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A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events a Comparison of Glyburide with Other Secretagogues and with Insulin

A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events a Comparison of Glyburide with Other Secretagogues and with Insulin

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A Systematic Review and Meta-Analysis of and Cardiovascular Events A comparison of glyburide with other secretagogues and with

1,2 2 AZIM S. GANGJI, MD, FRCPC CHARLES H. GOLDSMITH, PHD 1–2% (6). Differences in chemical struc- 2,3 1,2 TALI CUKIERMAN, MD CATHERINE M. CLASE, MB, FRCPC ture, pharmacokinetic, and pharmacody- 2,3 HERTZEL C. GERSTEIN, MD, FRCPC namic properties between may lead to differences in the rates of hy- poglycemic reactions. Glyburide (called OBJECTIVE — Glyburide is the most widely used but has unique pharmaco- in Europe), the most dynamic properties that may increase harm. We hypothesized that glyburide causes more hy- widely used sulfonylurea (7), has a rela- poglycemia and cardiovascular events than other secretagogues or insulin. tively long terminal half-life in chronic dosing compared with other sulfonyl- RESEARCH DESIGN AND METHODS — Data sources were Medline, Embase, ureas, owing to its high affinity for the Cochrane, and three other web-based registers (1966–2005). Parallel, randomized, ␤ controlled trials in people with comparing glyburide monotherapy with mono- -cell sulfonylurea receptor and the accu- therapy using secretagogues or insulin were selected. Outcomes were hypoglycemia, glycemic mulation of active metabolites that are ex- control, cardiovascular events, body weight, and death. Titles and abstracts of 1,806 publications creted through the (7). Several were reviewed in duplicate and 21 relevant articles identified. Data on patient characteristics, observational studies have reported in- interventions, outcomes, and validity were extracted in duplicate using predefined criteria. creased rates of hypoglycemia with the use of glyburide compared with other sul- RESULTS — Glyburide was associated with a 52% greater risk of experiencing at least one fonylureas (3,4). A systematic review of episode of hypoglycemia compared with other secretagogues (relative risk 1.52 [95% CI 1.21– randomized controlled trials (RCTs) evalu- 1.92]) and with 83% greater risk compared with other sulfonylureas (1.83 [1.35–2.49]). Gly- buride was not associated with an increased risk of cardiovascular events (0.84 [0.56–1.26]), ating the risk for hypoglycemia associated death (0.87 [0.70–1.07]), or end-of-trial weight (weighted mean difference 1.69 kg [95% CI with the use of glyburide has not, to our Ϫ0.41 to 3.80]) compared with other secretagogues. Limitations included suboptimal reporting knowledge, been previously conducted. of original trials. Loss to follow-up exceeded 20% in some studies, and major hypoglycemia was The University Group Diabetes Pro- infrequently reported. gram (UGDP) RCT (8) noted excess car- diac deaths in patients treated with CONCLUSIONS — Glyburide caused more hypoglycemia than other secretagogues and ; whether this was attribut- other sulfonylureas. Glyburide was not associated with an increased risk of cardiovascular able to higher baseline cardiac risk in the events, death, or weight gain. patients allocated to tolbutamide or to a Diabetes Care 30:389–394, 2007 true biological effect has been widely de- bated. Consistent with the findings of the UGDP study, experimental laboratory he global prevalence of diagnosed risk for severe hypoglycemia, which is as- data have suggested that sulfonylureas, type 1 and 2 diabetes was estimated sociated with mortality and morbidity particularly glyburide, might increase the to be 2.8% in 2000 and projected to (3,4). T risk of cardiovascular events. During cor- be 4.4% by 2030 (1). The UK Prospective Sulfonylurea drugs bind the sulfonyl- ϩ onary angioplasty, with each subsequent Diabetes Study (UKPDS) showed that im- urea receptor, an ATP-sensitive K chan- balloon dilatation, the extent of ST seg- proving glycemic control reduced long- nel, and inhibit potassium efflux, which ment depression decreases and the time term microvascular complications (2). facilitates insulin secretion (5). Compared However, intensive therapy increases the with placebo, they reduce A1C levels by to onset of ST depression and the time to onset of angina increase. This phenome- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● non, known as ischemic preconditioning, From the 1Division of Nephrology, McMaster University and St. Joseph’s Healthcare, Hamilton, Ontario, is thought also to occur in acute coronary Canada; the 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, On- syndromes. Sulfonylurea-induced potas- tario, Canada; and the 3Division of Endocrinology & Metabolism and Population Health Research Institute, sium efflux has been shown to reduce McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. cardiac ischemic preconditioning in ani- Address correspondence and reprint requests to Catherine M. Clase, 708-25 Charlton Ave. East, Hamil- ton, Ontario L8P 3P7, Canada. E-mail: [email protected]. mal studies (9). In humans undergoing Received for publication 23 August 2006 and accepted in revised form 12 November 2006. coronary angioplasty, the infusion of gli- Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ mepiride has the same effect on ST de- dc06-1789. pression and time to onset of angina as Abbreviations: FPG, fasting plasma glucose; RCT, randomized controlled trial; UKPDS, UK Prospective Diabetes Study; WMD, weighted mean difference. placebo, whereas the infusion of gly- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion buride leads to a reduction in each of the factors for many substances. effects of preconditioning (10). DOI: 10.2337/dc06-1789 This systematic overview of random- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby ized controlled trials in people with type 2 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. diabetes was conducted to determine

