An Evidence Map of Systematic Reviews to Inform Interventions in Prediabetes

Can J Diabetes 36 (2012) 281e291

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Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com

Review

An Evidence Map of Systematic Reviews to Inform Interventions in Prediabetes Kavita Singh BSc PHM, RPh, MPH a, Mohammed Ansari MD, MMedSc, MPhil a, James Galipeau PhD a, Chantelle Garritty BA, DCS, MSc a, Erin Keely MD, FRCPC b, c, Janine Malcolm MD, FRCPC b, c, Mistrel Pratt MES a, Becky Skidmore MLS a, Alexander Sorisky MD, FRCPC b, c, * a

Centre for Practice-Changing Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada c Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 March 2012 Received in revised form 15 June 2012 Accepted 22 June 2012

Impaired glucose tolerance and impaired fasting glucose, referred to as prediabetes, are predisease states that may progress to type 2 diabetes mellitus. The value of intervening in these states, especially with respect to cardiovascular outcomes, is unclear. The purpose of this study was to develop a broad synopsis of the available literature through an evidence map of systematic reviews about interventions in adults with prediabetes. The Cochrane Library Issue 4, 2011, Ovid MEDLINE (1946eJanuary 4, 2012) and grey literature were searched. Studies were selected according to defined eligibility criteria. Fourteen relevant systematic reviews, of mostly high quality, were retrieved. The majority of reviews evaluated pharmacotherapeutic interventions or diet/exercise/lifestyle. A few reviews assessed complementary alternative medicine, behavioural strategies, standard prevention education or gastric bypass surgery. Very few reviews reported data on clinical cardiovascular endpoints. Most reviews reported either shorter-term surrogate markers of cardiovascular outcomes or progression to type 2 diabetes mellitus. Based on an assessment of authors’ overall conclusions, the value of pharmacotherapeutic interventions and diet/exercise/lifestyle ranged from beneficial to inconclusive, behavioural strategies were beneficial, and gastric bypass surgery was probably beneficial. The value of complementary alternative medicine was inconclusive. A considerable amount of evidence pertaining to interventions in prediabetes exists. Future research should synthesize the available systematic review evidence base in an overview of reviews. In addition, more primary research should be conducted to assess clinical cardiovascular endpoints. Ó 2012 Canadian Diabetes Association

Keywords: cardiovascular disease diabetes mellitus glucose intolerance impaired fasting glucose impaired glucose tolerance prediabetes primary prevention

r é s u m é Mots clés: maladie cardiovasculaire diabète sucré intolérance au glucose altération de la glycémie à jeun diminution de la tolérance au glucose prédiabète prévention primaire

La diminution de la tolérance au glucose et l’altération de la glycémie à jeun, qui sont associées au prédiabète, sont des états présents avant la maladie pouvant évoluer vers le diabète sucré de type 2. La valeur de l’intervention sur ces états, particulièrement en ce qui concerne l’évolution cardiovasculaire, est imprécise. Le but de cette étude était d’élaborer une synopsis générale de la littérature disponible par un plan de données des revues systématiques sur les interventions chez les adultes ayant un prédiabète. La publication 4 de la librairie Cochrane 2011, Ovid MEDLINE (1946 au 4 janvier 2012) et la littérature grise ont été scrutées. Les études ont été choisies selon des critères d’admissibilité définis. Quatorze revues systématiques pertinentes, la plupart de grande qualité, ont été extraites. La majorité des revues évaluaient les interventions pharmacothérapeutiques, ou la diète, l’exercice et le mode de vie. Quelques revues évaluaient la médecine complémentaire, les stratégies comportementales, l’éducation préventive standard ou le pontage gastrique. Très peu de revues rapportaient des données sur les critères de jugement cardiovasculaires. Au lieu de cela, la plupart des revues rapportaient soit les critères de substitution à court terme de l’évolution cardiovasculaire ou de la progression vers le diabète sucré de type 2. Selon l’évaluation des conclusions de l’ensemble des auteurs, la valeur des interventions pharmacothérapeutiques, et la diète, l’exercice et le mode de vie allaient de bénéfiques à peu concluantes, les stratégies comportementales étaient avantageuses et le pontage gastrique était probablement avantageux. La valeur de la médecine complémentaire était peu concluante. Un nombre considérable de

* Address for correspondence: Alexander Sorisky, Ottawa Hospital Research Institute, General Campus, Office C-4421, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. E-mail address: [email protected] (A. Sorisky). 1499-2671/$ e see front matter Ó 2012 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2012.06.004

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preuves concernant les interventions lors d’un prédiabète existent. D’autres recherches devraient synthétiser la revue systématique disponible fondée sur des données probantes dans un aperçu de revues. En outre, plus de recherches primaires devraient être menées pour évaluer les critères de jugement cardiovasculaires. Ó 2012 Canadian Diabetes Association

