Supplementary Text A. Full search strategy for each of the searched databases

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1 Supplementary Text A. Full search strategy for each of the searched databases MEDLINE: ( diabetes mellitus, type 2 [MeSH Terms] OR type 2 diabetes mellitus [All Fields]) AND ( hypoglycemia [MeSH Terms] OR hypoglycemia [All Fields] OR hypoglycaemia [All Fields]) AND ( cardiovascular diseases [MeSH Terms] OR cardiovascular diseases [All Fields] OR ( cardiovascular [All Fields] AND diseases [All Fields]) OR ( cardiovascular [All Fields] AND disease [All Fields])) Embase: 'cardiovascular diseases'/exp OR 'cardiovascular diseases' AND ('non insulin dependent diabetes mellitus'/exp OR 'non insulin dependent diabetes mellitus') AND ('hypoglycemia' OR 'hypoglycemia'/exp OR 'hypoglycaemia') AND [embase]/lim Cochrane library: (hypoglycemia):ti,ab,kw AND (Diabetes Mellitus, Type 2):ti,ab,kw AND (Cardiovascular Diseases):ti,ab,kw Web of Science: Topic=(hypoglycemia) AND Topic=(cardiovascular disease) AND Topic=(type 2 diabetes) 1

2 Supplementary Text B. Study characteristics and quality assessment (In-depth version) Tables 1 and 2 show the characteristics of the studies included in the meta-analysis. Two studies (the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] trial 1 and the Veterans Affairs Diabetes Trial [VADT] 2 ) were secondary analyses of randomised clinical trials (RCTs) and the other 4 studies (Johnston et al, 3 Zhao et al, 4 Rathmann et al 5, and Hsu et al 6 ) were studies based on administrative databases. The number of participants ranged from 1522 to , with a mean age range of years and a mean diabetes duration of years; the follow-up period ranged from 1 to 5.6 years. The VADT, 2 Johnston et al, 3 and Zhao et al 4 were conducted in the United States; the ADVANCE 1 was done in Europe, Asia, Australia/New Zealand, and Canada; 1 the Rathmann et al 5 in German; and the Hsu et al 6 in Taiwan. The ADVANCE 1 and VADT 2 studies prospectively documented episodes of severe hypoglycaemia and used severe hypoglycaemia as an exposure of interest. The other 4 studies 3-6 used information from electronic medical records, 4 claims-based databases, 3 6 or primary care databases 5 to retrospectively identify hypoglycaemic episodes, using the ICD-9-CM (international classification of diseases, ninth revision, clinical modification) or ICD-10 (international classification of diseases, 10th revision) 5 diagnosis coding. The identification of hypoglycaemia through ICD-9-CM coding has been shown to have relatively high sensitivity and specificity. 7 Because most hypoglycaemic episodes identified using diagnosis coding are likely to be sufficiently severe to require medical care, these were classified as severe hypoglycaemia. In the ADVANCE 1 and VADT 2 studies, pre-specified cardiovascular outcomes were prospectively collected and adjudicated by independent committees. The other 4 studies 3-6 identified cardiovascular outcomes through diagnosis coding. The outcomes included heterogeneous manifestations (cardiac death, acute myocardial infarction, unstable angina, stroke, congestive heart failure, and peripheral artery disease). 2

3 All studies were adjusted for age and use of antihyperglycaemic agents; the study by Rathmann et al 5 consisted of patients with newly prescribed sulphonylureas or dipeptidyl peptidase-4 without additional antihyperglycaemic agents, except metformin. Four studies adjusted for prior cardiovascular disease (CVD); Zhao et al excluded participants with prior CVD 4, while Rathmann et al 5 adjusted for the Charlson comorbidity index (CCI) (i.e., a weighted index that accounts for the number and seriousness of comorbid diseases, including myocardial infarction, cerebrovascular disease, and peripheral vascular disease). 8 9 All studies, except the VADT 2 and Hsu et al 6, adjusted for baseline microvascular complications; the VADT 2 and Hsu et al 6 adjusted for a surrogate of microvascular complications, such as duration of diabetes. The VADT mainly consisted of male participants 2 ; the other 5 studies adjusted for gender The ADVANCE, 1 the VADT, 2 and Zhao et al 4 controlled for smoking status by using the multivariable models; the other 3 studies did not adjust for smoking status. The VADT 2 and Zhao et al 4 controlled for race; Rathmann et al 5 consisted of German patients; Hsu et al 6 consisted of Taiwanese patients; and the ADVANCE 1 did not control for race. The ADVANCE 1 and VADT 2 controlled for creatinine and HbA 1c levels. Zhao et al, 4 Johnston et al, 3 and Rathmann et al 5 controlled for baseline health status by using the CCI 8 9 ; the other 3 studies simultaneously adjusted for comorbid diseases. All studies, except ADVANCE 1, controlled for total cholesterol, 2 statin use, 4 hypercholesterolaemia, 3 5 or dyslipidaemia. 6 The ADVANCE 1 and Zhao et al 4 controlled for body mass index; the VADT did not control for BMI, because there was no univariate association between body mass index and CVD. 2 3

