Risk of diarrhea in patients with type 2 diabetes mellitus treated with sitagliptin: a meta-analysis of 30 randomized clinical trials

Figures & data

Table 1 Baseline characteristics of 30 included trials in the meta-analysis (n=8,891)

First author/sponsor	Year	No NCT	Treatment arm	Mean age (years)	Treatment duration (weeks)	ΔHbA1c a	ΔFPGb	Events of diarrhea	Total events	Jadad score
Charbonnel^Citation19	2006	NCT0086515	Sitagliptin 100 mg qd + metformin	54.4	24	−0.67%	0.9 mmol/L	12	464	5
			Placebo + metformin	54.7	24	−0.02%	0.5 mmol/L	6	237
Rosenstock^Citation26	2006	NCT00086502	Sitagliptin 100 mg qd + pioglitazone	55.6	24	−0.85%	16.7 mg/dL	3	175	4
			Placebo + pioglitazone	56.9	24	−0.15%	1.0 mg/dL	2	178
Aschner^Citation9	2006	NCT00087516	Sitagliptin 100 mg qd	53.4	24	−0.61%	0.7 mmol/L	11	238	4
			Sitagliptin 200 mg qd	54.9	24	−0.76%	0.9 mmol/L	10	250
			Placebo		24	0.18%	0.3 mmol/L	6	253
Raz^Citation37	2006	NR	Sitagliptin 100 mg qd	53.6	18	−4.8%	0.7 mmol/L	8	205	3
			Sitagliptin 200 mg qd	55.4	18	−0.36%	0.6 mmol/L	2	206
			Placebo	55.5	18	0.12%	0.12 mmol/L	4	110
Hermansen^Citation38	2007	NR	Sitagliptin 100 mg qd + glimepiride ± metformin	55.6	24	−0.45%	−4.4 mg/dL	3	222	3
			Placebo + glimepiride ± metformin	56.5	24	0.28%	15.7 mg/dL	6	219
Goldstein^Citation27	2007	NCT00103857	Sitagliptin 100 mg qd	53.3	24	−0.66%	17.5 mg/dL	5	179	4
			Placebo	53.6	24	0.17%	5.8 mg/dL	7	176
Scott^Citation45	2008	NCT00541775	Sitagliptin 100 mg qd + metformin	55.2	18	−0.73%	11.7 mg/dL	3	94	4
			Placebo + metformin	55.3	18	−0.22%	6.1 mg/dL	1	91
Chan^Citation20	2008	NR	Sitagliptin 50 mg qd	68.9	54	−0.7%	1.0 mmol/L	7	65	5
Raz^Citation29	2008	NCT00337610	Sitagliptin 100 mg qd + metformin	53.6	30	−1.0%	1.6 mmol/L	6	96	4
			Placebo + metformin	56.1	30	0	−0.2 mmol/L	5	94
Mohan^Citation39	2009	NCT00289848	Sitagliptin 100 mg qd	50.9	18	−0.7%	1.4 mmol/L	0	352	3
			Placebo	50.9	18	0.3%	0.3 mmol/L	0	178
Aschner^Citation30	2010	NCT00449930	Sitagliptin 100 mg qd	56.3	24	−0.43%	11.5 mg/dL	19	528	4
Bergenstal^Citation31	2010	NCT00637273	Sitagliptin 100 mg qd	52	26	−0.9%	−0.9 mmol/L	16	166	4
Williams–Herman^Citation22	2010	NCT00103857	Sitagliptin 100 mg qd	54.1	104	−1.2%	26.8 mg/dL	8	179	5
Barzilai^Citation32	2011	NCT00305604	Sitagliptin 100 mg qd	71.6	24	−0.5%	−16 mg/dL	1	102	4
			Placebo	72.1	24	0.2%	11 mg/dL	1	104
Chien^Citation40	2011	NR	Sitagliptin 100 mg qd	73.5	24	−1.1%	38.3 mg/dL	0	49	3
Pratley^Citation41	2011	NCT00700817	Sitagliptin 100 mg qd	55	52	−0.88%	0.59 mmol/L	14	219	3
Rosenstock^Citation42	2012	NCT00642278	Sitagliptin 100 mg qd	51.7	12	−0.74%	12.6 mg/dL	2	65	3
			Placebo	53.3	12	−0.22%	3.6 mg/dL	2	65
Aschner^Citation33	2012	NCT00751114	Sitagliptin 100 mg qd	53.3	24	−1.13%	12.4 mmol/L	10	264	4
Russell-Jones^Citation10	2012	NCT00676338	Sitagliptin 100 mg qd	52.3	26	−1.15%	−1.1 mmol/L	9	163	4
Bergenstal^Citation23	2012	NCT00754988	Sitagliptin 100 mg qd	55.5	156	−0.66%	0.83 mmol/L	10	184	5
Yang^Citation34	2012	NCT00813995	Sitagliptin 100 mg qd + metformin	54.1	24	−1.00%	−1.1 mol/L	4	191	4
			Placebo + metformin	55.1	24	−0.10%	0	1	194
Dobs^Citation24	2013	NCT00350779	Sitagliptin 100 mg qd + metformin + rosiglitazone	54.4	54	−1.1%	1.7 mmol/L	8	170	5
			Placebo + metformin + rosiglitazone	54.8	54	−0.3	0.6 mmol/L	5	92
Kobayashi^Citation43	2014	NR	Sitagliptin 50 mg qd	64.3	24	−0.56%	0.67 mmol/L	2	59	3
Merck Sharp & Dohme Corp^Citation62,c	2013	NCT01076088	Sitagliptin 100 mg qd	51.7	24	−0.99%	−21.86 mg/dL	3	120	3
			Placebo	53.6	24	−0.59%	−11.93 mg/dL	4	126
Merck Sharp & Dohme Corp^Citation63,c	2014	NCT00411554	Sitagliptin 50 mg qd	60.8	12	−0.7%	19.6 mg/dL	4	163	3
Arjona Ferreira^Citation35	2013	NCT00509236	Sitagliptin 25 mg qd	60.5	54	−0.74%	24.7 mg/dL	2	64	4
Merck Sharp & Dohme Corp^Citation64,c	2010	NCT00094770	Sitagliptin 100 mg qd	56.8	104	−0.54%	NR	1	588	3
Schernthaner^Citation25	2013	NCT01137812	Sitagliptin 100 mg qd	56.6	52	−0.66%	5.85 mg/dL	26	378	5
Lavalle–Gonzalez^Citation61	2013	NCT01106677	Sitagliptin 100 mg qd	55.5	52	−0.73%	17.7 mg/dL	23	366	5
Arjona Ferreira^Citation36	2013	NCT00509262	Sitagliptin 50 mg/25 mg qd	64.2	54	−0.7%	16.7 mg/dL	11	210	4