DIABETES CARE, VOLUME 30, NUMBER 2, FEBRUARY 2007 389 Hypoglycemia: glyburide vs. secretagogues/insulin

tent of agreement between reviewers. Dis- agreements were resolved by consensus.

Validity assessment We assessed validity in duplicate using the following criteria: 1) method of ran- domization, 2) presence of allocation con- cealment, 3) blinding, 4) loss to follow- up, and 5) reporting of an intention-to- treat analysis.

Data abstraction For each study, we abstracted, in dupli- cate: 1) inclusion and exclusion criteria; 2) baseline characteristics for the different treatment arms, including the number of participants at the start of the study; 3) the intervention and comparator (including dose, frequency, target A1C, and A1C achieved); 4) follow-up period and num- ber of participants at study completion; and 5) the definitions used to report hy- poglycemia and cardiovascular events. For each treatment arm we abstracted: 1) Figure 1—Study flow diagram. AG, Azim S. Gangji; TC, Tali Cukierman. all episodes of hypoglycemia (number of participants with one or more episodes and number of episodes per unit of per- whether people taking glyburide are at in- tially appropriate articles and each was re- son-time), 2) number of episodes of major creased risk for hypoglycemia or cardio- viewed independently for eligibility. and minor hypoglycemia, 3) number of vascular events compared with those cardiovascular events, 4) number of taking other secretagogues (other sulfo- Study selection deaths from any cause, and 5) weight nylureas and ) or those taking Eligible studies 1) described people with change and end-of-trial weight. When the insulin. For completeness of our analysis type 2 diabetes; 2) compared glyburide study included more than two arms, we of important harms, we also examined monotherapy with monotherapy using chose the comparator with the largest weight gain. other sulfonylureas, meglitinides, or insu- number of people. lin; 3) reported one or more of the follow- RESEARCH DESIGN AND ing outcomes: hypoglycemia (major, Data analysis METHODS — We followed the rec- minor, or all), cardiovascular events, or We summarized studies that compared ommendations of the Quality of Report- weight change; 4) described a parallel de- glyburide with other secretagogues sepa- ing of Meta-Analyses (QUOROM) sign RCT; and 5) were written in English. rately from studies that compared gly- conference (online appendix 1 [available For hypoglycemia and cardiovascular buride with insulin. Because of the at http://dx.doi.org/10.2337/dc06-1789]) events, we accepted the definition or out- unique pharmacokinetic and pharmaco- (11). come cluster reported in the original dynamic properties of glyburide, we pre- manuscript. Cardiovascular events in- specified a subgroup analysis comparing Search strategy cluded incident myocardial infarction, glyburide with other sulfonylureas. We searched biomedical databases (Med- stroke, amputation, episodes of conges- We assessed patient characteristics, line, Embase, the Cochrane library, clini- tive heart failure, or cardiovascular death. interventions, and outcomes for clinical caltrials.gov, controlled-trials.com, and Where multiple outcomes were reported, heterogeneity and used the I2 statistic to the U.K. national register of RCTs) and we selected the cluster that most closely quantify the proportion of total variation the bibliographies of relevant and review matched the definition above. If no clus- that was due to statistical heterogeneity. articles for reports of RCTs comparing ter was reported, we selected the single We calculated relative risk (RR) and 95% glyburide with other secretagogues or outcome we thought best represented CIs to summarize the effect size for di- with insulin. In Medline and Embase the cardiovascular outcomes. We excluded chotomous outcomes (number of partici- searches combined generic and brand studies with Ͻ20 participants in each arm pants with at least one hypoglycemic names of glyburide with key words spec- or a follow-up of Ͻ4 weeks. If studies event, number of major and all hypogly- ifying RCTs according to the strategy were reported in more than one publica- cemic events, cardiovascular events, and recommended by the Cochrane colla- tion, we extracted data from the most re- overall mortality), and rate ratios and boration (online appendix 2) (12). cent article that met the inclusion criteria 95% CIs were calculated for event rates. Two authors (A.S.G. and T.C.) inde- using data from related publications For continuous data, we calculated the pendently reviewed this initial list (Fig. when necessary. weighted mean difference (WMD) for 1). Full text was obtained for all poten- We used ␬-statistics to express the ex- each study and summarized this as an