4 REFERENCES 1. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363: Duckworth WC, Abraira C, Moritz TE, Davis SN, Emanuele N, Goldman S, et al. The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications 2011;25: Johnston SS, Conner C, Aagren M, Smith DM, Bouchard J, Brett J. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care 2011;34: Zhao Y, Campbell CR, Fonseca V, Shi L. Impact of hypoglycemia associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. Diabetes Care 2012;35: Rathmann W, Kostev K, Gruenberger JB, Dworak M, Bader G, Giani G. Treatment persistence, hypoglycaemia and clinical outcomes in type 2 diabetes patients with dipeptidyl peptidase-4 inhibitors and sulphonylureas: a primary care database analysis. Diabetes Obes Metab 2013;15: Hsu PF, Sung SH, Cheng HM, Yeh JS, Liu WL, Chan WL, et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study. Diabetes Care 2013;36: Ginde AA, Blanc PG, Lieberman RM, Camargo CA, Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord 2008;8:4. 8. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40: Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:

5 Supplementary Figure A. Assessment of publication bias by funnel plot ADVANCE indicates Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial. VADT indicates Veterans Affairs Diabetes Trial. 5

6 Supplementary Table A. Quality assessments on the studies included in the meta-analysis Study 1. Is this a prospective study? a, b 2. Is the source population clearly defined? 3. Was the follow-up time longer than 1 year? 4. Was the exposure clearly defined? 5. Was the outcome reviewed by an endpoints committee? ADVANCE a Yes Yes Yes Yes Yes Yes VADT Yes Yes Yes Yes Yes Yes Johnston et No No No No No Yes al Zhao et al No No Yes No No Yes Rathmann et No No Yes No No Yes al Hsu et al No No Yes No No Yes 6. Were measured potential confounding factors adequately adjusted for? c a Prospective studies: studies that prospectively identify a group of people, assesse exposures of interest, and follow them for incidence of outcome events. b Retrospective studies: studies that use existing data records to retrospectively identify a group of people, and assess exposures of interest and incidence of outcome events. c Adjustment of following measured potential confounding factors: age, sex, history of cardiovascular disease, history of microvascular complications or its surrogate, baseline health status, and use of antihyperglycaemic agents. Abbreviations: ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT = Veterans Affairs Diabetes Trial. 6

7 Supplementary Table B. Random-effects meta-analysis with bias analysis Prevalence of severe illness in patients without severe hypoglycaemia Prevalence of severe illness in patients with severe hypoglycaemia RR of severe illness and CVD 7 Bias-adjusted RR of severe hypoglycaemia and CVD risk 95% CI 0.5% 0.5% to % 0.5% to % 1.0% to % 1.0% to % 1.0% to % 1.0% to % 1.0% to % 1.0% to % 2.0% to % 2.0% to % 2.0% to % 2.0% to % 2.0% to % 2.0% to % 5.0% to % 5.0% to % 5.0% to % 5.0% to % 5.0% to % 5.0% to % 1.0% to % 1.0% to % 5.0% to % 5.0% to % 5.0% to % 5.0% to % 5.0% to % 10.0% to % 10.0% to % 10.0% to % 10.0% to % 15.0% to % 15.0% to % 15.0% to 1.12

8 Abbreviations: CVD = cardiovascular disease; CI = confidence interval; RR = relative risk. Bias-adjusted RRs of severe hypoglycaemia and CVD were computed to examine the sensitivity of the association to possible confounding by comorbid severe illness. 8