 Not a randomized controlled study
`3 Abstracts without available data
`for meta-analyses
`
`29 Randomized controlled trials included
`in systematic review
`
`Figure 2. Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for GLP-1 Analogues vs Control in Adults With Type 2
`Diabetes
`
`Source
`Buse et al,11 2004
`DeFronzo et al,12 2005
`Kendall et al,13 2005
`Heine et al,14 2005
`Nauck et al,15 2007
`Zinman et al,16 2007
`Kim et al,17 2006
`Madsad et al,18 2004
`
`Comparisons
`GLP-1 vs placebo11-13,16-18
`Exenatide vs placebo11-13,16
`Exenatide vs insulin14,15
`
`Study
`Duration, wk
`30
`30
`30
`26
`52
`16
`15
`12
`
`No. of
`Studies
`6
`5
`2
`
`No.of
`Participants
`252
`226
`488
`535
`501
`233
`29
`57
`
`Weighted Mean Difference
`(95% CI) for Change
`in Hemoglobin A 1C, %
`–0.96 (–1.24 to –0.68)
`–0.90 (–1.18 to –0.62)
`–1.00 (–1.21 to –0.79)
`0.02 (–0.12 to 0.16)
`–0.15 (–0.32 to 0.01)
`–0.98 (–1.21 to –0.74)
`–2.10 (–2.93 to –1.27)
`–0.75 (–1.10 to –0.40)
`
`1285
`1228
`1036
`
`–0.97 (–1.13 to –0.81)
`–1.01 (–1.18 to –0.84)
`–0.06 (–0.22 to 0.10)
`
`I2, %
`44
`45
`59
`
`Favors incretin
`(GLP-1 analogue)
`
`Favors
`control
`
`CI indicates confidence interval; GLP-1, glucagonlike peptide 1. The I 2 statistic describes the percentage of total variation across studies that is due to heterogeneity
`rather than chance.
`
`©2007 American Medical Association. All rights reserved.
`
`(Reprinted) JAMA, July 11, 2007—Vol 298, No. 2 199
`
`–2.5
`
`0
`–0.5
`–1.0
`–1.5
`0.5
`–2.0
`Weighted Mean Difference (95% CI), %
`
`1.0
`
`MPI EXHIBIT 1132 PAGE 6
`
`

