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Address correspondence to: Jianwei Xuan, Health Economic Research Institute, Sun Yat-sen University, 132 East Waihuan Road, Guangzhou University City, Guangzhou 510006, China.
In the Guidelines for the Prevention and Control of Type 2 Diabetes in China (2017 edition), intensive lifestyle interventions are recommended for preventing the progression of impaired glucose tolerance (IGT) to type 2 diabetes mellitus. Acarbose and metformin can also be considered if intensive lifestyle modification has been ineffective for 6 months. But the effects of intensive lifestyle modification and glucose-lowering drug interventions that work best in the population with IGT are unclear. This network meta-analysis assessed the effectiveness of intensive lifestyle modification, acarbose, and metformin in treating populations with IGT.
Methods
We systematically searched both Chinese- and English-language databases, including China Knowledge, the Cochrane Library, Embase, PubMed, VIP, and Wanfang, for articles published between database inception and September 2019. Randomized, controlled clinical trials in patients with IGT treated with acarbose, metformin, and intensive lifestyle modification were assessed for eligibility. The data from all included studies were evaluated by 2 reviewers independently in accordance with the Cochrane Handbook for Systematic Reviews of Intervention version 6.0. A network meta-analysis was performed by using R software version 3.6.1.
Findings
The data from 53 randomized controlled trials were included in the review, with a sample size of 21,208 patients. Compared with the control group, the use of acarbose, metformin, and/or intensive lifestyle modification was associated with reduced rates of progression to diabetes (relative risks [RRs] [95% credible intervals]: acarbose, 0.37 [0.29–0.47]; metformin, 0.39 [0.30–0.50]; intensive lifestyle modification, 0.61 [0.50–0.73]). The surface under the cumulative ranking (SUCRA) value of acarbose was 88.35%, supporting that acarbose was more effective in reducing the rate of progression to diabetes compared with controls. With acarbose, metformin, and intensive lifestyle modification, the rates of achieving a normal glucose level were increased by RR = 2.1, 1.7, and 1.2, respectively when compared with control group. The SUCRA value of acarbose was 99.69%, supporting the optimal effect of acarbose in achieving a normal blood glucose level.
Implications
In this meta-analysis in patients with IGT, compared with controls, acarbose and metformin were associated with decreased rates of progression to diabetes and increased rates of achieving a normal glucose level. Acarbose use was associated with an increased rate of achieving a normal glucose level, while intensive lifestyle modification was not.
Prediabetes refers to the transition period from normal glucose metabolism to diabetes. At this stage, a patient's blood glucose level is higher than normal, but it does not meet the diagnostic criterion for diabetes.
According to the World Health Organization's 1999 Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications, IGT is defined as an FPG of <7.0 mmol/L and a 2-hour postprandial blood glucose (2hPG) level between 7.8 and 11.0 mmol/L. In China, the prediabetic population is defined as a group at high risk for diabetes based on the current guideline on the management of diabetes in China,
Without intervention, about 15.7% of cases of prediabetes progress to diabetes each year, of which about 6% to 10% of cases of IGT progress to type 2 diabetes each year.
In 2007, the direct medical costs related to diabetes and its complications in China were about 26 billion US dollars (USD), accounting for 18.2% of the total national health care costs (144.5 billion USD).
Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial.
Journal of the American Society of Nephrology.2003; 14: 108S-113S
intensive lifestyle modification and glucose-lowering drug interventions in populations with IGT effectively reduced the progression of IGT to diabetes. Based on those findings, the use of intensive lifestyle modification and glucose-lowering drugs at the prediabetes stage would be expected to reduce the number of diabetic patients and correspondingly decrease the economic burden and health care resource utilization related to diabetes and its complications in the long term.
The effects (ie, the rate of progression to diabetes and the rate of achieving a normal glucose level) of intensive lifestyle modification and glucose-lowering drug interventions have seldomly been compared head to head, especially in Asian populations. Little is understood about which of these interventions are optimal in a given population. This network meta-analysis compared and evaluated the effects of acarbose, metformin, and intensive lifestyle modifications in populations with IGT.
