The authors have declared that no competing interests exist.
Conceived and designed the experiments: GL GHdB KJJvH PvD KHG SH ROBG HJGB NK. Analyzed the data: GL KJJvH PvD KHG GHdB. Contributed reagents/materials/analysis tools: GL KHG GHdB. Wrote the paper: GL GHdB KJJvH PvD KHG SH ROBG HJGB NK. Final approval of the version to be published: GL GHdB KJJvH PvD KHG ROBG SH HJGB NK.
Gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156)
Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database.
Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used.
Nineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin, gliclazide was slightly more effective (−0.13% (95%CI: −0.25, −0.02, I2 55%)). One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I2 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes.
The methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.
At present, metformin is the pharmacological cornerstone for patients with type 2 diabetes (T2DM)
The new Dutch type 2 diabetes management guideline specifically advises gliclazide as the preferred second treatment option and not SUs as a group. Specifically advising gliclazide is – amongst others - based on evidence from observational studies showing cardiovascular benefits of gliclazide over other SUs
The role of gliclazide in the new Dutch guideline, the presumed differences between individual SUs, the possibility of a lower hypoglycemia risk, possible cardiovascular safety benefits together with the absence of a systematic review or meta-analysis examining gliclazide specifically, brought us to summarize the results from randomized studies comparing gliclazide with other oral glucose lowering agents.
The eligibility criteria, outcomes, main and sensitivity analyses were pre-specified and published on PROSPERO (2013:CRD42013004156), see
A study was considered eligible if it was a randomized controlled trial that: treated non-pregnant adults (aged 18 or older) with type 2 diabetes; excluded patients during Ramadan; had a study duration of at least 12 weeks; reported change in glycated hemoglobin (HbA1c); compared gliclazide with other oral glucose lowering drugs. Trials comparing gliclazide with placebo, diet, insulin and rosiglitazone were excluded. The two preparations of gliclazide (gliclazide regular formulation and gliclazide MR) were grouped for all analyses.
An electronic search without language restrictions was performed in Medline (using PubMed), EMBASE and the Cochrane Library (April 17 2013).
Publications retrieved from Medline, EMBASE, and the Cochrane Library, were imported in reference management software (
A data extraction form was designed and two reviewers (GL and PvD) independently abstracted data; discrepancies were resolved by consensus (see attachment). From each study, the following characteristics were extracted; author identification, year of publication, Clinical Trial number, sample size, type of intervention, duration of intervention, participants' baseline characteristics; age, sex, race, diabetes duration, previous treatment, HbA1c, body weight and pre-specified outcomes of efficacy and safety.
The primary safety outcome was the number of patients experiencing at least one severe hypoglycemic event. A hypoglycemic event was considered severe when treatment by a third party was necessary.
Secondary safety outcomes included total number of confirmed non-severe hypoglycemic events, cardiovascular events and mortality. A non-severe confirmed event was defined as an event with symptoms and a glucose measurement with a plasma blood glucose <4.0 mmol/L. Cardiovascular events were defined as a combined endpoint of unstable angina, acute myocardial infarction, stroke and fatal cardiovascular events.
The primary outcome was change in HbA1c from baseline to endpoint of the intervention, and its difference with the active comparator(s). The secondary efficacy outcome was the change in body weight from baseline to endpoint of the intervention. Time between baseline and endpoint measurements was considered as a covariate between studies.
Pre-specified subgroup analyses were planned regarding efficacy outcomes comparing gliclazide to other SUs/meglitinides, comparing gliclazide to other drugs except metformin, comparing gliclazide use as a second additive step in therapy and studies with at least 24 weeks follow-up. For the hypoglycemia analysis we planned a subgroup analysis in studies using a maximum gliclazide dose of 240 mg.
Data from intention to treat (ITT) (all participants randomized) or modified ITT (all randomized participants who received intervention and had at least one measurement after baseline) were used when these were available either in a published paper or on websites of pharmaceutical companies and trial registries.