Introduction Type 2 diabetes mellitus is preceded by an intermediate stage of impaired glucose metabolism, often referred to as prediabetes. The term prediabetes was first introduced in the literature in 1965 (1). Subsequent input by the World Health Organization (WHO) and the American Diabetes Association (ADA) defined diagnostic thresholds to classify patients with prediabetes as having either impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or both. Although there is still ongoing debate as to whether IGT and IFG should be categorized as diseases, evidence has shown that they are risk factors for the development of diabetes and adverse cardiovascular outcomes (2). IGT is characterized by peripheral insulin resistance and a defect in late-phase insulin secretion response (3,4). IFG is characterized by hepatic insulin resistance (3), leading to elevated hepatic glucose output, and a defect in early-phase insulin secretion response with preserved late-phase insulin secretion (2,4). IGT is diagnosed based on the plasma glucose level 2 hours after a 75 g oral glucose tolerance test (OGTT) whereas IFG is diagnosed based on the fasting plasma glucose level (5). Since 1965, the WHO has made several revisions to the diagnostic criteria for IGT (WHO 1965, WHO 1980, WHO 1985 and WHO 1999) (5). The most current definition for IGT by WHO (1999) and ADA (2003) is a plasma glucose level of 7.8 to 11.0 mmol/L after an OGTT (5). This glycemic range was chosen based on data showing increased incidence of type 2 diabetes (5). In practice, a fasting plasma glucose level is measured before the glucose load; to preclude a diagnosis of diabetes and qualify as IGT, the fasting glucose level should be <7.0 mmol/L. IFG was introduced by the ADA in 1997 and adopted by the WHO in 1999. The original ADA 1997 and WHO 1999 criteria for classifying IFG was a fasting plasma glucose range of 6.1 to 6.9 mmol/L. The ADA subsequently lowered the criteria to 5.6 to 6.9 mmol/L in 2003 to maximize the sensitivity and specificity for diabetes prediction. The WHO, however, retained the original lower threshold of 6.1 mmol/L (5). The Canadian Diabetes Association (CDA) defines IFG based on the WHO 1999 criteria of 6.1 to 6.9 mmol/L (6). Although the diagnosis of prediabetes is based on lower bound glucose cut-points, evidence suggests that the association between glucose level and adverse outcomes is continuous or J-shaped, with higher risk of complications present even below the lower thresholds (5,7). According to the NHANES III (Third National Health and Nutrition Examination Survey) study, the prevalence of IGT and IFG in American adults 40 to 74 years of age is 14.9% and 8.3%, respectively (2). IGT is generally more common than IFG in most populations (2). In addition, studies have shown that IGT tends to be more common in women and IFG more common in men (2). In most populations, the prevalence of IGT increases linearly with age, but for IFG the prevalence plateaus in middle age (2,8). IGT and IFG may co-exist; most studies have shown that up to 50% of individuals with IFG also have IGT and approximately 20% to 30% with IGT have IFG (2,8). According to the Decode Study, the percentage of European men and women diagnosed with both IGT and IFG based on WHO 1999 criteria was 26.1% and 20.3%, respectively (8). About 25% of individuals with IGT or IFG will develop diabetes, 50% will remain prediabetic, and 25% will return to normal glucose levels over 3 to 5 years. However, most people with IGT or IFG will develop diabetes if observed for a longer time (4). In addition to the

development of type 2 diabetes, prediabetes has been associated with adverse cardiovascular risk factors (e.g., hypertension, dyslipidemia, hyperinsulinemia, microalbuminuria, inflammatory/ hemostatic markers, and carotid artery intima-media thickness), and with total and cardiovascular mortality (2,3,9). Although the observed increase in cardiovascular risk appears largely due to the development of diabetes, some studies have shown that IGT and IFG themselves remain independent risk factors even after adjustment for other cardiovascular risk factors (4). Preventative strategies are classified as universal, selective, or indicated (10). Universal and selective strategies target the general population and subpopulations with higher than average risk respectively. Interventions for prediabetes fall under the indicated category, which target individuals with signs and symptoms. Randomized controlled trials (RCTs) of lifestyle interventions consisting of physical activity and healthy diet in individuals with IGT have shown a reduction in the progression to type 2 diabetes by up to 40% to 60% (3). In addition, pharmacological agents such as metformin, acarbose, rosiglitazone and orlistat have been shown to reduce progression to type 2 diabetes (3). The ADA recently suggested that metformin may be considered as an adjunct or replacement to lifestyle modification in individuals with combined IGT and IFG plus one other risk factor (4). Compared with IGT, much less evidence is available for intervening in isolated IFG (2). Furthermore, evidence related to the effect of interventions for either IGT or IFG on long-term clinically important cardiovascular endpoints is lacking. The purpose of this study was to create an evidence map of systematic reviews of interventions in individuals with prediabetes. The primary objective was to assess the effect of interventions on clinical cardiovascular outcomes, however, data on surrogate markers, such as blood pressure and progression to type 2 diabetes were also evaluated. This evidence map was commissioned by the Public Health Agency of Canada (PHAC) and was undertaken as part of a larger project that examined 3 other predisease states (i.e. prehypertension, overweight and borderline hypertriglyceridemia) in addition to prediabetes. For reasons of feasibility, we limited the evidence map to systematic reviews, which will indirectly inform about the underlying primary evidence base. The results reported here focus only on the prediabetes component of the evidence map. Evidence mapping is a systematic and reproducible methodology for understanding the extent and distribution of evidence on clinical topics (11). The purpose of evidence mapping is to provide a broad synopsis of the available research (12). Unlike systematic reviews, an evidence map does not provide details of study results or incorporate meta-analytic techniques for pooling effect estimates. Based on the results of an evidence map, decision-makers and guideline developers may decide to conduct additional reviews in areas where they are lacking, or use the available highquality reviews for developing guidelines and policies.

Methods Whereas this study focuses on prediabetes, the methods reported below were developed for the broader evidence mapping project that included additional predisease states.

