Effectiveness of dietetic intervention for people with type 2 diabetes: a meta-analysis

Background Diet is central to treatment of type 2 diabetes. This review aimed to compare the effectiveness of nutrition therapy delivered by dietitians to nutrition advice delivered by other healthcare professionals in adults with type 2 diabetes on metabolic parameters. Methods Cochrane CENTRAL, CINAHL, EMBASE, MEDLINE and PsychINFO were searched for randomised controlled trials of three months duration or longer, published from 1st January 2008 to 18th June 2019. Relevant data were extracted from studies with additional author information. Random-effects meta-analysis assessed mean changes in HbA1c and other clinical parameters. PROSPERO CRD42019130528. favour decreases in medication, as well as anthropometric outcomes (BMI, weight and waist circumference) and changes in nutrients and food groups. The Cochrane risk-of-bias (ROB) tool was used to assess the quality of the studies on aspects of selection (random-sequence generation and allocation concealment), performance and detection (blinding of participants, personnel, and assessors), appropriateness of analysis (selective outcome reporting), and other sources of bias in accordance with the recommendations of the Cochrane Collaboration. Studies were ranked by two authors (GS and MAF) as “low risk”, “high risk”, or “unclear” (either a lack of information or uncertainty over a potential bias). 18 Authors resolved discrepancies by discussion.


Results
The search yielded 2477 records. Two records were identi ed through hand-searching the reference lists. Six hundred and nineteen duplicates (619) were removed and the remaining 1860 abstracts were assessed for eligibility (Fig. 1). One thousand seven hundred and ninety four (1794) abstracts were excluded during the primary exclusion round and a further 52 were excluded after assessing the full text articles. The reasons for exclusion of the full articles are shown in the appendix (p 12). Fourteen studies [24][25][26][27][28][29][30][31][32][33][34][35][36][37] were included in the qualitative synthesis and thirteen of them in the meta-analysis. 24-31,33−37 Maindal et al. 32 was not possible to be included in the metaanalysis due to missing values. The author responded to the initial inquiry to provide the requested data but did not follow through. Two reminder email requests were sent to no avail. Three of these studies 24,26,28 have been cited in previous nutrition guidelines for diabetes management. 38 All but one 29 trial were conducted in outpatient settings. Thirteen trials involved a parallel RCT design 24-29,31−37 and one trial 30 cluster randomization with each cluster representing a community. In total, 3338 subjects with type 2 diabetes, representing a diverse range of participants from eighteen countries from the six inhabited continents, were included (appendix p 20 and 27). Only the "diet" group that was randomly assigned to nutrition therapy (n = 248), and not the "diet plus activity" group (n = 246), was included from the study by Andrews et al. 24 Table 1 summarizes the study characteristics. Supplementary tables 1, 2 and 3 (appendix pp [22][23][24][25][26][27][28][29][30] list details of each study and a summary of participants' demographics and clinical characteristics. The mean age of participants was 55·8 years. The majority of participants were of white European ethnic background (40%), with one quarter Asian and 12% black African. Approximately half of the participants were males (49%) and half females (51%). One-third of the participants (35%) had completed less than high-school education and half (53%) were employed. Participants were on average diagnosed with type 2 diabetes for six years and 10 weeks and about one in ten was a self-reported smoker. The mean BMI at baseline was 31·5 kg/m 2 and the mean HbA1c was 7·89%. The majority of the participants were on oral hypoglycaemic agents (59%), antihypertensives (68%) and lipid modifying medication (51%). No signi cant differences at baseline between the pooled intervention versus the control group were observed.