In case of missing, incomplete or per protocol (PP) data regarding the primary and secondary outcomes, the corresponding authors were contacted (three attempts maximum). In case of not responding, the pharmaceutical companies, if applicable, were contacted and ITT or modified ITT data were requested.
In case of multiple reports or companion papers of the same study (published results of an extension period) outcome data from the original study were extracted, unless the first report was a planned interim analysis.
The Cochrane Collaboration's risk of bias tool was used to assess risk of bias
The risk of bias was regarded high in case of the presence of high bias in any domain, low if all key domains (all domains except random sequence generation and allocation concealment) were of low bias, and unclear in all other cases. When only the risk of bias in the 7th domain (other bias) was unclear it was regarded as low risk of bias
Mean differences between the intervention group and all active comparator groups with standard deviations (SDs) were calculated for continuous outcomes with an inverse variance random effects model. If a specific study did not report standard deviations, this was calculated from the standard error or the 95% confidence interval (CIs). For dichotomous outcomes, risk ratios and 95% CIs were used, again using an inverse variance random effects model.
In the absence of a gliclazide group receiving the maximum approved dose of 240 mg, data regarding the group receiving the highest dose were analyzed.
Statistical heterogeneity (I2) values of 30–60% and between 60–90% represent moderate and considerable heterogeneity, respectively
All analyses were performed with RevMan 5.1 (Nordic Cochrane Centre).
In total, 19 studies were included (see
Presentation of the procedure of literature searching and selection with numbers of articles at each stage.
Although some authors or pharmaceutical companies responded
Primary study | Study arm (max dose) | Comparison arm (max dose) | Study duration (month) | HbA1c (%) | Age | Add on to: | N | Sex % female | Diabetes duration (years) | Weight (kg) |
Harrower 1985 | Gliclazide 320 mg | Glibenclamide 30 mg | 52 | 12 | 60 | No | 20/19 | n.a. | 4 | 61 |
Jerums 1987 | Gliclazide 240 mg | Glibenclamide 15 mg | 104 | 9.6 | 60 | No | 9/8 | 35 | 8 | n.a. |
Collier 1989 | Gliclazide 240 mg | Metformin 3 g | 24 | 11.9 | 54 | No | 12/12 | n.a. | 0 | n.a. |
Noury 1991 | Gliclazide 240 mg | Metformin 1.7 g | 13 | 9.7 | 55 | No | 27/30 | 51 | 3 | 80 |
Tessier 1994 | Gliclazide 320 mg | Glibenclamide 20 mg | 26 | 8.6 | 72 | No | 11/11 | 18 | 5 | n.a. |
Tessier 1999 | Gliclazide 320 mg | Metformin 1.7 g | 24 | 7.5 | 59 | No | 18/18 | 31 | 5 | 82 |
Guvener 1999 | Gliclazide 320 mg | Acarbose 600 mg | 26 | 8.5 | 56 | Insulin | 18/20 | 79 | 11 | n.a |
Salman 2001 | Gliclazide 320 mg | Acarbose 600 mg | 24 | 8.8 | 54 | No | 30/27 | 42 | 4 | na |
NCT01022762 2010 | Gliclazide 240 mg | Repaglinide 12 mg | 16 | 7.2 | 62 | Metformin | 218/217 | 46 | 1 | n.a. |
Furlong 2003 | Gliclazide 240 mg | Repaglinide 12 mg | 13 | 9.3 | 59 | Insulin | 39/41 | 47 | 8 | 91 |
Lawrence 2004 | Gliclazide 320 mg | Pioglitazone 45 mg Metformin 3 gr | 24 | 7.7 | 61 | Low dose oral glucose lowering agents 66% | 20/20/20 | 35 | n.a. | 68 |
Schertnhamer 2004 | Gliclazide 120 mg XR | Glimepiride 6 mg | 27 | 8.3 | 61 | Metformin/acarbosis | 388/427 | 49 | 6 | 84 |
Charbonell 2004 | Gliclazide 320 mg | Pioglitazone 45 mg | 52 | 8.7 | n.a. | No | 1270 total | n.a. | n.a. | n.a. |
