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Drug & Lifestyle Intervention Prevents Diabetes in Impaired Glucose Tolerance
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"Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis"
BMJ, doi:10.1136/bmj.39063.689375.55 (published 19 January 2007)
Clare L Gillies, medical statistician1, Keith R Abrams, professor of medical statistics1, Paul C Lambert, senior lecturer in medical statistics1, Nicola J Cooper, MRC senior training fellow in health services research1, Alex J Sutton, reader in medical statistics1, Ron T Hsu, clinical senior teaching fellow in epidemiology and public health1, Kamlesh Khunti, clinical senior lecturer2
1Centre for Biostatistics and Genetic Epidemiology, Department of Health Sciences, University of Leicester, Leicester LE1 7RH
2Clinical Division of General Practice and Primary Health Care, Department of Health Sciences, University of Leicester
WHAT IS ALREADY KNOWN- Type 2 diabetes can reduce life expectancy by up to 15 years and accounts for around 5% of NHS (UK) resources People with impaired glucose tolerance are at greater risk of developing type 2 diabetes Lifestyle and pharmacological interventions may be effective at delaying or preventing type 2
diabetes
WHAT THIS STUDY ADDS
Interventions can halve the risk of type 2 diabetes in people with impaired glucose tolerance Lifestyle interventions seem to be at least as effective as pharmacological interventions. Additional considerations: overall effectiveness of a potentially lifetime intervetion; cost effectivenessess; side effects and adverse events over a long-term.
In 2000 an estimated 171 million people in the world had diabetes, and the numbers are projected to double by 2030.26 Interventions to prevent type 2 diabetes will therefore have an important role in future health policies.
People with impaired glucose tolerance (glucose challenge test) have a high risk of developing type 2 diabetes. A number of studies report higher rates of impaired glucose tolerance, impaired fasting glucose, and diabetes among HIV+ individuals than in the general population. HIV+ individuals tend to have more risk factors: elevated triglycerides, sedentary lifestyle, poor diet, familial or genetic predisposition, and perhaps exposure to ART that increases risk for glucose abnormalities. Glucose abnormalities increase risk for heart disease. As well, a number of studies find increased risk for heart disease in HIV+ individuals. Metabolic syndrome can contribute to fatty liver both in patients with or without hepatitis C or hepatitis B.
The researchers included all relevant papers from Medline, Embase, and the Cochrane library from 1979 through July 2006 on interventions including diet, exercise or the combination, oral diabetes drugs, the anti-obesity drug Xenical (orlistat), and the Chinese herbal remedy jiangtang bushen recipe. Rezulin (troglitazone) was excluded because liver toxicity caused it to be withdrawn. Most of the studies appeared to provide standard advice and/or education in addition to the intervention. Included in this analysis were randomised controlled trials that evaluated interventions to delay or prevent type 2 diabetes in individuals with impaired glucose tolerance. 21 trials met the inclusion criteria, of which 17, with 8084 participants with impaired glucose tolerance, reported results in enough detail for inclusion in the metaanalyses.
The authors concluded: "Lifestyle and pharmacological interventions
reduce the rate of progression to type 2 diabetes in people with impaired glucose tolerance. Lifestyle interventions seem to be at least as effective as drug
treatment". Diet and exercise reduced risk for developing diabetes by 33-50%. The authors said the study data provided 'overwhelming evidence' in support of intervention to prevent diabetes. "Both forms of pharmacological intervention-oral
diabetes drugs and the anti-obesity drug-also showed a highly significant benefit of intervention compared with control".
The study omitted the Tripodw34 study and the arm of the diabetes prevention programme (DPP) trialw1 that assessed troglitazone from the meta-analyses as troglitazone is no longer a viable intervention for delaying diabetes because of safety concerns. Both trials showed a significant reduction in the development of diabetes with troglitazone.
Since we carried out our literature search a further relevant trial has been published-the diabetes reduction assessment with ramipril and rosiglitazone medication (DREAM) trial.28 29 Unfortunately we could not include it as we were unable to obtain relevant data. This trial reported only combined results for individuals with either impaired glucose tolerance or impaired fasting glucose so it is not directly comparable with our meta-analyses here, but in summary they found the ACE inhibitor ramipril did not significantly reduce the incidence of diabetes (hazard ratio 0.91, 0.80 to 1.03) but rosiglitazone, an oral diabetes drug, did (0.38, 0.33 to 0.44). Heneghan et al have recently expressed concern over the rate of cardiovascular events in the rosiglitazone group.30
RESULTS
The study shows interventions can delay or prevent diabetes from occurring. All the meta-analyses provided overwhelming evidence to support the benefit of interventions to prevent or delay type 2 diabetes.
The pooled effect for all forms of lifestyle interventions gave a hazard ratio of 0.51 (95% confidence interval 0.44 to 0.60, P<0.001) (fig 2), indicating a relative 49% reduction in risk of developing diabetes.