390 DIABETES CARE, VOLUME 30, NUMBER 2, FEBRUARY 2007 Gangji and Associates Etmt neibedet eeoeet.†odt ncrivsua ucm lsesbtdt nmoada nacinetatdfo igestu single from extracted infarction myocardial on data but clusters outcome cardiovascular on data. data no †No ND, applicable; heterogeneity. to due unreliable *Estimate al 1— Table nui .8(.530)9.% D009(.1–.0)8.% D08 07–.4 A .7(.912)N‡–.8(24 o–.4 0% –2.14) to (–2.42 –2.28 NA‡ (0.79–1.20) 0.97 31.4% 3.80) to (–0.41 1.69 NA† (0.70–1.14) 0.89 0% (0.70–1.07) 0.87 5.47 to (–0.48 2.49 12.6% (0.56–1.26) 0.84 ND 33.7% (0.47–1.32) 0.79 0% (0.71–1.19) 0.92 ND 83.1%* (0.019–0.408) 0% 0.089 (0.78–28.08) 4.69 17.6% ND (1.13–1.85) 1.44 76.8%* (1.06–3.09) 1.80 92.5%* (0.25–3.06) 0.88 ND ND 43.4% (1.35–2.49) 1.83 Insulin 42.1% (1.21–1.92) 1.52 Sulphonylureas secretagogues All overall WMD and 95% CI. We used ran- to 10 years. Some of the studies specified Comparator dom effects assumptions throughout. the target A1C or fasting plasma glucose To assess for publication bias, we (FPG) to be achieved. Though this value constructed a funnel plot of the SE of the varied widely between studies, the target i or sulphonylureas, secretagogues, all with compared glyburide change: weight and death, events, cardiovascular hypoglycemia, of risk of Summary log of the RR plotted against the RR for level was always identical for the two arms experiencing at least one episode of hypo- within each study (2,14–16,18,20– glycemia. 23,25,27,28). Hypoglycemia was defined We used MetaView 4.2 in Cochrane as symptoms (without a threshold glu- hypoglycemic any ainswith Patients 9%C)I CI) (95% Review Manager 4.2 (Cochrane Collabo- cose level) in some studies and in others episode ration, Oxford, U.K.) and Comprehensive as symptoms coexisting with low capil- ͓

Meta-Analysis 2.2 (Biostat, Englewood, lary blood glucose levels (minimum RR 2 NJ). P Ͻ 0.05 was considered statistically threshold 48 mg/dl [2.7 mmol/l], maxi- ͔ significant, and an I2 value of Ͼ50% in- mum 63 mg/dl [3.5 mmol/l]). Major hy- dicated excess statistical heterogeneity. poglycemia was defined as an episode hypoglycemic ainswith Patients requiring assistance or hospital admis- I CI) (95% episode