For the individual studies, there were few signi cant differences in baseline characteristics between groups. In the study by Huang et al., 28 patients in the control group had higher BMI and diastolic BP than those of the intervention group at baseline. In two studies, 31,37 the intervention group had at least twice as many smokers as the control group. In the study by Eakin et al. 27 the control group was of a lower education status. Baseline BMI was much lower in the four Asian studies 28,30,36,37 than in the eight studies of non-Asians. 24-27, 29,31-35 HbA1c was just above normal at baseline in one study, 32 close to normal in another one, 24 just < 8% in ve studies, 27,30,31,34,35 and > 8% in the other seven studies. 25,26,28,29,33,36,37 Interventions lasted from four months to three years. In most studies (79%), the participants consulted with the dietitians at least six times. A few studies reported on the duration of each session, but in most this was not clear. Sessions were either face-to-face, telephone, individual, group or a combination of some of the aforementioned. The reported dropout rate varied considerably, from 2% in the study by Andrews et al., 24 to 20% in the study by Huang et al., 28 but with no signi cant difference between groups. Shahid et al. 36 did not report attrition.
Risk of bias was assessed at the study level using the Cochrane Risk of Bias tool. 18 In all fourteen studies, subjects were randomly assigned before the intervention. The random-sequence-generation method was stated in all the studies but two. 30,36 In the study by Liu et al., 30 two Chinese communities were randomly assigned to either the intervention or a control. This assignment involves high risks of recruitment and selection bias. The study by Shahid et al. 36 reported that patients were "randomly distributed" but there was no reference to a methodology. Allocation was not concealed, or it was unclear, in ve studies. 28-30, 33,36 In one study doctors were unaware of allocation of participants but dietitians and nurses were. 24 The blinding of participants and personnel (performance bias) was not possible in the present studies. The blinding of outcome assessors was reported in four studies. 24,27,31,35 Handling of missing endpoints (e.g. intention-to-treat, multiple imputation) was not clear in some studies. 28,29,30,37 The reporting in two trials was not consistent with their registration information 28,34,37 and two trials were not registered. 30,33 Three studies did not report con ict of interest. 31,35,36 In one study that reported industry funding, authors stated a liations with the funding body. 34 No other potential sources of bias were identi ed from the studies (Fig. 2). Con icts of interest and funding sources are listed in the appendix (p 31). The risk of bias ratings meant the overall rating of the body of evidence was downgraded despite all being RCTs.
All trials reported changes in HbA1c, with nine reporting it as the primary outcome and three 27,32,34 as a secondary outcome. Ten-year modelled cardiovascular risk was the primary outcome for Maindal et al. 27 and changes in body weight for the other two. 32,34 Ten studies reported changes in BMI and weight, twelve reported on blood pressure and eight on low-density lipoprotein (LDL) cholesterol. Less than half of the studies reported changes in energy and nutrient intake, medication use, waist circumference and physical activity.
Pooled participants in the intervention group (n = 1334) achieved more than four times the reduction in HbA1c, i.e. -0·65% (± 0·42), versus − 0·15% (± 0·39) that was achieved by the participants in the control group (n = 1177). In addition, pooled participants in the intervention group (n = 998) reduced their weight on average by about 1·35 kilogram (± 0·75 kg), whereas participants in the control group (n = 830) gained on average 78 grams (± 910 grams) (data not shown). This weight reduction in the intervention group corresponded to approximately 2% of their baseline weight.
We conducted a series of secondary analyses excluding one of all possible combinations of two of, three of, four of, ve of, six of and all seven of studies that scored poorly in the ROB assessment. 28-30, 33,34,36,37 None of the different combinations changed the direction of associations, but some of them affected the statistical signi cance of the HbA1c, BMI and weight outcomes (data not shown). When only the six studies 24-27, 31,35 that scored higher on ROB (at least ve "low risk" elds in total and mandatory "low risk" assessment for randomisation process, detection bias and selective reporting) were analysed, the results remained statistically signi cant albeit attenuated, e.g. HbA1c was − 0·29 [-0·50, -0·07] %.
We performed another series of secondary analyses, this time including only the eight studies that followed up for at least 12 months. 24,25,27,28,30,33−35 Removing the ve datasets of the studies that followed up at six months or sooner 26,29,31,36,37 attenuated the result for HbA1c (-0·24 [-0·41, -0·07] %) but increased it for weight (-1·62 [-2·73, -0·51] kg). None of these changes were statistically signi cant and the point estimate gained precision. The directions of association and measured effects were not statistically different for the LDL cholesterol and blood pressure outcomes. On the contrary, the BMI outcome crossed the line of no-effect (data not shown).
