Supplementary Figure S1. Search terms* *mh = exploded MeSH: Medical subject heading (Medline medical index term); tw = text word; pt = publication type; the asterisk (*) stands for any character(s) #1: Type 2 Diabetes Mellitus ("Diabetes Mellitus, Type II" [mh] OR "Insulin Resistance" [mh] OR "Metabolic Syndrome X" [mh] OR "Obesity in Diabetes" [mh] OR impaired glucose tolerance [tw] OR "glucose intolerance" [tw] OR "insulin resistance" [tw] OR "obese diabetes" [tw] OR "obesity diabetes" [tw] OR "obese diabetic" [tw] OR MODY [tw] OR NIDDM [tw] OR "non insulin dependent" [tw] OR "noninsulin dependent" [tw] OR "non insulindependent" [tw] OR "noninsulindependent" [tw] OR "non-insulin dependent" [tw] OR noninsulinodependent [tw] OR "non insulin treated" [tw] OR "noninsulin treated" [tw] OR "non insulintreated" [tw] OR "noninsulintreated" [tw] OR "noninsulin treated" [tw] OR noninsulinotreated [tw] OR ((non insulin [tw] OR noninsulin [tw] OR type 2 [tw] OR type II [tw]) AND diabetes [tw]) OR type 2 DM [tw] OR type II DM [tw] OR DMNID [tw] OR "type II diabetes" [tw] OR "type 2 diabetes" [tw] OR "type II diabetic" [tw] OR "type 2 diabetic" [tw] OR diabetes type 2 [tw] OR diabetes type II [tw] OR diabetes mellitus type 2 [tw] OR diabetes mellitus type II [tw] OR "adult diabetes" [tw] OR "maturity onset diabetes" [tw] OR "late onset diabetes" [tw] OR "stable diabetes" [tw] OR "adult diabetic" [tw] OR "maturity onset diabetics" [tw] OR "late onset diabetics" [tw] OR "stable diabetics" [tw] OR metabolic syndrome [tw] OR syndrome X [tw]) NOT ("Diabetes Insipidus" [mh] OR "diabetes insipidus" [tw]) #2: Adherence ( patient compliance [tw] OR exp Patient compliance OR complian* [tw] OR adhere* [tw] OR noncomplian* [tw] OR nonadhere* [tw] OR medication adherence* [tw] OR patient dropouts* [tw] OR ((patient$ or treatment$ or medication or pharmaceutical or prescription) adj2 (compliance or noncompliance or complied or comply$ or noncomply$ or cooperat$ or co-operates$ or discontinu$ or abstention or abstain$ or stop$ or adher$ or nonadher$ orabandon$ or dropout$)) #3: Cardiovascular disease (designed in accordance with Cochrane Heart Group methods and guidance and used by previous Cochrane reviews) exp Cardiovascular Diseases OR cardio* [tw] cardia* [tw] OR heart* [tw] OR coronary* [tw] OR angina* [tw] OR ventric* [tw] OR myocard* [tw] OR pericard* [tw] OR isch?em* [tw] OR emboli* [tw] OR arrhythmi* [tw] OR thrombo* [tw] OR atrial fibrillat* [tw] OR tachycardi* [tw] OR endocardi* [tw] OR (sick adj sinus) [tw] OR exp Stroke OR (stroke or stokes) [tw] OR cerebrovasc* OR cerebral vascular [tw] OR apoplexy.tw OR (brain adj2 accident*) [tw] OR ((brain* or cerebral or lacunar) adj2 infarct*) [tw] OR exp Mortality OR mortality* [tw] OR death* [tw] OR hospitalisation* [tw] OR hospitalization* [tw] OR ((hospital) adj2 (admission*))
Supplementary Table S1. PRISMA checklist Section/topic # Checklist item Reported on page # 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, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. 2, 5 INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 2, 3 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 4 METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 5 5 5 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Appendix Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 5
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 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. 5 5, 6 6 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 5, 6 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. 6 6 N/A 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. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. 6, Figure 1 6, Table 1 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). 6, 7, Appendix Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 6, 7, Figures 2 and 3 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6, 7, Figures 2 and 3 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 6, 7,
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). N/A DISCUSSION Appendix Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). 7, 8, 9 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
Supplementary Table S2. MOOSE checklist Reporting background should include Problem definition Hypothesis statement Description Type of exposure or intervention used Type of study designs used Study population Reporting of search strategy should include Qualifications of searches (e.g. librarians and investigators) Search strategy, including time period included in the synthesis and keywords Effort to include all available studies, including contact with authors Databases and registries searched Search software used, name and version, including special features Use of hand searching (e.g. reference lists of obtained articles) List of citations located and those excluded including justification Method of addressing articles published in languages other than English Method of handling abstracts and unpublished studies Description of any contact with authors Available on request No No Reporting methods should include Description of relevance or appropriateness of studies assembled for assessing the hypothesis to be tested Rationale for the selection and coding of data (eg, sound clinical principles or convenience) Documentation of how data were classified and coded (eg, multiple raters, blinding, and interrater reliability) Assessment of confounding (eg, comparability of cases and controls in studies where appropriate) Assessment of study quality, including blinding of quality assessors; stratification or