RESULTS sion. Details of study characteristics and major a study validity are available in the online ͓ Search appendix (Tables A and B). RR 2 We identified 1,806 publications, of ͔ which 21 articles describing 20 studies Quantitative data synthesis were relevant (Fig. 1) (2,13–32). Esti- Table 1 provides a summary of effect 2 mated ␬ for agreement on relevance was sizes, 95% CIs, and I values for the meta- hypoglycemic All 9%C)I CI) (95% psdsper episodes patient-year ͓

0.86 (95% CI 0.81–0.91). Of the 21 arti- analyses of harms. ratio rate cles, 12 compared glyburide with an oral hypoglycemic agent and reported this as Hypoglycemia and glycemic control 2 patients experiencing at least one episode Figure 2 shows a 52% greater risk of ex- ͔ of hypoglycemia (13,15–17,20,21,23, periencing at least one episode of hypo- 25–27,29,30); an additional 3 articles glycemia for participants receiving only reported total number of hypoglyce- glyburide compared with those receiving mic episodes (14,18,19); 3 articles com- other secretagogues (RR 1.52 [95% CI hypoglycemic Major 9%C)I CI) (95% psdsper episodes pared glyburide with insulin (22, 27,31); 1.21–1.92]). In the planned subgroup patient-year ͓ and 3 studies only reported a change in analysis comparing glyburide with other ratio rate weight (24,28,32). sulfonylureas, glyburide was associated

with an 83% higher risk of causing at least 2 Validity assessment one episode of hypoglycemia (1.83 ͔ Five of the 21 studies described the [1.35–2.49]). method of randomization (2,14,22, Five studies compared glyburide with 30,33); 3 of these used a computer gen- other secretagogues and reported their re- ͓ R(5 I I CI) (95% RR erated method (2,22,27). The method of sults as total number of hypoglycemic ep- Cardivascular allocation concealment was described isodes (14,15,19,20,26) (Table 1). These events only in the UKPDS trial, which used con- studies were heterogeneous (I2 76.8%). secutive opaque envelopes. Seven studies There was an 80% higher rate of hypogly- 2 reported blinding of participants and cemic episodes with glyburide (rate ratio ͔ caregivers (13,15,16,19–21,25). The 1.80 [95% CI 1.06–3.09]) compared not NA, 33). (UKPDS study single from ‡Data 33). (UKPDS dy UKPDS study reported that there was with other secretagogues. Limiting the blinding of outcome assessors and data analysis to studies comparing glyburide ͓ analyzers (2). with other sulfonylureas led to a decrease I CI) (95% RR

Twelve of the 21 studies reported the in heterogeneity to within acceptable lim- Death use of an intent-to-treat analysis (13,15– its (I2 17.6%); the increased risk associ- 17,20,21,23,25–27,29,30). Loss to fol- ated with glyburide compared with other 2 low-up was reported in 19 studies (2,14– sulfonylureas was 44% (1.44 [1.13– ͔ 23,25–32). There was a large amount of 1.85]) (14,15). Two studies, both using a variability (0–37%) in the percentage of sulfonylurea as a comparator (14,15), re- patients lost to follow-up. Reasons for loss ported major hypoglycemic episodes. nsulin ͓ M 9%C)I CI) (95% WMD

to follow-up included inadequate glyce- The risk of major hypoglycemic events (kg) gain Weight mic control, hypoglycemia, other adverse was over four times higher for glyburide events, noncompliance, and moving out compared with other sulfonylureas (4.69 of the study area. [0.78–28.08]); however, this was not sta- tistically significant. 4.9% )

Study characteristics Studies reporting A1C were all com- 2 Included studies reported on 7,047 peo- parisons of glyburide with sulfonylureas: ͔ ple with follow-up periods from 1 month no significant difference was identified

DIABETES CARE, VOLUME 30, NUMBER 2, FEBRUARY 2007 391 Hypoglycemia: glyburide vs. secretagogues/insulin

Figure 2—RR for experiencing at least one hypoglycemic episode: glyburide versus other secretagogues. Chlp, ; Glic, glicazide; Glim, glimiperide; Glip, ; Repg, .