`

`EFFICACY AND SAFETY OF INCRETIN THERAPY IN TYPE 2 DIABETES
`
`exenatide produced a dose-dependent
`decrease in postprandial glucose
`excursions up to 87% at the highest
`dose compared with baseline.12-14
`
`Nonglycemic Outcomes. Weight. In
`trials that reported data on changes in
`weight,11-18 there was a statistically sig-
`nificant weight loss observed with
`
`GLP-1 analogues vs comparator groups
`(weighted mean difference, −2.37 kg;
`95% CI −3.95, −0.78). The weight loss
`was more pronounced when ex-
`
`Table 2. Summary of Meta-analyses of Outcomes in Patients With Type 2 Diabetes Treated With Incretin-Based Therapy vs
`Non–Incretin-Based Therapy (Controls)
`
`No. of
`Studies
`Contributing
`Data
`
`Risk
`Ratio
`(95% CI),
`Incretin
`vs Control
`
`Weighted
`Mean
`Difference
`(95% CI)
`in Change
`From Baseline,
`Incretin
`vs Control
`GLP-1 Analogues
`
`I 2
`Heterogeneity,
`%
`
`Incretin-Based Therapy
`
`Control
`
`Mean %
`(95% CI)
`Achieving
`Outcome
`
`No. of
`Participants
`With Data
`Analyzed
`
`Mean %
`(95% CI)
`Achieving
`Outcome
`
`No. of
`Participants
`With Data
`Analyzed
`
`45 (32-60)
`
`39 (26-53)
`
`561
`
`502
`
`10 (7-14)
`
`35 (16-60)
`
`562
`
`497
`
`43 (39-47)
`
`44 (39-51)
`
`1442
`
`1113
`
`17 (15-20)
`
`1146
`
`18 (16-21)
`
`38 (31-45)
`
`317
`
`15 (11-20)
`
`43 (32-55)
`
`1237
`
`47 (42-52)
`
`821
`
`325
`
`965
`
`5
`
`2
`
`7
`
`5
`
`2
`
`8
`
`5
`
`2
`
`9
`
`5
`
`4
`
`3
`
`15
`
`7
`
`8
`
`4
`
`4.19
`(3.17-5.53)
`1.10
`(0.81-1.50)
`
`2.47
`(2.14-2.84)
`2.43
`(2.03-2.92)
`2.40
`(1.78-3.24)
`0.93
`(0.77-1.11)
`
`−27
`(−33 to −21)
`−27
`(−34 to −20)
`13
`(−16 to 41)
`
`−2.37
`(−3.95 to −0.78)
`−1.44
`(−2.13 to −0.75)
`−4.76
`(−6.03 to −3.49)
`
`DPP4 Inhibitors
`
`−18
`(−22 to −14)
`−22
`(−26 to −18)
`−12
`(−16 to −7)
`11
`(−1 to 123)
`
`11
`
`34
`
`96
`
`98
`
`92
`
`70
`
`63
`
`50
`
`3
`
`91
`
`Outcome
`
`Achieved HbA1c ⬍7%
`Exenatide vs placebo
`injection11-13,16,17
`Exenatide vs insulin14,15
`
`Fasting plasma glucose level, mg/dL
`All GLP-1 analogues vs placebo
`injection11-13,16-19
`Exenatide vs placebo
`injection11-13,16,17
`Exenatide vs insulin14,15
`
`Weight, kg
`All GLP-1 analogues vs
`control11-18a
`Exenatide vs placebo
`injection11-13,16,17
`Exenatide vs insulin14,15
`
`Achieved HbA1c ⬍7%
`All DPP4 inhibitors vs
`placebo15,21-24,26,28,29,31,33
`Sitagliptin vs placebo15,21-24,26
`
`Vildagliptin vs placebo28,29,31,33
`
`All DPP4 inhibitors vs
`hypoglycemic agents25,36,38b
`Fasting plasma glucose level, mg/dL
`All DPP4 inhibitors vs
`placebo20-24,26-31,33,35,37,39
`Sitagliptin vs placebo20-24,26,27
`
`Vildagliptin vs placebo28-31,33,35,37,39
`
`All DPP4 inhibitors vs
`hypoglycemic
`agents25,34,36,38b
`Weight, kg
`All DPP4 inhibitors vs
`placebo20-22,24,26,28-33,35,37
`Sitagliptin vs placebo20-22,24,26
`
`Vildagliptin vs placebo28-33,35,37
`
`0.48
`(0.30 to 0.66)
`0.52
`(0.28 to 0.76)
`0.42
`(0.12 to 0.72)
`Abbreviations: CI, confidence interval; DPP4, dipeptidyl peptidase 4; GLP-1, glucagonlike peptide 1; HbA1c, hemoglobin A1c.
`SI conversion: To convert glucose to mmol/L, multiply by 0.0555.
`aControl is placebo injection or insulin.
`bHypoglycemic agents were glipizide, rosiglitazone, pioglitazone, or metformin.
`
`13
`
`5
`
`8
`
`0
`
`4
`
`0
`
`200 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted)
`
`©2007 American Medical Association. All rights reserved.
`
`MPI EXHIBIT 1132 PAGE 7
`
`

`

`enatide was compared with insulin
`(Table 2).14,15 Weight loss with ex-
`enatide was progressive, dose-
`dependent, and without apparent pla-
`teau by week 30.11-16 Several studies
`noted a nonsignificant trend toward
`greater weight reduction in patients
`who experienced at least 1 episode of
`nausea while receiving exenatide.11,14,15
`However, participants who did not re-
`port nausea also lost weight.11-16 Weight
`loss was less pronounced with
`liraglutide.18,19
`Lipids. In the 3 trials that reported
`data,11,15,16 there were no changes in lipid
`profile with the exception of a small im-
`provement in high-density lipopro-
`tein cholesterol favoring biphasic as-
`part insulin over exenatide15 and a small
`decrease in low-density lipoprotein cho-
`lesterol favoring exenatide over pla-
`cebo injection.11
`Adverse Events. Hypoglycemia. Se-
`vere hypoglycemia (requiring assis-
`tance) was rare with GLP-1 ana-
`logues, reported in only 5 of 2781
`patients treated with exenatide and only
`in patients who also received sulfonyl-
`urea.13,14 When data were combined,
`mild to moderate hypoglycemia was
`more commonly reported in ex-
`enatide vs placebo injection (16% vs
`7%, respectively; risk ratio, 2.3; 95% CI,
`1.1-4.9), especially when coadminis-
`tered with a sulfonylurea.11,13 Hypogly-
`cemia peaked during initiation of
`therapy with exenatide then de-
`creased over time.11,13,14,18 The risk of hy-
`poglycemia was similar between ex-
`enatide vs insulin (⬇2% in both groups;
`risk ratio, 1.0; 95% CI, 0.5-2.3).14,15 Hy-
`poglycemia was less common with li-
`raglutide compared with glimepiride
`(6% vs 35%, respectively) in the single
`study with such data.18
`Other Adverse Events. D