Mettews 2005 | Gliclazide 320 mg | Pioglitazone 45 mg | 52 | 8.6 | 57 | Metformine | 313/317 | 50 | 6 | 92 |
Kardas 2005 | Gliclazide MR 90 | Glibenclamide 10 mg | 16 | 7.2 | 62 | Metformine in 28% | 49/50 | 60 | 3 | 77 |
Pierriello 2006 | Gliclazide 320 mg | Pioglitazone 45 mg | 52 | 8.8 | 59 | Diet or 1 oral drug | 140/135 | 35 | 9 | 80 |
Ristic 2006 | Gliclazide 240 mg | Nateglinide 180 mg | 24 | 7.6 | 62 | Metformin | 133/129 | 48 | 7 | n.a. |
Foley 2009 | Gliclazide 320 mg | Vildagliptine 100 mg | 104 | 8.6 | 55 | No | 533/530 | 44 | 2 | 84 |
Filozof 2009 | Gliclazide 320 mg | Vildagliptine 100 mg | 52 | 8.5 | 59 | Metformin | 490/503 | 48 | 7 | 85 |
The primary end point between studies varied, the most common endpoint being change in HbA1c. Five studies had a non-inferiority design
Gliclazide was compared to other SUs/meglitinides in eight studies
In 12 studies
Eight studies contributed to the weight analysis. Two studies with metformin
None of the trials was designed to assess cardiovascular safety and/or efficacy. In two larger studies, comparing gliclazide with glimepiride and pioglitazone respectively, specification of cardiovascular events was not possible. Therefore, they were not included in the meta-analysis
Overall risk of bias for the primary outcome was low in one study
Few studies described differences in weight with SD's for the ITT or modified ITT populations
In those studies, in which severe hypoglycemic events were systematically reported, there was one severe hypoglycemic event in 2,387 gliclazide users and one in the 2,430 patients in the comparator group
Symptomatic confirmed hypoglycemia's could be evaluated in 7 studies
Three out of 7 studies were responsible for all symptomatic confirmed hypoglycemic events
One study, with low risk of bias, comparing gliclazide (XR 120 mg) with glimepiride showed an advantage regarding non-severe, confirmed symptomatic and confirmed asymptomatic hypoglycaemia episodes in favour of gliclazide. 15 patients experienced a hypoglycaemic episode in 403 gliclazide users compared to 39 patients in 439 glimepiride users (p<0.02)
Compared to all other interventions, gliclazide was more effective: −0.12% (95%CI: −0.23, −0.01) on the primary outcome measure; change in HbA1c from baseline (see
The main effect outcome HbA1c; gliclazide versus other glucose lowering agents. Metf = metformin, SU is sulphonylurea, Pio is pioglitazone.
After excluding 3 studies
In the 12 studies where the risk for severe hypoglycemia could be evaluated; gliclazide was more effective (−0.11% (95%CI: −0.2, −0.01, I2 26%)). When comparing to other SUs, there was no significant difference in HbA1c: −0.21% (95% CI: −0.46, 0.05, I2 74%). Inclusion of studies with a maximum dose set at 240 mg gliclazide
The difference in weight was 0.47 kg (95%CI −0.75, 1.70) in favor of the control group with high heterogeneity (I2 87%) among the studies. The analysis was based on eight studies including 616 patients using gliclazide and 616 for the reference population
When comparing gliclazide to other SUs or metiglinides the effect estimate was: −0.09 kg (95%CI −1.72, 1.55, I2 87%). This analysis was based on four studies including 401 patients for gliclazide and 411 for SU or metiglinides
When comparing gliclazide to metformin the effect estimate was 1.37 kg (95%CI 0.15, 2.60, I2 28%). This analysis was based on two studies including 45 patients for gliclazide and 48 for metformin
Studies with pioglitazone or DPP-4 inhibitors had a high risk for selective reporting; further weight comparisons with these individual drug classes were not performed.