K. Singh et al. / Can J Diabetes 36 (2012) 281e291

Data sources A systematic search strategy was developed and used to search the following databases: the Cochrane Library Issue 4, 2011 (includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessments) and Ovid MEDLINE (1946 to January 4, 2012). The search strategies had a combination of controlled vocabulary (e.g. prediabetic state, glucose intolerance, primary prevention) and keywords (e.g. prediabet*, pre-disease*, prevent*). No language or date restrictions were applied, but animal studies were excluded. Web sites of relevant specialty societies and organizations, health technology assessment agencies and guideline collections were also scanned. All records were downloaded and imported into a database and duplicate records were removed. Screening Retrieved records were screened at 2 main levels using a dedicated software program (Distiller Systematic Review Software). At Level 1, reviewers liberally screened titles and abstracts; at least 2 reviewers were needed to exclude articles and one reviewer to include. Records were excluded because they did not meet one of the inclusion criteria. Full-text screening was divided into 3 sublevels to account for the diverse expertise of reviewers. In the first sublevel (Level 2a), reviewers with methodological expertise assessed whether records fulfilled the criteria to be classified as a systematic review. At the second sublevel (Level 2b), reviewers with clinical content expertise determined if records fulfilled eligibility criteria for intervention, outcomes and population. At the third sublevel (Level 2c), studies were further restricted based on whether a quantitative or qualitative synthesis was present on a predisease population; reviewers with both methodological and clinical expertise completed this sublevel. Two reviewers verified all excluded citations at Level 2. Discrepancies were resolved by consensus or third party adjudication. Inclusion and exclusion criteria English-language systematic reviews were eligible for inclusion if the following criteria were met:
The study was classified as a systematic review based on the following conditions: 1) at least one database was searched with a specified search date, 2) at least one eligibility criterion was reported and 3) the included studies were quality assessed (e.g. use of a tool or set of criteria). It was also necessary that quality assessment was reported or utilized in evidence syntheses (e.g. either reported for each individual study or used in a sensitivity analysis). A description of general study limitations in the discussion section was considered insufficient to meet the quality assessment criterion. An operational definition of systematic review is provided in Table 1.
With a primary or secondary intent, the review investigated an intervention to reduce the risk of adverse cardiovascular endpoints, surrogate cardiovascular outcomes or progression to overt disease (e.g. type 2 diabetes) in adults (18 years of age) with one of the predisease states of interest, or in women with history of pre-eclampsia, eclampsia or gestational diabetes. Reviews that had a population with a predisease in combination with an overt disease, such as hypertension or obesity, were considered for inclusion as long as the intervention was geared toward the predisease condition or the outcome of disease progression was assessed. The reference values used to define the predisease states of interest are

283

Table 1 Operational terms Term

Reference values/definition

Prediabetes (36,37)

IFG: 6.1e6.9 mmol/L IGT: 7.8e11.0 mmol/L 2-hour post-75 g oral glucose load Systolic: 120e139 mm Hg or Diastolic: 80e89 mm Hg BMI: 25e29.9 kg/m2 Triglyceride: 1.7e2.3 mmol/L

Prehypertension (38) Overweight (39) Borderline hypertriglyceridemia (40,41) Systematic review

A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarize the results of the included studies. See also Cochrane Review (42).

BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.

reported in Table 1. Although the reference ranges for prediabetes specified in Table 1 are based on WHO 1999 criteria, reviews that were based on other prediabetes criteria (e.g. ADA 2003) were also considered for inclusion.
There was an identifiable quantitative or qualitative synthesis of evidence from primary studies on a predisease population. At least 75% of the studies included in the synthesis should have been in a predisease population. Primary studies and overview of reviews were excluded. In addition, systematic reviews were excluded in the following circumstances:
Were published only as books or chapters in books.
Investigated interventions to treat gestational diabetes, preeclampsia or eclampsia.
Were restricted to the pediatric age group.
Focused exclusively on populations with pre-existing cardiovascular disease (i.e. secondary prevention) or other diseases (e.g. cancer, chronic kidney disease, mental health disorders, osteoarthritis).
Described interventions in populations with metabolic syndrome, unless a predisease state had been specified explicitly.
Did not describe an intervention to prevent adverse cardiovascular endpoints, address surrogate markers of cardiovascular outcomes or mitigate disease progression.
Evaluated cost-effectiveness outcomes only.
Described screening of populations with predisease, because screening was not an intervention of interest for this evidence map.
Included only observational studies of exposures rather than interventions.

Data extraction and quality assessment Data extraction forms were developed and pilot tested to ensure that questions would be answered consistently among reviewers. One reviewer extracted data and another reviewer independently verified the extractions. Data were collected on general study characteristics (e.g. year of publication, country of corresponding author, data sources, search dates and funding source), population

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Table 2 Categorization of authors’ conclusions Category

Example

Beneficial

The language is clearly indicative of a beneficial effect. The language suggests a guarded statement of benefit. The language is clearly indicative of a harmful effect. Language that denotes no difference between intervention and comparator. Language that suggests no conclusions can be drawn due to mixed results or limitations of the included studies. N/A

Probably beneficial Harmful No effect Inconclusive

No conclusion provided N/A, not applicable.