Materials and Methods
Eligibility Criteria and Search Strategies
The search strategy for this meta-analysis is shown in Supplemental Table I (see the online version at doi:10.1016/j.clinthera.2021.07.014). China Knowledge, the Cochrane Library, Embase, PubMed, VIP, and Wanfang were searched for randomized, controlled trials (RCTs) published between database inception and September 2019. Trials in populations with IGT, defined in the Guidelines for the Prevention and Control of Type 2 Diabetes in China (2017 edition)
as an FPG of <7.0 mmol/L and a 2hPG between 7.8 and 11.0 mmol/L, were included. Normal glucose level was defined as an FPG of <6.1 mmol/L and a 2hPG of <7.8 mmol/L.
Interventions included were acarbose, metformin, intensive lifestyle modification (including healthy diet, eg, increased vegetable intake and reduced alcohol and sugar intake; and regular exercise, ie, moderate-intensity activity for ≥20 min/d [or ≥150 min/wk]), and encouraging overweight or obese patients (body mass index of >25 kg/m2) to reduce weight by 7%. Only groups that received diet and exercise modification were included in this meta-analysis.
For intervention trials of glucose-lowering drugs, only groups that received monotherapy with the drugs of interest were included, regardless of dose and dosing schedules. Controls included placebo and no intervention or normal lifestyle modification (verbal education). No restriction was placed on complications, such as metabolic syndrome (eg, hypertension, hyperlipidemia, obesity) and cardiovascular disease (eg, coronary heart disease). Eligible trials had a follow-up period 1 year or longer.
The outcomes included were the rates of progression to diabetes and of achieving a normal blood glucose level. Studies were excluded if they included non-IGT populations, such as patients with elevated FPG or with other serious comorbidities (eg, IGT in pregnancy or after kidney transplantation), and/or if the outcome indicators did not meet the outcomes of interest of the present meta-analysis. Studies with unavailable full text, with only an abstract available, without a control group, or with self-controlled groups were excluded.
MeSH terms with key words were used in the search. There were 3 groups of search terms: (1) disease (impaired glucose tolerance, glucose Intolerance, IGT, prediabetes, and prediabetes); (2) treatment (metformin, acarbose, lifestyle intervention, lifestyle modification, intensive lifestyle modification, and intensive lifestyle modification); and RCTs (randomized controlled trial and controlled clinical trial). Because Chinese-language databases were searched and articles in Chinese were included, the corresponding Chinese words were also used in the search.
Data Extraction and Risk-for-Bias Assessment
Yue ZHANG and Yuyan FU independently reviewed the title, abstract, and full text of each retrieved article. Full texts were strictly selected in pairs according to the inclusion criteria established in the protocol by the 2 reviewers independently. Any controversial article was discussed by both reviewers to reach an agreement. Data were extracted from the selected literature and input into the formatted data-extraction chart, independently by both reviewers. The charts were compared by the 2 reviewers. All included studies were evaluated by the 2 reviewers independently, in accordance with the Cochrane Handbook for Systematic Reviews of Intervention version 6.0.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019. Available at: www.training.cochrane.org/handbook Dec 2020.
Discrepancies were resolved through discussion between the 2 researchers and assistance from a third Jianwei XUAN when needed. The risk for bias depended on how much the study satisfied the following criteria10: allocation sequence generation, allocation sequence concealment, blinding, selected outcomes reported, and other bias. The study would be considered as low risk for bias if all criteria were satisfied, but as high risk if no criteria were met.
Data Analysis
Analyses were performed using Bayesian random-effects models using R language in R software version 3.6.1 (http://www.rstudio.com). The analyses were conducted using Markov chain Monte Carlo simulation. Potential inconsistency between direct and indirect evidence in the network was assessed whenever there were feedback loops using a node-splitting approach and quantified using a Bayesian P value. Transitivity was assessed by comparison of the similarities between studies (including study design, study population, and study interventions). The I2 statistic was used to test for and quantify between-study heterogeneity. Results were compared directly and indirectly. Relative risk (RR) and 95% credible intervals were calculated using the Gemtc package in R software. Network plot was drawn to illustrate the relationships among the studies. A surface under the cumulative ranking (SUCRA) value (0 [ineffective intervention] to 1 [effective intervention]) was assigned to facilitate decision making by the researchers. Interventions were ranked according to the SUCRA values.