Notes:

a Value of HbA_1c change from baseline.

b Value of FBG change from baseline.

c Trial date obtained from clinical trial registration website.

Abbreviations: No NCT, number of NCT; n, number of patients; NR, no record; NCT, National Clinical Trial; qd, once a day; HBA, hemoglobin; FBG, fasting blood glucose.

Figure 1 Flow chart demonstrating the process of study selection.

Abbreviation: OHA, oral hypoglycemic agent.

Figure 2 Incidence of diarrhea associated with sitagliptin.

Note: ^aProportion represents diarrhea as a proportion of the different types of reactions to sitagliptin.
Abbreviations: CI, confidence interval; W, weight.

Figure 3 Incidence and risk of diarrhea with sitagliptin use based on subgroups.

Note: ^aProportion represents diarrhea as a proportion of the different types of reactions to sitagliptin.
Abbreviations: CI, confidence interval; W, weight.

Figure 4 Odds ratios of diarrhea associated with sitagliptin versus controls.

Abbreviations: OR, odds ratio; CI, confidence interval; W, weight.

Figure 5 Funnel plot of standard error by odds ratio for diarrhea.

Figure S1 Embase search strategy.

Abbreviation: exp, extensive search.

Figure S2 PubMed search strategy.

Figure S3 Cochrane Library search strategy.

Abbreviations: ab, abstract; kw, keyword; ti, title.

Table S1 PRISMA 2009 checklist

Section/topic	No	Checklist	Reported on page no
Title
Title	1	Identify the report as a systematic review, meta-analysis, or both	1
Abstract
Structured summary	2	Provide a structured summary including, as applicable: background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number	1
Introduction
Rationale	3	Describe the rationale for the review in the context of what is already known	1
Objectives	4	Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS)	1
Methods
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (eg, web address), and, if available, provide registration information including registration number	2
Eligibility criteria	6	Specify study characteristics (eg, PICOS, length of follow-up) and report characteristics (eg, years considered, language, publication status) used as criteria for eligibility, giving rationale	2
Information sources	7	Describe all information sources (eg, databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched	2
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated	2
Study selection	9	State the process for selecting studies (ie, screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis)	2
Data collection process	10	Describe method of data extraction from reports (eg, piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators	2
Data items	11	List and define all variables for which data were sought (eg, PICOS, funding sources) and any assumptions and simplifications made	2
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level) and how this information is to be used in any data synthesis	2
Summary measures	13	State the principal summary measures (eg, risk ratio, difference in means)	2
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated	2
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (eg, publication bias, selective reporting within studies)	2
Additional analyses	16	Describe methods of additional analyses (eg, sensitivity or subgroup analyses, meta-regression), if done, indicating which were prespecified	2
Results
Study selection	17	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram	3
Study characteristics	18	For each study, present characteristics for which data were extracted (eg, study size, PICOS, follow-up period) and provide the citations	3
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12)	3
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group and (b) effect estimates and confidence intervals, ideally with a forest plot	3
Synthesis of results	21	Present results of each meta-analysis done, including confidence intervals and measures of consistency	3
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies (see item 15)	4
Additional analysis	23	Give results of additional analyses, if done (eg, sensitivity or subgroup analyses, meta-regression [see item 16])	3
Discussion
Summary of evidence	24	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (eg, health care providers, users, and policymakers)	4
Limitations	25	Discuss limitations at study and outcome level (eg, risk of bias) and at review level (eg, incomplete retrieval of identified research, reporting bias)	4–5
Conclusions	26	Provide a general interpretation of the results in the context of other evidence, and implications for future research	5
Funding
Funding	27	Describe sources of funding for the systematic review and other support (eg, supply of data); role of funders for the systematic review	5

Reproduced from Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Plos Med. 2009;6(7): e1000097.¹

Abbreviations: No, number; PICOS, patient, intervention, comparison, outcome and study; PRISMA, preferred reporting items for systematic reviews and meta-analyses.

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