characteristics (e.g. ethnicity, age, gender), intervention and comparator details, study outcomes and authors’ overall conclusions about the intervention under study. Interventions were broadly categorized as pharmacotherapy, complementary alternative medicine, diet, exercise, behavioural/psycho-social and others. Study outcomes were clinical cardiovascular endpoints (mortality, stroke, myocardial infarction, angina/acute coronary syndrome, revascularization procedures, peripheral vascular disease and others), surrogate markers of cardiovascular outcomes (blood pressure, weight, glucose/glycated hemoglobin [A1C], triglycerides and others) and incidence of disease progression. Aside from reviews that found no relevant primary studies (i.e. empty reviews), the data extracted on study population, interventions, comparators and outcomes were based on the results section rather than the methods of the review. Using a priori guidelines (Table 2), 2 methodologists with clinical backgrounds consensually evaluated authors’ overall conclusions about an intervention. No independent evidence syntheses were carried out. The quality of systematic reviews was assessed with the 11-point validated AMSTAR tool (A MeaSurement Tool to Assess Reviews) (13). With the exception of empty reviews, the overall quality of reviews was rated according to the following classification: 0 to 3 points (low quality), 4 to 7 points (moderate quality) and 8 to 11 points (high quality) as per recommendations by the Canadian Agency for Drugs and Technologies in Health (14). All quality assessments were verified independently by a second reviewer. Results Figure 1 depicts the flow of retrieved records in a PRISMA diagram. The searches yielded a total of 7127 records after removal of duplicates. Six records were companions or provisional abstracts of full-text reports. The full-texts of 1380 records were screened at Level 2. Of these, 1361 records were excluded (for reasons, see Figure 1). Most records were excluded because they did not satisfy one of the criteria for systemic reviews. Nineteen studies were eventually found to be of relevance to a predisease population. Of these, 14 studies (15e28) and one informative companion report (29) pertained to prediabetes. Overview of included studies Table 3 provides detailed characteristics of the 14 systematic reviews included in the prediabetes evidence map. The reviews were published between 2004 and 2011. Prediabetes was a primary objective in 12 of 14 studies (86%) (16e19,21e28). Multiple databases were searched by almost all reviews (15,17,18,20e28) and most (93%) included a supplementary search, such as manual scan of reference lists and contacting authors or experts in the field

(15,16,18e28). MEDLINE or PubMed were databases common to all studies. The funding sources of most reviews were not-for-profit (78%), which included an academic institution, government or professional association (15,17,18,20e24,26e28). Only one review was clearly funded by a for-profit, industry-based source (25). The number of included primary studies in the reviews that were relevant to a prediabetes population ranged from 0 (i.e. an empty review that found no eligible primary studies) to 21. Some primary studies appeared repeatedly in several reviews. These included the Diabetes Prevention Program (DPP) (30), the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOPNIDDM) (31), Troglitazone in Prevention of Diabetes (TRIPOD) (32), and the Finnish Diabetes Prevention Study (DPS) (33), among others.

Study population The study populations were generally derived from outpatient and community dwelling settings (18,20,21,23,24). Subjects were described as having either IGT (15e28), IFG (18,19,21,23e26) or both (21). Some reviews included women with previous gestational diabetes (16,17,25,27). Various diagnostic criteria for IGT and IFG were specified across reviews and, even within a single review, the included primary studies usually varied in the definition of prediabetes. IGT was diagnosed based on WHO 1980, WHO 1985, WHO 1998, WHO 1999 or ADA 1997 recommendations (17,18,20,21,24e26,28). IFG was diagnosed based on WHO 1999 or ADA 1997 recommendations (18,26). In some reviews, other glucose ranges were used such as fasting plasma glucose of 5.3 to 6.9 mmol/L (19) or 5.5 to 7.7 mmol/L (21,28). Several reviews did not report any diagnostic criteria (15,16,22,23,27). In more than half of the reviews, a portion of the study population also had overt metabolic condition(s), such as obesity or hypertension, in addition to prediabetes (15e19,21,24,25). Generally, the populations included a mix of male and female subjects. One review included females only (27) and another review had a gender-specific analysis (15). Information about the ethnicity of study population was reported in 5 reviews (15,18,19,24,26) and included European/Caucasian, Hispanic, African-American, Asian, American Indian, Aboriginal, and Asian Indian.

Interventions Table 4 details interventions evaluated in the included systematic reviews. A majority of reviews focused on either pharmacotherapeutic interventions (64%) or diet, exercise and/or lifestyle interventions (57%). Lifestyle interventions generally included dietary and/or exercise components. Several classes of pharmacotherapy were investigated, including biguanides (16,17,19,23,25,26), sulfonylureas (17,25), alpha-glucosidase inhibitors (16,17,23,25,26,28), thiazolidinediones (16,17,22,23,25), metaglinides (25), weight-reducing (16,17,23) agents and medication for blood pressure (23). Diet, exercise and/or lifestyle interventions included individualized medical nutrition therapy (16), dietary advice (20), prescribed diets (20,24), and promotion of physical activity or supervised exercise programs (24). Three reviews assessed complementary and alternative medicine interventions, including chromium (26) and Chinese herbal medicines (17,18). One review examined a behavioural intervention that consisted of motivational strategies, goal setting, self-feedback with food and exercise diaries, stress management, and coping skills (21). Lastly, 2 reviews evaluated the effects of other types of interventiondone was an intervention consisting of standard prevention education (17) and the other was gastric bypass surgery for obesity (15).

K. Singh et al. / Can J Diabetes 36 (2012) 281e291

285

Figure 1. PRISMA flow diagram.

Outcomes Most reviews (93%) measured the incidence of progression from prediabetes to overt type 2 diabetes mellitus (Table 5) (15e26,28). Many reviews (43%) also provided data on surrogate markers of glycemic control and metabolic risk factors, such as A1C, fasting or postprandial glucose, lipids, blood pressure and weight (18,20,21,24,26,28). Only 4 reviews provided data on a clinical cardiovascular endpoint (23,24,26,28). Quality assessment The majority of reviews were deemed to be of high quality (AMSTAR score 8e11) (15,17,18,20,21,23,24,26,28); most of these were Cochrane reviews (18,20,21,24,28). Three reviews were of moderate quality (AMSTAR score 4e7) (19,22,25) and one review was of low quality (AMSTAR score 0e3) (16). An overall quality rating was not provided for the review by Tieu et al. (27) because the results were empty (i.e. no relevant studies were found). Rating of authors’ overall conclusions about interventions Table 6 provides ratings for authors’ overall conclusions for each interventional category along with quality assessments. The ratings for pharmacotherapy ranged from beneficial to inconclusive and the quality of this evidence ranged from low to high. Beneficial