Data from 53 RCTs were included in the review, with a population size of 21,208 patients. Fourteen studies included were in English, and 39 were in Chinese. Figure 1 shows the selection algorithm. The trials included in the review were conducted in multiple countries, including Canada, China, Finland, Germany, India, Japan, the Netherlands, Thailand, and the United States. There were 10 multicenter trials, and the rest were single-center research studies. The durations of intervention varied from 1 to 6 years, with a mean of 2.07 years. The mean age of the patients was 53.17 years, and 56% were males. The mean body mass index was 27.09 kg/m2, and the mean hemoglobin A1c was 6%, with a mean preprandial glucose level of 6.15 mmol/L and a 2hPG of 9.16 mmol/L (see Supplemental Table II in the online version at doi:10.1016/j.clinthera.2021.07.014).
Figure 1Algorithm for the selection of studies to be included in this meta-analysis of the effects of acarbose, metformin, and intensive lifestyle modification in patients with impaired glucose tolerance.
The risk-assessment tool for bias in RCTs was used, as recommended in the Cochrane Handbook, to assess the risk for bias in the 53 selected RCTs. The results are shown in Supplemental Table III (see the online version at doi:10.1016/j.clinthera.2021.07.014). Among the included Chinese-language studies, 33 did not mention allocation sequence generation or the allocation sequence concealment,
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019. Available at: www.training.cochrane.org/handbook Dec 2020.
The preventive effect of metformin on schizophrenic inpatients with impaired glucose tolerance from becoming diabetes mellitus: a 3-year follow up study.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019. Available at: www.training.cochrane.org/handbook Dec 2020.
The preventive effect of metformin on schizophrenic inpatients with impaired glucose tolerance from becoming diabetes mellitus: a 3-year follow up study.
Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial.
Journal of the American Society of Nephrology.2003; 14: 108S-113S
Prevention of type 2 diabetes in adults with impaired glucose tolerance: the European Diabetes Prevention RCT in Newcastle upon Tyne. 9. UK. BMC Public Health,
2009
A community based primary prevention programme for type 2 diabetes integrating identification and lifestyle intervention for prevention: the Let's Prevent Diabetes cluster randomised controlled trial.
A study of the effects of acarbose on glucose metabolism in patients predisposed to developing diabetes: the Dutch Acarbose Intervention Study in Persons with Impaired Glucose Tolerance (DAISI).
Diabetes/Metabolism Research and Reviews.2008; 24: 611-616
Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial.
Journal of the American Society of Nephrology.2003; 14: 108S-113S
Prevention of type 2 diabetes in adults with impaired glucose tolerance: the European Diabetes Prevention RCT in Newcastle upon Tyne. 9. UK. BMC Public Health,
2009
A community based primary prevention programme for type 2 diabetes integrating identification and lifestyle intervention for prevention: the Let's Prevent Diabetes cluster randomised controlled trial.
A study of the effects of acarbose on glucose metabolism in patients predisposed to developing diabetes: the Dutch Acarbose Intervention Study in Persons with Impaired Glucose Tolerance (DAISI).
Diabetes/Metabolism Research and Reviews.2008; 24: 611-616
Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial.
Journal of the American Society of Nephrology.2003; 14: 108S-113S
Prevention of type 2 diabetes in adults with impaired glucose tolerance: the European Diabetes Prevention RCT in Newcastle upon Tyne. 9. UK. BMC Public Health,
2009
A study of the effects of acarbose on glucose metabolism in patients predisposed to developing diabetes: the Dutch Acarbose Intervention Study in Persons with Impaired Glucose Tolerance (DAISI).