The robustness of the estimate was examined by sequentially removing each study and reanalysing the remaining datasets. The estimated effect sizes ranged from − 0·51 to -0·30% for HbA1c; -0·47 to -0·30 kg/m 2 for BMI; -1·68 to -1·13 kg for weight; -0·19 to -0·07 mmol/L for LDL cholesterol; -1·50 to -0·34 mm Hg for systolic blood pressure; and − 1·51 for − 0·19 mm Hg for the diastolic blood We also tested whether the xed-effects model would produce different results to the random-effects one. The xed-effects model rendered the LDL cholesterol and blood pressure outcomes statistically signi cant and maintained statistical signi cance in the HbA1c, weight and BMI outcomes, augmenting the effect size of HbA1c. It resulted in narrower con dence intervals, as expected.
Publication bias was assessed via visual inspection of funnel plots (appendix p 37). The data appeared skewed for the HbA1c and the diastolic BP outcomes. The asymmetry observed for the HbA1c is likely a result of the heterogeneity. 39 Whereas the skewed distributions seen for the diastolic BP outcome is largely due to an excess of medium to large studies with negative effects on the outcome. The asymmetry manifested in the weight outcome is likely due to an excess of small to medium studies with positive effects on the outcome. There was no evidence of publication bias for systolic BP. Publication bias could not be assessed for the BMI and LDL cholesterol outcomes as the number of studies is not adequate to distinguish chance from real asymmetry. 19 Discussion Type 2 diabetes is a major growing global health challenge. Medical nutrition therapy (MNT) has been shown to improve clinical parameters of type 2 diabetes. Our aim was to compare MNT delivered by accredited dietitians to nutrition advice delivered by other healthcare professionals (verbal or written). In this systematic review, we identi ed fourteen RCTs from eighteen countries from all six inhabited continents, involving 3338 participants with diverse backgrounds, that compared nutrition interventions for people with type 2 diabetes delivered by accredited dietitians with nutrition advice delivered by other healthcare professionals. The meta-analysis of thirteen studies found improved outcomes when nutrition intervention was delivered by a dietitian compared with nutrition advice delivered by other healthcare professionals. Dietitian-delivered MNT achieved a statistically as well as clinically signi cant reduction in HbA1c, with participants in the intervention group reducing their HbA1c four-and-a-half times more than participants in the control group. In addition, nutrition therapy achieved statistically signi cant reductions in BMI and weight in favour of the dietitian-led intervention. However, the overall magnitudes of change in BMI and weight were small and neither was considered clinically signi cant, but the estimate was precise as re ected by the narrow con dence intervals. Substantial heterogeneity was observed for all outcomes, as expected when combining data from eighteen countries with different health systems, guidelines and practices. In addition to the heterogeneity, the indirectness of reporting surrogate outcomes and the publication and risk of bias, resulted in the overall strength of evidence being rated very low.
Nutrition intervention delivered by dietitians achieved greater reductions for all outcomes, compared with when nutrition advice was delivered by other health care professionals in written or verbal form, with the reductions for HbA1c, BMI and weight being statistically signi cant and the LDL cholesterol narrowly missing this classi cation. However, only the reduction for HbA1c was clinically signi cant. [40][41][42] A reduction in HbA1c of half a percentage point (0·5%) is considered clinically signi cant, 40,41 which is consistent with the 0·47% reduction in HbA1c in this review. A 3-5% of reduction in body weight is considered clinically signi cant, 42,43 but this was not demonstrated in this analysis. It has been previously argued that even small reductions in the concentrations of metabolic syndrome parameters can yield clinically signi cant improvements due to their synergistic effects. 44 Therefore, although not attaining the conventional clinically signi cant cut-off point, the weight reduction seen in the intervention group may be clinically meaningful, especially when considering that the intervention group achieved a greater reduction than the control group. Factoring in the observations that participants in the intervention group also reduced all other parameters, i.e. LDL cholesterol and blood pressure compared with the control group, and achieved a clinically signi cant reduction in HbA1c, the synergistic interplay between these metabolic parameters may be clinically meaningful. Our analysis indicated that participants in the intervention group reduced their weight by about 2%, which is close to the suggested minimum reduction of 2·5% that was shown to produce improvement in glycaemic outcomes in the Look AHEAD trial. 45 Future, longitudinal studies in people with type 2 diabetes should further explore the effects of multi-metabolic-parameter improvements in the overall manifestation of diabetes related co-morbidities and complications.