When they separately considered diet, exercise, and diet and exercise in combination they all showed a similar reduction in risk (hazard ratios 0.67, 0.49 to 0.92, P=0.013; 0.49, 0.32 to 0.74, P=0.001; and 0.49, 0.40 to 0.59, P<0.001, respectively). In other words diet reduced risk for developing diabetes by 33%, exercise by 51%, diet+exercise by 51%.
Among the trials overall, the five-year cumulative incidence of diabetes was 37.1%, similar to that found with other studies. Baseline risk of type 2 diabetes was not consistent between trials and ranged from 2.6 to 30.0 cases per 100 person-years.
The absolute reduction in the occurrence rate of diabetes by intervention was:
-- 15.8% for lifestyle intervention (95% CI 19.8% to 11.9%),
-- 9.3% for oral diabetes drugs (95% CI 12.4% to 6.7%),
-- 18.4% for Xenical (95% CI 24.6% to 13.1%), and
-- 22.7% for the jiangtang bushen (37.9% to -11.7%).
The numbers needed to treat for benefit were:
-- 6.4 for lifestyle intervention (95% CI 5.0 to 8.4),
--10.8 for oral diabetes drugs (95% CI 8.1 to 15.0),
-- 5.4 for Xenical (95% CI 4.1 to 7.6), and
-- 4.0 for jiangtang bushen (NNT for harm 16.9 to NNT for benefit 24.8).
Both forms of pharmacological intervention-oral diabetes drugs and the anti-obesity drug-also showed a highly significant benefit of intervention compared
with control (hazard ratios 0.70, 0.62 to 0.79, P<0.001, and 0.44, 0.28 to 0.69, P<0.001, respectively; fig 3). The one trial that assessed a herbal intervention
had a favourable hazard ratio, although this was not significant (0.32, 0.03 to 3.07, P=0.323). In other words:
For pharmacologic interventions, the results were:
--Xenical reduced relative risk by 56% (HR 0.44, 95% CI 0.28 to 0.69, P<0.001), and
-- Oral diabetes drugs reduced the relative risk of developing diabetes by 30% compared to control (HR 0.70, 95% CI 0.62 to 0.79, P<0.001).
The one trial that assessed a herbal intervention had a favourable hazard ratio, jiangtang bushen recipe tended to reduce risk compared with standard diabetes advice, although this was not significant (0.32, 0.03 to 3.07, P=0.323).
For lifestyle intervention each one unit increase in the mean body mass index at baseline led to a decrease in the hazard ratio of _7.3% (_13.6 to _0.9), P=0.029. This provides evidence that as the average body mass index at baseline increased, the effectiveness of the lifestyle intervention also increased, meaning that lifestyle interventions were more effective in trials that recruited participants with higher body mass index values.
Adverse events
Most adverse events possibly related to the intervention drugs were gastrointestinal, hypoglycemia, or, in the case of troglitazone, a decline in liver function. Although adverse events varied widely between trials, all were more
commonin the intervention than in the placebo groups.
Regarding the long term impact of interventions, the diabetes prevention programme reported progression to type 2 diabetes after withdrawal from troglitazone and metformin.w127 Results showed the treatment effect was not sustained after treatment stopped. It is therefore important that longer term follow-up is assessed and also that patients are comfortable during treatment.
Even minor adverse events, such as the gastrointestinal adverse effects summarised here, take on greater importance if interventions have to be taken
for life. Generally we can assume that lifestyle interventions incur fewer and less serious side effects than drug treatment, but, as with the pharmacological interventions, their effect may not be permanent and advice on diet and exercise may need to be reinforced on a regular basis. Additionally, although compliance was high in these trials, we still do not know whether compliance could be maintained outside of a trial setting.
AUTHOR CONCLUSIONS
While we have shown the clinical effectiveness of both pharmacological and lifestyle interventions in significantly reducing the risk of developing type 2 diabetes
in people with impaired glucose tolerance, several issues remain. Determining the best approach to intervention, be it pharmacological or lifestyle, depends not
just on their performance in trial settings but on issues not yet resolved. For pharmacological interventions adverse effects need to be fully understood to enable potential harms and benefits to be assessed. Also should what is fundamentally a lifestyle issue really be treated with a lifelong course of medication? As compliance is the key to the success of lifestyle interventions,
strategies to assist compliance need to be carefully thought through and implemented. Finally, the evidence meta-analysed here is on patients already identified as having impaired glucose tolerance. The overall effectiveness and cost effectiveness of a policy of prevention or delay of diabetes must consider how different identification and screening strategies would affect the overall evaluation of such policies.
Most of the hazard ratios and incidence rate ratios included in the meta-analyses were unadjusted, except those used for Wein et al,w35 STOP-NIDDM,w33 and
Indian diabetes prevention programme (IDDP).w39 As trial arms were similar at baseline for unadjusted and adjusted characteristics, it is unlikely that adjustment
introduced any inconsistency into the meta-analyses.