pharmacotherapeutic agents for preventing diabetes included biguanides (low to moderate quality), alpha-glucosidase inhibitors (low to moderate quality), thiazolidinediones (low to moderate quality) and orlistat (low quality) (16,17,19,25). The conclusions of pharmacotherapeutic agents listed as probably beneficial came from high quality evidence and made reference to uncertainty about the effects on long-term outcomes (23,28). One review concluded that sulfonylureas and metaglinides are not effective for preventing diabetes (moderate quality) (25). Other reviews indicated that evidence was inconclusive for the comparative efficacy among thiazolidinediones (moderate quality) (22) and for pharmacological interventions in general for preventing diabetes and improving long-term outcomes (high quality or no quality rating provided) (26,27). Ratings for diet, exercise and/or lifestyle interventions also ranged from beneficial to inconclusive and evidence came from low to high quality reviews. Beneficial interventions were intensive lifestyle modification, exercise, and weight loss strategies to reduce progression to diabetes (low or high quality) (16,17,21,24,26). The conclusions of the probably beneficial lifestyle and weight loss interventions were from high quality reviews and referred to the lack of data on long-term outcomes (15,23). Interventions with inconclusive evidence were dietary interventions to prevent diabetes, and exercise and/or dietary interventions for preventing diabetes or improving cardiovascular outcomes (high quality) (20,24,26).

286

Table 3 Detailed characteristics of systematic reviews in prediabetes Nstudies*

Search dates and sources

Funding source

Aucott et al. (2004) (15) Companion: Avenell et al. (2004) (29) Curtis et al. (2005) (16)

1966e 2001 MEDLINE/PubMed; Embase; CINAHL; HealthSTAR; reference lists

Not-for-profit

1965e2004 MEDLINE/PubMed; contacting experts

NR

12

Gillies et al. (2007) (17)

1966e2006 MEDLINE/PubMed; Embase; Cochrane Library; reference lists; expert opinions

Not-for-profit

21

Grant et al. (2009) (18)

Inceptione2009 MEDLINE/PubMed; Embase; Cochrane Library; AMED; CBM; CMCC; TCMLARS;CDDB;CACP; CMAC; trial registries; Grey literature; reference lists; contacting authors 1966e“to present” MEDLINE/PubMed; reference lists

Not-for-profit

16

Lily et al. (2009) (19)

Nield et al. (2008) (20)

Norris et al. (2005) (21)

NR

Not-for-profit NRe2007 MEDLINE/PubMed; Embase; CINAHL; Cochrane Library; AMED; current controlled trials; UK National Research Register; National Institutes of Health; contacting experts; reference lists 1966e2004 Not-for-profit MEDLINE/PubMed; Embase; CINAHL; Cochrane Library; ERIC; nutrition abstracts and review; PsycInfo; Web of Science; Biosis; manual searching of journals; reference lists; contacting experts

3

3

1

9

Population

I/C

Overweight or obese nondiabetics with IGT Ethnicity: European/Caucasian; African-American; Asian Mean age: NR

I: diet þ exercise; gastric bypass Disease progression: incidence of diabetes surgery C: no treatment; general oral and written advice about diet and exercise

IGT or women with previous gestational diabetes Portion was also obese Ethnicity: NR (one study was in Hispanics) Mean age: NR IGT or women with previous gestational diabetes Portion was also obese Ethnicity: NR (some studies in Chinese, Japanese Americans, Hispanics, and native Asian Indians) Mean age range: 43e56.7 years IGT or IFG Portion also had hypertension or was obese Ethnicity: Asian Age range: 44e66 years Mean age (SD): 52 (NR)

I: pharmacotherapy; lifestyle interventions C: placebo; information on healthy eating patterns and exercise I: pharmacotherapy; diet; exercise; diet þ exercise; behavioural (e.g. exercise program); lifestyle interventions; education; CAM C: placebo; an active agent; lifestyle; diet; routine advice I: CAM (Chinese herbal medicines) C: placebo; an active agent; nonpharmacological interventions (e.g. diet, exercise, lifestyle)

IGT or IFG Portion was also obese Ethnicity: European/Caucasian; African-American; Asian Age range: 25e60 years IGT Ethnicity: NR (based in China) Mean age (SD): 44.7 (9.4) and 46.5 (9.3) years

Overweight or obese prediabetics with IGT, IGF, or bothy Portion was also obese Ethnicity: NR (some studies took place in Americans with Japanese ancestry, Swedish community, Chinese community, the Netherlands, and Finland) Mean age (SD): 51.2 (NR) years

Outcomes assessed

Overall conclusion rating

Amstar score and quality rating

Probably beneficial: diet þ exercise and gastric bypass surgery

10 High

Disease progression: incidence of diabetes

Beneficial: lifestyle interventions Probably beneficial: pharmacotherapy

0 Low

Disease progression: incidence of diabetes

Beneficial: lifestyle and pharmacological interventions

8 High

Surrogate: BP, weight, glucose (e.g. A1C), fasting insulin, TG, cholesterol, HDL Disease progression: incidence of diabetes

Inconclusive: CAM

10 High

I: pharmacotherapy C: placebo; usual care; standard lifestyle recommendation

Disease progression: incidence of diabetes

Beneficial: pharmacotherapy

4 Moderate

I: diet C: general information about diabetes and IGT

Surrogate: glucose (e.g. A1C) Disease progression: incidence of diabetes

Inconclusive: diet

11 High

Beneficial: diet; exercise; behavioural interventions

8 High

Surrogate: BP, weight, glucose I: diet; exercise; behavioural (e.g. A1C), TG, cholesterol, (consisted of goal setting, selfLDL, HDL feedback with food or Disease progression: incidence exercise diaries, stress of diabetes management, or improved coping skills) C: behavioural (e.g. exercise program); diet; usual care; written/oral information