regression on possible predictors of study results Assessment of heterogeneity Description of statistical methods (eg, complete description of fixed or random effects models, justification of whether the chosen models account for predictors of study results, dose-response models, or cumulative meta-analysis) in sufficient detail to be replicated Provision of appropriate tables and graphics Reporting of results should include Graphic summarizing individual study estimates and overall estimate Table giving descriptive information for each study included Results of sensitivity testing (eg, subgroup analysis) Indication of statistical uncertainty of findings No Reporting of discussion should include Quantitative assessment of bias (eg, publication bias) Justification for exclusion (eg, exclusion of non English-language citations) Assessment of quality of included studies Reporting of conclusions should include Consideration of alternative explanations for observed results Generalization of the conclusions (ie, appropriate for the data presented and within the domain of the literature review) Guidelines for future research Disclosure of funding source
Supplementary Table S3. Table of adherence measurement methodology in included studies Study Measure of adherence Medications included Calculation Gibson et al 2010 Percentage of days covered Anti-hyperglycaemic medication (including insulin) % of days with prescription drug claim for antihyperglycaemic medication over 18 month period Zhu et al 2015 Percentage of days covered Oral antihyperglycaemic (OHA) medication % of days with prescription drug claim for at least 1 OHA available over 12 month period Hong et al 2011 Medication possession ratio Oral antihyperglycaemic (OHA) medication % of days with possession of prescription drug claim for at least 1 OHA available over 24 month period Ho et al 2006 Percentage of days covered Oral antihyperglycaemic (OHA), antihypertensives and statin medications Average PDC across 3 medication classes (% of days with prescription drug claim over up to 240-365 day period) Encinosa et al 2010 Medication possession ratio Anti-hyperglycaemic medication (including insulin) % of days with prescription drug claim for antihyperglycaemic medication over 12 month period Jha et al 2012 Medication possession ratio Non-insulin antihyperglycaemic medication Highest % of days with possession of prescription drug claim for any non-insulin antihyperglycaemic medication over 1 calendar year Lau et al 2004 Medication possession ratio Non-insulin antihyperglycaemic medication Average % of days with prescription drug claim for antihyperglycaemic medication (across all agents) over 12 month period White et al 2004 Medication possession ratio Oral antihyperglycaemic (OHA) medication Average days supply of OHA divided by number of days therapy between first prescription fill and last fill weighted over follow-up period
Supplementary Table S4. Quality assessment with Newcastle-Ottowa Quality Assessment Scale for Cohort Studies Study No of participants Outcome(s) Selection (4) Comparability (2) Outcome/ Exposure (3) Score Gibson et al 2010 96734 CVD ** ** *** 7 Zhu et al 2015 Hong et al 2011 Ho et al 2006 24067 All-cause mortality; hospitalisation 40082 All-cause mortality; hospitalisation 11532 All-cause mortality; hospitalisation *** ** *** 8 *** ** *** 8 *** ** *** 8 Encinosa et al 2010 Jha et al 2012 Lau et al 2004 White et al 2004 12046 Hospitalisation ** ** *** 7 81807 Hospitalisation ** ** *** 7 900 Hospitalisation ** * *** 6 50957 Hospitalisation ** * *** 6
Supplementary Figure S2. Funnel-plot analysis, with pseudo 95% CIs for studies reporting all-cause hospitalisation by adherence
Supplementary Figure S3. Association between medication adherence and all-cause hospitalisation by method of measuring adherence (medication possession ratio versus percentage of days covered) Study Events (good) Events (poor) RR (95% CI) Weight MPR Hong et al 2011 33 1456/11800 3714/28282 0.94 (0.89, 0.99) 17.60 Jha et al 2012 35 16617/61544 6079/20263 0.90 (0.88, 0.92) 25.50 Lau et al 2004 36 33/641 27/259 0.49 (0.30, 0.80) 0.61 White et al 2004 37 6663/34244 3680/16713 0.88 (0.85, 0.92) 22.86 2 I = 66.8%, p = 0.029 0.90 (0.86, 0.94) 66.56. PDC Encinosa et al 2010 34 847/6322 784/5724 0.98 (0.89, 1.07) 11.07 Zhu et al 2015 39 377/2269 21798 0.92 (0.83, 1.01) 10.20 Ho et al 2006 38 1743/9076 570/2456 0.83 (0.76, 0.90) 12.17 2 I = 72.8%, p = 0.025 0.90 (0.82, 1.00) 33.44. 2 Overall I = 63.4%, p = 0.012 0.90 (0.87, 0.94) 100.00.5.8 1 1.5 Favours good adherence Favours poor adherence