From the meta-regression results it seems that lifestyle interventions may have a greater impact the higher the mean baseline body mass index. Use of study level data, however, can lead to problems of aggregation bias, where there seems to be an association when in fact one does not exist at an individual
There was great diversity in study quality, with the lifestyle trials generally scoring lower on the Jadad score, because blinding of treatment was not possible.
The trial of Heymsfield et alw28 combined data from three randomised controlled trials on weight loss. Though it was not a true single study we treated it as such for the purposes of these analyses as results were not available for each trial individually. All three trials were almost identical in their design and had not been
individually powered to assess incidence of type 2 diabetes as an outcome.
Background & additional study information
Type 2 diabetes is a growing health problem, with the prevalence of the disease set to rise dramatically in Westernised societies. Individuals with diabetes have
a life expectancy that can be shortened by as much as 15 years, with up to 75% dying of macrovascular complications.1 In England around 1.3 million people
are currently diagnosed with diabetes and incidence is increasing in all age groups.2 Around 5% of total NHS resources and up to 10% of hospital inpatient resources is used for the care of people with diabetes.2 Interventions to delay or even prevent type 2 diabetes have the potential to improve the health of a population and reduce the burden of healthcare costs.
People with impaired glucose tolerance have a high risk of developing type 2 diabetes,3 and consequently many trials of interventions for prevention of type 2
diabetes have focused on such individuals. Interventions assessed have been diverse and include pharmacological, lifestyle, and herbal remedies.
Several current reviews have been carried out on prevention of type 2 diabetes,1 4-9 covering different aspects such as pharmacological interventions or the
effects of weight loss. We consolidated the evidence by considering all forms of intervention in a systematic review and undertook a meta-analysis.
Study objective: Objective To quantify the effectiveness of pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance.
Data sources: Medline, Embase, and the Cochrane library searched up to July 2006. Expert opinions sought and reference lists of identified studies and any relevant published reviews checked. Study selection Randomised controlled trials that evaluated interventions to delay or prevent type 2 diabetes in individuals with impaired glucose tolerance.
Study selection: Randomised controlled trials that evaluated interventions to delay or prevent type 2 diabetes in individuals with impaired glucose tolerance.
21 trials met the inclusion criteria, of which 17, with 8084 participants with impaired glucose tolerance, reported results in enough detail for inclusion in the metaanalyses.
Study selection was restricted to randomised controlled trials to ensure the inclusion of only high quality evidence. Studies had to have an intervention to delay or prevent type 2 diabetes in a sample or subsample of individuals with impaired glucose tolerance. Development of diabetes was a required outcome measure.
Interventions were either lifestyle, comprising diet and exercise interventions, or pharmacological and herbal, comprising oral diabetes drugs, the anti-obesity
drug orlistat, and jiangtang bushen recipe, a Chinese herbal remedy.
We identified 11 383 articles by the Medline and Embase searches (fig 1). We assessed the titles and abstracts and obtained the full articles for any that
were potentially relevant (see web reference list on bmj.com). Of these, 27 were in English, and they reported 22 trials. A further study, the early diabetes
intervention trial (EDIT),w3 w4 was identified in a published review.1 We excluded six because the treatment allocation process had not been fully randomisedw5-w8 or the primary aim of the administered intervention was not to prevent type 2 diabetes.w9-w11 We additionally assessed 10 foreign language papers, four Chinese, three Japanese, one Spanish, one Russian, and one German. Four were excluded as they were discussion papers rather than presenting original findings,w12-w15 and one was excluded as although it met most of our inclusion criteria, type 2 diabetes was not a reported outcome.w16 Of the five remaining relevant articles, two reported results from the Japanese diabetes prevention programme (JDPP)w17 w18 and three were results from three separate Chinese studies.w19-w21
Twenty one trials met the inclusion criteria for this systematic review,w1 w2 w17-w39 and 17 of them, with 8084 participants, were included in the meta-analyses (tables 1-4). The trials were heterogeneous in terms of interventions, ethnicity, weight, and age. Because of the time period covered by the trials (1979-2006) several definitions for type 2 diabetes and impaired glucose tolerance had been used.18-22 Most definitions were similar: for type 2 diabetes they involve a plasma glucose reading of Γ11.1 mmol/l two hours after a 75 g glucose load and a
fasting plasma glucose concentration of Γ7.8 mmol/l.
For impaired glucose tolerance the definition is 7.8- 11.1 mmol/l two hours after a glucose load. In 1997 the American Diabetes Association revised the criteria21 and the fasting plasma glucose concentration for diagnosis of type 2 diabetes was lowered from Γ7.8 mmol/l to Γ7.0 mmol/l. The World Health Organization
endorsed this reduction. Seven of the more recent studies in our review used this lower threshold in their definitions. We did not included three relevant studies in the
meta-analyses because they reported insufficient data and we could not obtain further data from the authors.w3 w4 w17 w18 w36
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