Diabetes/Metabolism Research and Reviews.2008; 24: 611-616
Prevention of type 2 diabetes in a primary healthcare setting: three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance.
Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.
The Lancet Diabetes & Endocrinology.2017; 5: 877-886
Data on the following interventions were included in this review: placebo (control); no intervention or normal lifestyle modification (verbal education); and acarbose, metformin, and intensive lifestyle modification (positive intervention). Of the 53 selected RCTs, 26 were RCTs of acarbose compared with other interventions; 24, metformin compared with other interventions; and 19, intensive lifestyle modification. There were 42 RCTs involving 2 interventions, 5 RCTs involving 3 interventions; and 4 RCTs involving 4 interventions. The network diagram of the interventions is shown in Figure 2.
Figure 2Network diagram of the interventions included in this meta-analysis of the effects of acarbose, metformin, and intensive lifestyle modification in patients with impaired glucose tolerance.
The rates of progression to diabetes and achieving a normal blood glucose level in the 53 selected RCTs are summarized in Supplemental Table IV (see the online version at doi:10.1016/j.clinthera.2021.07.014). A review of some related literature on subgroup analysis
suggested that the duration of intervention and the research population could largely affect clinical outcomes; therefore, in the present meta-analysis, subgroup analyses of duration and population were conducted. Groups were assigned to 1 of 3 subgroups according to the duration of interventions: 1 year, 2 years, and >3 years. Analysis was conducted separately in Asian and non-Asian populations (see Supplemental Figure in the online version at doi:10.1016/j.clinthera.2021.07.014).
Progression to Diabetes
All 53 selected studies reported the prevalence of diabetes after intervention in patients with IGT. Network meta-analysis was performed on the clinical results of the 53 RCTs. The global heterogeneity analysis showed high heterogeneity (I2 = 79.46%), so a random-effects model was used. Consistency analysis results showed that there was no inconsistency between direct comparison and indirect comparison (P = NS) (see Supplemental Table V in the online version at doi:10.1016/j.clinthera.2021.07.014).
Results of comparisons between each of intervention are shown in Figure 3. Compared with controls, the use of acarbose, metformin, and intensive lifestyle modification in patients with IGT was associated with a reduced rate of progression to diabetes (RR [95% credible intervals]: acarbose, 0.37 [0.29–0.47]; metformin, 0.39 [0.30–0.50]; intensive lifestyle modifications, 0.61 [0.50–0.73]) (Figure 3). The hypoglycemic drugs (acarbose and metformin) were significantly more effective than intensive lifestyle modifications. There was no significant difference between acarbose and metformin in terms of prevalence of diabetes.
Figure 3Relative risk ratios (95% credible intervals) of the rates of progression to diabetes and of achieving a normal blood glucose level in patients with impaired glucose tolerance. ILM = intensive lifestyle modification.
The intervention that had the highest probability of ranking first with the highest SUCRA value was acarbose (SUCRA = 88.35%), indicating that acarbose had the highest likelihood of being the most effective intervention in diabetes risk reduction (Figure 4 and see Supplemental Table VI in the online version at doi:10.1016/j.clinthera.2021.07.014).
Figure 4Histograms of ranking probability (A) and cumulative ranking probability (B) of progression to diabetes with the 4 interventions—placebo or no intervention (control; 10% grey), acarbose (black), metformin (50% grey), and intensive lifestyle modification (25% grey)—in patients with impaired glucose tolerance. SUCRA = surface under the cumulative ranking.
Eight subgroup analyses were performed to further evaluate the prevalence of diabetes. The prevalence of diabetes was analyzed in the following subgroups: (1) Asian population; (2) population with at least 1 year of intervention; (3) Asian population with at least 1 year of intervention; (4) non-Asian population with at least 1 year of intervention; (5) Asian population with at least 2 years of intervention; (6) all patients with at least 3 years of intervention; (7) Asian population with at least 3 years of intervention; and (8) non-Asian population with at least 3 years of intervention.