The incidence of cardiovascular events could be evaluated in 9 studies
Severe hypoglycemic events caused by gliclazide are extremely rare and the occurrence of confirmed symptomatic non-severe hypoglycemic events in gliclazide users could exclusively be ascribed to studies using a gliclazide dose of 320 mg instead of the advised maximum dose of 240 mg. Gliclazide probably has advantages over glimepiride regarding hypoglycemia risk. Gliclazide appears to have a non-relevant beneficial effect on glycemic control compared to other oral glucose lowering agents. There were no trials investigating cardiovascular effects of gliclazide and weight comparisons were limited by a low number of trials and publication bias. The methodological quality of most studies was poor.
Gliclazide appears to be safe regarding severe hypoglycemia risk with one severe hypoglycemic event in 2,387 gliclazide users. Severe hypoglycemias were defined as the primary outcome, since severe episodes have the most deleterious effects
The maximum dose of gliclazide (regular formulation) between studies varied from 240 to 320 mg. Two industry-sponsored high bias trials, both comparing gliclazide to vildagliptine, were responsible for all symptomatic confirmed non-severe events in gliclazide users; both used the 320 mg gliclazide dose
Regarding hypoglycemic events, it should be noted that cut-off values can have great impact on the event rate
There seemed to be a small benefit of metformin compared to gliclazide regarding weight although the effect estimate was small. Most studies either did not report or did not report ITT-analyses on differences in weight between individual drugs (i.e. pioglitazone and vildagliptine) and gliclazide, suggesting a high risk for publication bias in the weight analysis. The lack of cooperation by authors and pharmaceutical companies in providing data after our request is disconcerting
Results from randomized trails in this review could not be used to confirm the observed beneficial cardiovascular effects found in cohort studies. The results regarding cardiovascular end-points and mortality must be interpreted with caution; none of the trials were designed to evaluate cardiovascular events, the number of randomized controlled trials included in the meta-analysis was low and the number of events was limited. Furthermore, study duration was relatively short in most cases. Also, a substantial number of studies did not report on specific adverse events. Randomized controlled trials are possibly not the best way of evaluating these adverse events, al least not when not designed for evaluating such endpoint and not endowed with a sufficiently long study duration
A considerable amount of heterogeneity in the primary efficacy analysis was noted. This heterogeneity could be explained by differences in primary research questions
We did not include the ADVANCE study in the meta-analyses. The ADVANCE investigated intense glucose control with gliclazide to a strategy with standard glucose control without gliclazide. Intensive glucose control itself (irrespective of the drug that is used) is associated with a lower HbA1c, increased risk for hypoglycemic events, weight increase and probably has beneficial effects on cardiovascular outcomes
Except for non-severe hypoglycemia risk, we were not able to make clinically relevant recommendations due a low number and quality of trails. Our conclusions regarding gliclazide as a second line treatment were not robust, due to a small number of trials.
We did not conduct separate analyses for each comparator class or looked at within-class difference because of scarcity of data. Furthermore, we did not conduct sensitivity analyses or meta-regression to examine the contribution of participants' baseline characteristics to the effect estimate of our primary outcome and did not conduct mixed treatment comparison/network meta-analysis. Exclusion of trials at high risk of bias in a sensitivity analysis did not relevantly alter the results of the main analysis, although this analysis included few trials.
Relative few studies used gliclazide as active comparator despite years of clinical experience, no need for dose adjustment in renal dysfunction, low costs and observational studies showing possible cardiovascular benefits. The risk of severe or confirmed hypoglycemia was extremely low with gliclazide. Gliclazide could have a relative favorable short-term safety profile; specifically compared to glimepiride, under the condition of not exceeding the maximum dose of 240 mg, without evidence for a loss of efficacy. The quality of reporting changes in weight in randomized controlled trials could benefit from substantial improvements. Although none of the trials were designed to evaluation cardiovascular end-points, the possibility of cardiovascular benefits as shown in observational studies warrants attention in future randomized trials.
An ethics statement was not required for this work.
The full dataset and technical appendix are available at request from the corresponding author.
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