K. Singh et al. / Can J Diabetes 36 (2012) 281e291

SR

Norris et al. (2007) (22)

Norris et al. (2008) (23)

1966e2005 MEDLINE/PubMed; Embase; Cochrane Library; dossiers submitted by pharmaceutical companies; reference lists; contacting experts 2001e2007 MEDLINE/PubMed; Cochrane Library; ClinicalTrials.gov; reference lists

Not-for-profit

2

Not-for-profit

11

6

IGT Ethnicity: NR Mean age: NR

I: pharmacotherapy C: placebo; an active agent

Disease progression: incidence of diabetes

IGT or IFG Ethnicity: NR (Some studies took place in Finland, India, Japan, China, New Zealand, and Sweden) Mean age range: 43.8e57 years IGT or IFG Portion was also obese Ethnicity; European/Caucasian; Hispanic; African-American; Asian; American Indian; Asian Indian Age range: 24e75 years Mean (SD): 50.3 (NR) years IGT, IFG, borderline diabetes, history of gestational diabetes Portion also had hypertension and/ or was obese Ethnicity: NR Mean age: NR

I: pharmacotherapy; diet; lifestyle interventions C: placebo; an active agent; lifestyle; usual care

Probably beneficial: Disease progression: incidence lifestyle interventions of diabetes and CV outcomes: all cause pharmacotherapy mortality, MI, incidence of CV disease

I: exercise; diet þ exercise C: no treatment; advice on diet and exercise Aside from 2 studies, some form of behavioural intervention, such as goal setting, was included in comparator groups I: pharmacotherapy C: placebo; an active agent

Surrogate: BP, weight, glucose (e.g. A1C), TG, cholesterol, lipids Disease progression: incidence of diabetes CV outcomes: all-cause mortality; CV morbidity

Beneficial: diet þ exercise Inconclusive: exercise

Disease progression: incidence of diabetes

Surrogate: BP. TG, incidence of hypertension, lipids Disease progression: incidence of diabetes CV outcomes: All-cause mortality, CV mortality, MI, ACS/angina, need for revascularization procedures, PVD, CHF, cerebrovascular events None (no studies found)

Beneficial: thiazolidine- 6 Moderate diones; alphaglucosidase inhibitors; biguanides No effect: sulfonylureas; meglitinides 9 Beneficial: diet þ High exercise Inconclusive: diet or exercise alone; pharmacotherapy

NRe2008 MEDLINE/PubMed; Embase; CINAHL; Cochrane Library; LILACS; current controlled trials; SocioFile; reference lists

Not-for-profit

Phung et al. (2011) (25)

1950e2010 MEDLINE/PubMed; Embase; Cochrane Library; reference lists

Industry

Santaguida et al. (2005) (26)

Not-for-profit 1979e2004 MEDLINE/PubMed; Embase; CINAHL; Cochrane Library; HealthSTAR; AMED; PsycInfo; reference lists; personal files

14

IGT or IFG Ethnicity: European/Caucasian; Hispanic; African-American; Asian; Aboriginal Mean age range: 37.5e70 years

I: pharmacotherapy; CAM; diet; exercise; diet þ exercise C: placebo; an active agent; lifestyle advice

Tieu et al. (2010) (27)

Not-for-profit 1922e2010 MEDLINE/PubMed; Cochrane Library; BioMed Central; hand searches of proceedings of major conferences; manual searching of journals Not-for-profit 1945e2006 MEDLINE/PubMed; Embase; Cochrane Library; LILACS; Web of Science; databases of ongoing trials; reference lists; contacting authors and other experts; contacting manufacturers and patent holders

0 (empty review)z

Women with IGT or previous gestational diabetes planning a pregnancy Ethnicity: N/A Mean age: N/A

I: pharmacotherapy C: placebo; an active agent

IGT and/or impairment in fasting glucose Ethnicity: NR (some studies took place in China, Canada, Europe, and Israel) Mean age range: 49.1e63.5 years

I: pharmacotherapy C: placebo; an active agent; diet þ exercise; no treatment

Van de Laar et al. (2006) (28)

17

5

Inconclusive: pharmacotherapy

Probably beneficial: Surrogate: BP, weight, glucose pharmacotherapy (e.g. A1C), fasting and postload insulin, TG, lipids, Cpeptide Disease progression: incidence of diabetes CV outcomes: all-cause mortality; CV mortality; MI; ACS/angina; need for revascularization procedures; PVD; CHF; cerebrovascular events; incidence of CV disease

7 Moderate

8 High

10 High

Rating not provided for empty reviews

K. Singh et al. / Can J Diabetes 36 (2012) 281e291

Orozco et al. (2008) (24)

Inconclusive: pharmacotherapy

11 High

287

A1C, glycated hemoglobin; ACS, acute coronary syndrome; BP, blood pressure; C, comparator; CAM, complementary alternative medicine; CHF, congestive heart failure; CINAHL, Cumulative Index to Nursing and Allied Health Literature; CV, cardiovascular; ERIC, Education Resource Information Center; HDL, high density lipoprotein; I, intervention; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL, low density lipoprotein; MI, myocardial infarction; N/A, not applicable; NR, not reported; PVD, peripheral vascular disease; SD, standard deviation; SR, systematic review; TG, triglycerides; UK, United Kingdom. * Number of studies in prediabetes population. y In some studies, the definition for abnormal glycemia overlapped with current criteria for diabetes. z Reviewers found no study that met inclusion criteria.