Sensitivity analyses showed no effect on the direction of associations for the HbA1c outcome, when poorly ROB-scoring studies were excluded, or when only long-term (one year or more) studies were included. However, the magnitude of the change in effect size was attenuated and was no longer clinically signi cant. The heterogeneity was considerable, indicating that the weight that even large trials receive is reduced in the pooled analysis and thus even adding another large trial in the future will only have a small effect on the pooled result and is unlikely to alter the conclusions of the present meta-analysis.
The current ndings are consistent with the only other previous meta-analysis that compared nutrition intervention delivered by a dietitian to nutrition advice delivered by other health care professionals. 14 In this review, we extend the evidence presented by Moller et al.
Data from 12 more countries, i.e. Argentina, Australia, Germany, India, Poland, Serbia, Slovakia, Slovenia, South Africa, Spain, Thailand and Turkey, as well as from four more sites in the USA, are included to further inform our understanding of the effectiveness of MNT on clinical parameters of type 2 diabetes, in a variety of geographic locations, economies, health care systems, as well as culturesconsidering the interwoven nature of culture and diet. We have focused on interpreting the data's clinical relevance, with the objective to inform and improve clinical practice. Our ndings further support the international guidelines that recommend involvement of the dietitian in the management of diabetes. [6][7][8] Physicians have previously reported a lack of education in medical curricula throughout the world as well as a lack of con dence in providing nutritional counselling to patients. 12,13,46 Dietitians receive extensive nutrition education and are therefore better informed to recommend optimal diets for the current 47,48 and future 49 management of type 2 diabetes. As the International Diabetes Federation guidelines state, "referral to a dietitian can be very useful to learn how to translate the caloric restriction into feasible meals and how to manage some barriers for caloric restriction such as emptiness and hunger". 8 A 2017 review of nutrition interventions by dietitians showed effectiveness in glycaemic control and weight loss but not in correcting atherogenic dyslipidemia. 50 This agrees with our ndings, as well as those of others, 51 that did not show any signi cant improvement in LDL cholesterol concentration.
It will be useful to determine the optimal number of visits to the dietitian required to elicit meaningful results. In our studies, most participants saw the dietitians about six to eight times. It has previously been reported that Australian dietitians believe that people with type 2 diabetes need to consult with the dietitian at least four times per annum. 52 In addition to the frequency of visits, the average duration of the visit required to achieve optimal metabolic results should be determined. Few of the studies included in our meta-analysis reported the duration of each session, and in most studies this was not clear. Dietetic consult session durations vary around the world with reports indicating sessions of an average of 45-60 minutes in Australia, 53 fty minutes in Canada 54 and about half an hour in Israel. 55 Patients appear to prefer longer sessions. 56 Of interest, government guidelines advise a minimum of twenty minutes per session in Australia 57 and about 30-40 minutes in the UK. 58 It will also be useful to examine the frequency of visits and costeffectiveness of treatments. Previous reports have demonstrated returns-on-investment in the order of about NZ$5·50-$99 for every NZ$1 spent on dietetic intervention in New Zealand 59 and €14 to €63 for every €1 in the Netherlands. 60 It will be interesting to assess whether the cost effectiveness can be further improved by optimising dietetic consult time and frequency, as well as to investigate other factors that may mediate and/or moderate the cost effectiveness of services, such as further use of telehealth, especially in areas with poor access to services. 61 The strengths of the current analyses lie in the use of standard methodology as documented in the PRISMA and Cochrane guidelines for conducting systematic reviews and meta-analyses; the fact that a demographically and culturally diverse cohort from eighteen countries from all six inhabited continents was included; the inclusion of additional data from lower and upper middle income countries; and the comprehensive series of sensitivity analyses performed to reinforce the main ndings. The narrow con dence intervals underline the great precision of the effect estimates. Møller et al. combined within-group differences in means with those of between-group ones in their meta-analyses, as a mixture of these were available in the published articles. 14 We communicated with the authors to consult with them on unpublished data and accurately calculate within-group differences in means for the meta-analysis, to increase the precision of the point estimate.