A random-effects model was used in the analyses of the subgroup of all Asian patients and of the subgroup of all patients with at least 3 years of intervention, because the results from their network meta-analyses of the selected literature showed high heterogeneity (I2 = 76.29% and 79.88%, respectively), while a fixed-effects model was used for the rest of the subgroups, as heterogeneity was not statistically significant. The prevalence of diabetes was lowest in the metformin group with a duration of intervention of 1 year, and in the acarbose group with a duration of intervention of at least 2 years. In the Asian population, the prevalence of diabetes was lower with acarbose and metformin than with intensive lifestyle modifications, and vice versa in the non-Asian population. All interventions showed a reduction in the prevalence of diabetes compared to controls in all subgroups (Figure 5).
Figure 5Rates of progression to diabetes among subpopulations of patients with impaired glucose tolerance (IGT).
A total of 32 studies reported the rate of achieving normal glucose level in patients with IGT; 29 were published in Chinese, and 3, in English. A random-effects model was adopted as the network meta-analysis of the results of the 32 RCTs showed high heterogeneity (I2 = 64.90%). Consistency analysis results showed no inconsistency between direct comparison and indirect comparison (P = NS) (see Supplemental Table V in the online version at doi:10.1016/j.clinthera.2021.07.014).
Compared with controls, acarbose, metformin, and intensive lifestyle modification were associated with an increased rate of achieving a normal glucose level (Figure 3). The hypoglycemic drugs (acarbose and metformin) were significantly more effective than intensive lifestyle modifications. Acarbose and metformin were not significantly different in terms of the rate of achieving a normal glucose level (Figure 3).
The intervention most likely to be ranked first and with the highest SUCRA value (SUCRA = 99.69%) was acarbose, indicating that acarbose was most likely to be the intervention most effective in restoring normal blood glucose (Figure 6 and see Supplemental Table VI in the online version at doi:10.1016/j.clinthera.2021.07.014).
Figure 6Histograms of ranking probability (A) and cumulative ranking probability (B) of achieving a normal blood glucose level with the 4 interventions—placebo or no intervention (control; 10% grey), acarbose (black), metformin (50% grey), and intensive lifestyle modification (25% grey)—in patients with impaired glucose tolerance. SUCRA = surface under the cumulative ranking.
A fixed-effects model was used in all subgroup analyses, as no statistically significant heterogeneity was shown from the network meta-analysis results. Acarbose and metformin were associated with increased rates of achieving a normal glucose level in nearly all subgroups. The differences between intensive lifestyle modification and placebo were not significant in any of the subgroup analyses, but the results showed a nonsignificant trend toward an increased rate of achieving normal glucose with intensive lifestyle modification in all subgroups (Figure 7).
Figure 7Rates of achieving a normal blood glucose level among subpopulations of patients with impaired glucose tolerance (IGT).
In this network meta-analysis, acarbose and metformin were associated with greater reductions in the rate of progression to diabetes compared with that with intensive lifestyle modification in the general population with IGT. Subgroup analysis was performed because the it was found that the duration of the intervention and the characteristics of the study population had great impact on the results of the network meta-analysis. The effect of metformin was the greatest if the duration of the intervention was 1 year, and acarbose was most effective if the intervention was 2 years or longer. Acarbose and metformin were more efficacious compared with intensive lifestyle modification in the Asian population, and vice versa in non-Asian population. The results of the network meta-analysis of the rate of achieving a normal blood glucose level were similar to the findings on the rate of progression to diabetes. Acarbose was most efficacious, and intensive lifestyle modification was the least efficacious, in the analysis of all patients (ie, without subgroup analysis). The trends found in 4 subgroups (the Asian population, the population with at least 1 year of intervention, the non-Asian population with at least 1 year of intervention, and the Asian population with at least 2 years of intervention) were the similar to the results from the overall population (ie, no subgroup analysis). All analyses indicated that acarbose was most efficacious and that intensive lifestyle modification was least efficacious.