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Table 4 Interventions for prediabetes investigated in systematic reviews Intervention category

Number of SRs

Intervention details

Pharmacotherapy

9 (16,17,19,22,23,25e28)

Biguanides: Metformin (16,17,19,23,25,26) Flumamine (17) Phenformin (17,25) Sulfonylureas: Glipizide (17) Tolbutamide (17,25) Alpha-glucosidase inhibitors: Acarbose (16,17,23,25,26,28) Voglibose (25) Thiazolidinediones: Pioglitazone (22,25) Rosiglitazone (22,23,25) Troglitazone (16,17,25) Metaglinides: Nateglinide (25)

Diet, exercise and/or lifestyle

8 (15e17,20,21,23,24,26)

Complementary alternative medicine

3 (17,18,26)

Behavioural

1 (21)

Other (e.g. education)

2 (15,17)

Others: Orlistat (16,17,23) Ramipril (23) Enalapril (26)* Pravastatin (26)y Examples: Individualized medical nutrition therapy, intensive lifestyle modification and support (16). Dietary advice and prescription of diets. Advice was to increase vegetable consumption and reduce intake of alcohol and simple sugars. Diet was to include 55%e65% carbohydrates, 10%e15% protein, and 25%e30% fat (20). Exercise interventions ranging from promotion of physical activity to supervised exercise programs. Most programs included exercises such as walking, jogging and cycling. Dietary intervention to reduce caloric and fat intake and increase fiber (24). Chromium (26) Jiangtang bushen recipe (17) Chinese herbal medicine (extracts from herbs, single or mixture preparations, or combined with a pharmacological intervention) (18) Motivational strategies, goal setting, self-feedback with food or exercise diaries, stress management, improved coping skill (21) Standard prevention education (17) Gastric bypass surgery (15)

SR, systematic review. * Evaluated in individuals with IFG and left ventricular dysfunction. y Evaluated in individuals with IFG and previous myocardial infarction. Table 5 Outcomes assessed in systematic reviews of prediabetes Outcome category

Number of SRs

Outcome details

Surrogate markers of CV disease

6 (18,20,21,24,26,28)

Glucose homeostasis: Glycosylated hemoglobin (18,21,28) Glucose (fasting or postload) (18,20,21,24,28) Incidence of hyperglycemia (20) Insulin (fasting or postload) (18,28) insulin sensitivity (18) Additional metabolic risk factors: Plasma lipids (18,21,26,28) Blood pressure (18,21,24,26,28) Incidence of hypertension (28) Weight (18,21,24,28)

Disease progression Clinical CV endpoints

13 (15e26,28) 4 (23,24,26,28)

Other: Inflammatory markers (18) Incidence of type 2 diabetes MI (23) Major CV event (26,28)* Incidence of CV disease (23) Incidence of CV events (23,24) Mortality (all-cause or CV-related) (23,24,28)

CV, cardiovascular; MI, myocardial infarction; SR, systematic review. * Major CV event was defined as MI, angina, cardiac revascularization procedure, mortality, congestive heart failure, cerebrovascular event or peripheral vascular disease.

K. Singh et al. / Can J Diabetes 36 (2012) 281e291

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Table 6 Ratings of authors’ overall conclusions about interventions Rating of conclusion

Details

Amstar score and quality rating

Pharmacotherapy Beneficial (16,17,19,25)

Biguanides to prevent diabetes (16,19,25).

0e6 Lowemoderate 0e6 Lowemoderate 0e6 Lowemoderate 0 Low 8 High 11 High

Alpha-glucosidase inhibitors to prevent diabetes (16,25). Thiazolidinediones to prevent diabetes (16,25). Orlistat to prevent diabetes (16).

Probably beneficial (23,28)

No effect (25)

Pharmacological interventions in general to reduce risk of progression to diabetes (17). Alpha-glucosidase inhibitors to prevent diabetes. Unclear if effect is due to prevention, delay or symptom masking. Prevention of CV events requires confirmation (28). Pharmacological interventions in general to reduce risk of progression to diabetes. Effects on long-term outcomes unknown (23). Sulfonylureas to prevent diabetes (25). Metaglinides to prevent diabetes (25).

Inconclusive (22,26,27)

Diet/exercise/lifestyle Beneficial (16,17,21,24,26)

Thiazolidinedionesdthe comparative efficacy of rosiglitazone and pioglitazone, especially on long-term outcomes (22). Pharmacological interventions in general to prevent diabetes (26) or improve glycemic control and long-term outcomes (27). Intensive lifestyle intervention for modest weight loss to prevent diabetes (16). Weight loss strategies using dietary, physical activity, or behavioural interventions to reduce incidence of diabetes (21). Combination of exercise and dietary interventions to reduce incidence of diabetes (24,26). Lifestyle interventions to reduce progression to diabetes (17).

Probably beneficial (15,23)

Intensive lifestyle interventions to reduce progression to diabetes. Data on long-term outcomes are lacking (23). Weight loss to reduce risk of developing diabetes (15). More long-term studies are needed.

Inconclusive (20,24,26)

Dietary interventions to prevent diabetes (20). Exercise only interventions or combined exercise and dietary interventions to improve quality of life, morbidity, mortality, and CV outcomes (24). Diet or exercise alone interventions to prevent diabetes (26).

Complementary alternative medicine Inconclusive (18) Behavioural Beneficial (21) Other Probably beneficial (15)

8 High 6 Moderate 6 Moderate 7 Moderate 9 High (25)/not rated (26) 0 Low 8 High 9e10 High 8 High 8 High 10 High 11 High 10 High 9 High

Chinese herbal medicines to improve glycemic control and reduce progression to diabetes. Evidence base has several limitations (18).