Our analyses also have limitations. We searched ve databases for studies in adults. The adult lter for Medline is > 19 years of age, whereas for EMBASE and PsychINFO it is > 18 years old. This means that articles listed in MEDLINE with participants between 18-19 years old may have been excluded. It is crucial to ensure consistency between the different databases in terms of how an "adult" person is de ned to avoid such discrepancies. We also restricted the search to articles in English-language. It has been previously reported that the proportion of RCTs with positive results published in English-language journals is almost twice those published in German-language journals. 62 Therefore, this may present a source of bias due to the potential overestimation of the reported intervention effect. However, other reports indicate a difference in just one out of 36 meta-analyses when the non-English publications are included. 63 Our publication bias analysis indicated asymmetrical distributions for three outcomes. Some of the included studies presented methodological limitations, for example the cluster randomisation protocol. Despite this, there was no evidence of reporting substantially different effects. All of the outcomes presented substantial heterogeneity. It has been proposed that pooling data from multiple heterogeneous trials and presenting a single summary estimate can be misleading. 64 However, we undertook several sensitivity analyses to test the robustness of the outcomes and the in uence of individual and combinations of studies on these with no signi cant changes in our inferences. Statisticians also argue that since clinical and methodological diversity always occur in a meta-analysis, statistical heterogeneity is inevitable. 19 Finally, the random effects model has been criticized for its limitation in taking covariates into account to explain heterogeneity. 65 However, carrying out the analysis using the xed-effects model did not produce any statistically signi cant different results for the HbA1c, BMI and weight outcomes. We therefore conclude that our methodology is robust and sound.

Conclusions
In summary, dietitian-delivered nutrition therapy for people with type 2 diabetes achieves better outcomes than nutrition advice delivered by other healthcare professionals. Improvements in glycaemic control and body weight are statistically signi cant and the former clinically signi cant as well. Future longitudinal studies in people with type 2 diabetes should further explore the effects of multi-metabolic-parameter improvements in the overall phenotypic manifestation of co-morbidities to elucidate the long-term effects of the interventions and inform clinical practice. The optimal length and frequency of dietetic consultations that produces clinically meaningful results in the most cost-e cient manner merits further investigation.  Figure 1 Study selection RCT=randomized controlled trial. T2DM=type 2 diabetes mellitus. HbA1c=haemoglobin A1c.

Figure 2
HbA1c meta-analysis Forest plot of Mean difference in HbA1c (expressed as %) during medical nutrition therapy delivered by accredited dietitians compared with nutrition advice delivered by other healthcare professionals. The size of the green squares indicates the weight of the evidence from each of the studies; studies with con dence interval (horizontal line) crossing zero (vertical line) are inconclusive; powerful studies (those with more participants) have narrower con dence intervals; the black diamond represents the summary effect size, with the width of the diamond indicating the 95% CI; a statistically greater signi cant reduction in HbA1c is seen in the intervention group, compared to the control group. The data present substantial heterogeneity. Risk-of-bias categories tra c light interpretation is as follows: green (+), low risk; red (-), high risk; no colour, unclear risk (information missing). References listed are Andrews et al. IV=inverse variance. 95% CI=95% con dence interval.

Supplementary Files
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