Although lifestyle modification is considered to be a more efficient intervention compared with pharmacologic treatments in the reduction of progression to diabetes in patients with IGT,
the present meta-analysis showed discrepancies between Asian and non-Asian populations. These findings may have been attributable to the intensity of implementation and the degree of obesity in patients, which can affect the efficacy of intensive lifestyle modification. Obesity has been a serious health problem in the Western world for a long time and is largely attributed to lifestyle, in particular poor diet and activity level. As a result, lifestyle modification has always been the main focus of weight control and obesity management. As the relationship between obesity and an increased risk for diabetes has been widely understood,
and lifestyle modification has been proven to be among the most efficient intervention for weight control, lifestyle modification is associated with the best outcomes in the prevention of diabetes.
Behavioral and pharmacotherapy weight loss interventions to prevent obesity-related morbidity and mortality in adults: updated evidence report and systematic review for the US Preventive Services Task Force.
However, the population in the present meta-analysis included significantly more non-Asians than Asians, with non-Asians requiring more intensive and comprehensive lifestyle modification. In addition, given that the severity of obesity is greater in non-Asians, intensive lifestyle modification may have a greater impact on this population, and a limited effect in the Asian population, as they may be less obese.
The gastrointestinal (GI)-related adverse effects of acarbose are well known. In the clinical trial STOP-NIDDM,
83% of patients in the acarbose group experience gastrointestinal adverse events compared with 60% in the placebo group; this difference was statistically significant. Although the GI-related adverse events were deemed as mild to moderate and no serious adverse events were considered as related to acarbose use, its widespread use may still be affected by its adverse-events profile. However, observational studies of acarbose have reported lower rates of GI-related adverse events. In a 2013 observational study, the population of which consisted of about 80% East Asian patients, the rates of drug-related GI adverse events were reported to be 1.49% for flatulence, 0.57% for abdominal distension, and 0.48% for diarrhea.
A multinational, observational study to investigate the efficacy, safety and tolerability of acarbose as add-on or monotherapy in a range of patients: the GlucoVIP Study.
A multinational, observational study to investigate the efficacy, safety and tolerability of acarbose as add-on or monotherapy in a range of patients: the GlucoVIP Study.
The discrepancy of the prevalences of these adverse events may have been due to under-reporting of the events known to be associated with acarbose, but in general, the prevalence of overall events in clinical practice is lower than that in clinical trials, as the GI-related adverse effects related to acarbose use in most patients are temporary. These events can be minimized by starting with low doses and gradually increasing to the target dose. Therefore, the use of acarbose is reasonable and feasible as its clinical benefits may outweigh its risks in Asian populations with IGT.
Our network meta-analysis is the first to focus on Asian populations in the study the impact of intensive lifestyle modification on the rates of progression to diabetes and of achieving a normal glucose level. As shown in the Results, the impact of intensive lifestyle modification may not be the same in Asian versus non-Asian populations with IGT. In addition, the prophylactic effect of acarbose and metformin have been reported to be dependent on race and duration of intervention. The present analysis was the first to demonstrate this the disparate effects of diabetes prophylaxis, which is meaningful in directing clinical decisions. Also, network meta-analysis was conducted instead of a simple meta-analysis because a head-to-head comparison study of the effect of the three selected interventions (acarbose, metformin, intensive lifestyle modification) would otherwise have been limited. Results of a network meta-analysis can provide a complete profile for all 3 interventions, as well as the ranking for all of the outcomes. The findings from the present analysis may thus be more comprehensive and informative in assisting with clinical decisions regarding the selection of the most appropriate intervention strategies for diabetes prevention in the prediabetich population.
The present results show clinical significance in the management of the populations with IGT. While intensive lifestyle modification may be an efficient intervention in glucose management and diabetes prevention, achieving the intensity level in trials is not always feasible in clinical practice. The efficacy of lifestyle modification in populations with IGT would not be optimized, especially in the Asian population according to the present results. Therefore, pharmacologic intervention may be warranted in addition to some lifestyle modification for better glucose management and reduction in the risk for diabetes. This analysis provides evidence support for clinicians with pharmacologic intervention options, where acarbose may demonstrate greater efficacy than metformin in glucose management in Asian populations with IGT. It is hoped that these results with raise awareness among clinicians with regard to the treatment of this specific population.