10 High

Behavioural strategies for weight loss to reduce incidence of diabetes (21).

8 High

Massive weight loss after gastric bypass surgery to reduce risk of developing diabetes (15). More long-term studies are needed.

10 High

CV, cardiovascular.

Evidence was inconclusive about the effect of Chinese herbal medicines on glycemic control and progression to diabetes (high quality) (18). Behavioural strategies for weight loss to reduce incidence of diabetes was found to be beneficial in one review (high quality) (21). Lastly, gastric bypass surgery to reduce incidence of diabetes was probably beneficial (high quality) (15).

Discussion The global prevalence of diabetes by 2025 is projected to be 380 million (34). Diabetes confers significant human and economic costs in countries around the world. It is imperative, therefore, that this growing problem be addressed by evidence-based interventions. One strategy to restrain the diabetes trend is to intervene at the stage before the development of diabetes.

A sizable evidence base of interventions during the prediabetes stage exists. This evidence map retrieved a total of 14 unique systematic reviews, of mostly high quality, that investigated the value of intervening in individuals with IGT, IFG or previous gestational diabetes. A diverse range of interventions have been examined, with the most common ones consisting of pharmacotherapeutic agents and diet, exercise and/or lifestyle modification. An assessment of authors’ overall conclusions suggests that certain types of interventions may be beneficial for curbing the risk of progression to diabetes. Pharmacological agents and diet/exercise/ lifestyle interventions, for instance, may be effective strategies for people with prediabetes. However, because the systematic review evidence provides mixed assessments for similar interventions, a formal evidence synthesis based on data from primary studies or data from the systematic reviews themselves will be needed before any definitive conclusions can be made about the value of these

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interventions. Reviews have generally synthesized data on only shorter term surrogate markers of cardiovascular disease and incidence of progression to type 2 diabetes rather than clinically important cardiovascular endpoints. The lack of data on clinical endpoints likely represents a limitation of the underlying primary studies. Strengths and limitations Although this evidence map did not synthesize evidence like a systematic review, it did use the rigourous and reproducible methods of systematic reviews to screen, select and extract data. A comprehensive search strategy was employed, supplemented with a search for unpublished grey literature and quality was assessed using a validated tool. Our results provide a succinct overview of a broad clinical topic and clearly delineate areas where research is available and where it is lacking. Due to resource limitations, eligibility was restricted to reviews reported in English. As such, it is possible that relevant reviews in non-English language were missed. Researchers conducting an overview of reviews should certainly consider including non-English publications to lower the potential for biased effect estimates. Additionally, given the stringent eligibility criteria for qualifying a study as a systematic review (i.e. database with search date, eligibility criteria and quality assessment), the evidence map likely favoured reviews of high quality. Reviews of interventions in prediabetes of lesser quality may have been excluded due to these eligibility requirements. Lastly, we recognize that this evidence map charted systematic reviews only and did not evaluate the primary evidence base. The full extent of the primary literature and the need for further systematic reviews, therefore, are unknown.

population-level interventions is to shift risk levels in the entire population (3). Given the high prevalence of IGT and IFG in the general population, such interventions may confer benefit to public health (3). It would be useful to study the effect of interventions targeted towards diet and exercise modification on the populationlevel. Future systematic reviews should synthesize the evidence for these types of interventions and, if such evidence is absent, then more primary studies of population-level interventions should be carried out. Conclusions Several systematic reviews of interventions in prediabetes have been conducted. The interventions that have been evaluated are pharmacotherapy, diet/exercise/lifestyle, complementary alternative medicine, behavioural strategies, education and gastric bypass surgery. Based on an assessment of authors’ conclusions, pharmacotherapy and diet/exercise/lifestyle may be beneficial for reducing the incidence of type 2 diabetes. Several gaps exist in the prediabetes literature. Scant data are available on the effects of interventions on clinical cardiovascular outcomes, on subgroups at high risk of diabetes and on population-level interventions. Future secondary research, therefore, should focus on conducting an overview of reviews with assessment of heterogeneity by prespecified subgroups, systematic reviews of complementary alternative medicine and systematic reviews of population-level interventions. In addition, future primary research should address clinical cardiovascular outcomes, be pragmatic in design and address interventions at the population-level if such evidence is absent. Acknowledgments

Recommendations for future research Given the existence of high quality systematic review evidence in prediabetes, the next research priority should be to synthesize this evidence in an overview of reviews. Synthesis of evidence on the effect of interventions in particular subgroups, such as Asians and African-Americans, would be useful to determine impact on specific segments of the population who are at higher risk of developing diabetes. Based on the systematic reviews, it seems that primary studies addressing clinical cardiovascular endpoints are lacking and that more research is needed in this area. However, because we did not evaluate the primary evidence itself, this potential research gap would need to be verified with an evidence map of the primary literature. In addition, although there seems to be a significant amount of evidence on pharmacological and nonpharmacological interventions, more primary or secondary research on the effects of complementary alternative medicine interventions in prediabetes would be informative given their ease of availability, high prevalence of use, and possibility of adverse effects and interactions with conventional medications. We propose that future secondary research collect information on whether primary studies are explanatory or pragmatic in design. Implementing interventions in individuals with a predisease may be rendered less effective due to nonadherence (35). Pharmacological interventions for prediabetes may be especially prone to non-adherence because even individuals with overt type 2 diabetes have challenges with taking their medications regularly (35). Issues of adherence may be masked in explanatory trials because they are conducted under well controlled and supervised conditions. Pragmatic trials, however, would provide effect estimates that are more likely to occur in real world clinical settings. None of the systematic reviews identified in the evidence map implemented interventions at the population-level. The purpose of

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