(A1C WMD Ϫ0.13% [95% CI Ϫ0.52 to glyburide (WMD Ϫ2.28 kg [Ϫ2.42 to CONCLUSIONS — The main find- 0.26; I2 43.7%]). Reports of FPG compar- Ϫ2.14]) (2,18,22). ings of this meta-analysis are that gly- ing glyburide with other secretagogues buride caused more hypoglycemia than were heterogeneous (WMD Ϫ0.49 other secretagogues and more hypoglyce- Cardiovascular events and overall mmol/l [95% CI Ϫ1.15 to 0.18; I2 mia than other sulfonylureas. In the meta- mortality 97.9%]). Heterogeneity was not present analysis of the two studies that reported Cardiovascular events were reported in in the analysis comparing FPG for gly- major hypoglycemia, there was a trend three studies including 2,822 participants buride with other sulfonylureas. There toward a greater number of events in pa- (2,15,21). There was no significant differ- was a small effect in the direction of im- tients treated with glyburide than with ence between glyburide and secreta- proved FPG with glyburide (WMD other sulfonylureas. The direction of ef- gogues (RR 0.84 [95% CI 0.56–1.26]). Ϫ0.34 mmol/l [95% CI Ϫ0.40 to Ϫ0.27; fect was consistent in all analyses (Table The same three studies reported no signif- I2 0%]). 1). UKPDS 33 reported the percentage of icant difference in overall mortality (0.87 Three studies (1,339 participants) patients per year with one or more epi- [0.70–1.07]). There were no studies that showed that the risk of hypoglycemia was sodes and with one or more major epi- reported a cardiovascular outcome clus- similar for people treated with glyburide sodes of hypoglycemia. Although we were ter for glyburide compared with insulin. and those treated with insulin, though CIs unable to include these results in our However, the UKPDS 33 (2) study re- were wide (RR 0.88 [95% CI 0.25–3.06]) meta-analysis because of the method of ported data from which the RR of myo- (22,27,31). reporting, our results (glyburide vs. other cardial infarction for glyburide compared sulfonylureas RR 1.83 [95% CI 1.35– with insulin could be calculated: RR 0.89 Weight change and end-of-trial 2.49]) are consistent with the findings of (95% CI 0.70–1.14). One study (UKPDS weight UKPDS 33, in which the mean percentage 33) reported data from which mortality End-of-trial weight was reported in three of patients per year with one of more ep- for glyburide compared with insulin studies of 498 people comparing gly- isodes of hypoglycemia was 17.7% for could be calculated: 0.97 (0.79–1.20). buride with other secretagogues glyburide and 11.0% for chlorpropamide (25,27,30). Overall, glyburide did not (RR 1.61), and the mean percentage of cause an increase in weight compared Assessment of publication bias patients per year with one or more major with other secretagogues (WMD 1.69 kg Visual inspection of the funnel plot of the hypoglycemic episodes was 0.6% for gly- [95% CI Ϫ0.41 to 3.80]). However, in the outcome “number of participants experi- buride and 0.4% for chlorpropamide (RR three studies of 1,840 people comparing encing at least one hypoglycemic episode” 1.50). glyburide with insulin, body weight in- demonstrated a paucity of studies with We did not find a difference in A1C creased by 2.28 kg more in people treated large SEs to the left of the overall estimate between patients treated with glyburide with insulin than in those treated with (available from the authors upon request). and those treated with other sulfonyl-