The present analysis had some limitations. Search terms were selected from both Chinese and English, the translation of which is not always equal. This issue may have impaired the sample size of the analysis. However, MeSH terms were used so that the search should be comprehensive. Also, the intensity of the implementation of intensive lifestyle modification, which may be have affected efficacy, may have been between trials. The intensity of lifestyle modification in different race groups could not be quantified in this analysis due to incomplete information available from the studies. Therefore, the effect of lifestyle-intervention intensity on the rates of progression to diabetes and of achieving a normal glucose level was not assessable. Another limitation was that several doses/dosing regimens were used in the metformin invention trials. A subgroup analysis of the effects of different metformin doses and dosing regimens was not conducted. A separate study with more details should be conducted to determine whether different metformin regimens would affect the outcomes. Lastly, the present meta-analysis was based on data from clinical trials, limiting the viability of the intervention (lifestyle modification) and the generalizability of the results.
Due to these limitations, future studies are warranted to understand the true benefits and treatment position of acarbose in populations with IGT. While conducting a head-to-head clinical trial may not be feasible both financially and ethnically, an observational study may be the design appropriate for answering this question. This topic will continue to be explored with the development of an observational study to resolve the limitations in the present analysis. Data from clinical practice, such as those from insurance claims or electronic medical records, would be considered for future analysis.
Conclusions
In the present study in patients with IGT, compared to controls, acarbose and metformin were associated with a decrease rate of progression to diabetes and an increased rate of achievement of a normal glucose level. Intensive lifestyle modification was also associated with a reduced rate of progression to diabetes, but not with an increased rate of achieving a normal glucose level, although a positive trend was seen. Due to the inability to quantify lifestyle-modification intensity, further studies are needed for a better understanding of the relationship between intensity of lifestyle modification and the rates of progression to diabetes and of achieving a normal glucose level.
Author Contributions
Y. Zhang and Y. Fu contributed equally to this work as cofirst authors; they contributed to the study design, literature review, data collection, and data analysis. Y. Mu contributed as a medical advisor. Y. Huang contributed to manuscript writing. J. Xuan contributed to the conception, design, execution, and analysis of the research.
DISCLOSURES
This study was sponsored by Bayer Healthcare Co Ltd. The authors have indicated that they have no other conflicts of interest with regard to the content of this article. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.
References
Chinese Experts Consensus of clinical intervention for pre-diabetes (draft for comments)
Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial.
Journal of the American Society of Nephrology.2003; 14: 108S-113S
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019. Available at: www.training.cochrane.org/handbook Dec 2020.
The preventive effect of metformin on schizophrenic inpatients with impaired glucose tolerance from becoming diabetes mellitus: a 3-year follow up study.
Prevention of type 2 diabetes in adults with impaired glucose tolerance: the European Diabetes Prevention RCT in Newcastle upon Tyne. 9. UK. BMC Public Health,
2009 (342-342)
A community based primary prevention programme for type 2 diabetes integrating identification and lifestyle intervention for prevention: the Let's Prevent Diabetes cluster randomised controlled trial.
A study of the effects of acarbose on glucose metabolism in patients predisposed to developing diabetes: the Dutch Acarbose Intervention Study in Persons with Impaired Glucose Tolerance (DAISI).
Diabetes/Metabolism Research and Reviews.2008; 24: 611-616
Prevention of type 2 diabetes in a primary healthcare setting: three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance.
Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.
The Lancet Diabetes & Endocrinology.2017; 5: 877-886
Behavioral and pharmacotherapy weight loss interventions to prevent obesity-related morbidity and mortality in adults: updated evidence report and systematic review for the US Preventive Services Task Force.
A multinational, observational study to investigate the efficacy, safety and tolerability of acarbose as add-on or monotherapy in a range of patients: the GlucoVIP Study.
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