392 DIABETES CARE, VOLUME 30, NUMBER 2, FEBRUARY 2007 Gangji and Associates ureas; however, there was a small, statis- cles has been identified as a source of bias decreased from 42.1 to 0% with the over- tically significant difference of question- in some circumstances (35). However, a all RR estimate changing from 1.52 to able clinical importance in the compari- recent retrospective analysis suggests that 1.33, both statistically significant). son of FPG between these two groups. On excluding trials published in languages the evidence of the A1C results, it seems other than English has generally little ef- Implications for practice unlikely that improved glycemic control fect on summary treatment effect esti- In 2003, it was estimated that 13.8 mil- accounts for the increase in hypoglycemia mates (36). lion people in the U.S. had established observed. There was a paucity of studies with type 2 diabetes; of these, 7.8 million peo- We did not find any difference in risk larger SEs to the left of the point estimate ple used at least one oral antidiabetes for hypoglycemia of glyburide compared in the funnel plot. Larger SEs can be due (41). Glyburide, available as a with insulin. CIs for this estimate are to either smaller sample size trials, studies generic, is relatively inexpensive and wide, so a difference cannot be excluded. with more variability, or both. This may widely used. Our results suggest that risk Other reasons for finding no difference suggest publication bias or a systematic of hypoglycemia and rates of hypoglyce- include: 1) inadequate titration of insulin error introduced by the loss to follow-up. mia for millions of patients are likely toward achieving glucose control (in one Statistically significant and clinically ϳ50% higher in those taking glyburide of the studies included in this review, the important results were obtained for the than they would be if they were taking an achieved end-of-trial A1C in the insulin meta-analyses of all episodes of hypogly- alternative sulfonylurea or nonsulfonylu- arm was 8.5% [22]), 2) the small dose cemia, most of which would likely have rea secretagogue. adjustments possible with insulin that are been minor. Though the clinical impor- not possible with an oral agent, or 3) that tance of minor hypoglycemia can be ques- Implications for research the difference is minimized in patients tioned, minor hypoglycemia has been Our review highlights the importance of with newly diagnosed disease who pre- shown to predict major hypoglycemia minimizing loss to follow-up in RCTs of dominated in our analysis. (37), and minor episodes lead to disrup- long duration, as our overall estimates in- Though data from animal and human tions in glycemic control (38,39) that are cluded some clinical trials in which loss to studies suggest that glyburide might ex- thought to have long-term consequences follow-up exceeded 20%. The clinical acerbate coronary ischemia more than (40). Although power to detect a differ- consequences of hypoglycemia, its effects other secretagogues and specifically more ence in the analysis of major hypoglyce- on patient compliance, and the direct than other sulfonylureas (10), the meta- mia was limited by the low number of health care costs of hypoglycemia are all analysis of cardiovascular events and studies reporting this outcome, seven of important issues that warrant inclusion in deaths provided no support for the hy- the eight major hypoglycemic episodes an economic evaluation of the relative pothesis that these effects lead to adverse reported occurred in glyburide-treated cost-effectiveness of glyburide compared cardiovascular outcomes. In addition, patients (14,15). UKDPS 33 results, with other secretagogues. weight gain with glyburide was similar to which were not reported in a format that that observed with other sulfonylureas enabled us to include them in the meta- and less than that observed with insulin. analysis, also show consistency between Acknowledgments— A.S.G. is a recipient of major episodes and all episodes in the di- the Kidney Foundation of Canada/Canadian Methodological limitations rection and magnitude of the RR when Society of Nephrology Fellowship Award. H.C.G. holds the Population Health Institute Limitations of the included studies. glyburide is compared with chlorprop- Chair in Diabetes Research (funded by The method of randomization and alloca- amide (see above), lending weight to the Aventis). tion were seldom described in the studies hypothesis that minor episodes may be a We thank Neera Bhatnagar for assistance reported here. Lack of allocation conceal- useful surrogate for more clinically im- with database searching. ment may significantly influence ob- portant major episodes. served treatment effects (34). Because all of our comparisons are There was great variability between with glyburide, we are unable to draw any References studies in the loss to follow-up, from 0 to conclusions about the properties of other 1. Wild S, Roglic G, Green A, Sicree R, King 37%. Since hypoglycemia and loss to fol- drugs compared with one another. H: Global prevalence of diabetes: esti- low-up have been shown to be associated Finally, statistical heterogeneity was mates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053, (19,26), differential follow-up of patients noted between the studies comparing the 2004 prone to hypoglycemia would lead to un- risk of at least one hypoglycemic episode 2. 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Diabetologia 24:412– rates. Indeed, when the UKPDS data were re- 417, 1983 Limitations of overall review. We did moved from the analysis, the studies were 4. Seltzer HS: Drug-induced hypoglycemia: not include studies published in lan- deemed homogenous without a signifi- a review of 1418 cases. Endocrinol Metab guages other than English in our review. cant change in the overall estimate (P Clin North Am 18:163–183, 1989 The lack of inclusion of non-English arti- value increased from 0.06 to 0.64 and I2 5. Aguilar-Bryan L, Nichols CG, Wechsler

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