LETTER

The importance of lifestyle-based efforts in reducing mortality inoverweight and obese individuals with type-2 diabetes

To the Editor:Diabetes is considered a 21st century epi-demic. Nearly 90% of patients with type-2diabetes are overweight or obese at the timeof incident diabetes (1), and it is well knownthat a sedentary lifestyle and unhealthy habitscontribute to both obesity and diabetes.Mounting evidence has revealed a benefitwith exercise and dietary interventions in dia-betes prevention (2,3). However, the benefi-cial effects of multifaceted lifestyleinterventions on clinically oriented outcomesin diabetic patients have not been clearlyshown.

A recent meta-analysis (4) concluded thatthere is no evidence of reduced all-cause mor-tality (in spite of a trend in that direction:risk ratio 0.75; 95% CI, 0.53–1.06): In partic-ular, the Look AHEAD (Action for Health inDiabetes) research group (5) randomlyassigned 5145 overweight or obese patientswith type-2 diabetes to participate in anintensive multicomponent lifestyle interven-tion that promoted weight loss throughdecreased caloric intake and increased physi-cal activity (intervention group), or to receivediabetes support and education (controlgroup). Weight loss was greater in the inter-vention group than in the control groupthroughout the study (8.6% vs. 0.7% at1 year; 6.0% vs. 3.5% at study end). How-ever, although the need for medications wasreduced, and several measures of well-beingwere improved, at a median follow-up of9.6 years, when the trial was prematurelystopped ‘for futility’, there was no significantdifference between the two groups in the rateof cardiovascular events.

This conclusion could push physicians andpatients to reduce lifestyle-based efforts, rely-ing only on drugs. We think that the trial (5)should not have been interrupted. Cardiovas-cular events were the main outcome, but amore patient-oriented outcome – any cause

deaths – showed a promising HR = 0.85(95% CI 0.69–1.04). With the planned 13.5-year follow-up and under the conservativehypothesis of constant mortality trend andHR, the number of deaths would increasefrom 376 to 529, with 95% CI 0.71–1.01 and90% CI 0.73–0.98. The latter may be moreappropriate because a priori one would nothave expected any detrimental effect of mod-erate physical activity/weight loss in patientswith a mean BMI of 36.0 � 6.0 (5). Becauseof the increasing age (nearly 59 years at base-line) and comorbidity, most likely the num-ber of deaths, and, therefore, the powerwould have been higher. More so if consider-ing the general population instead of thehealthy volunteers of a trial (6).

Indeed, in a longitudinal study of 1810older participants followed up for 18 years(7), several lifestyle behaviours were associ-ated with longevity, even after age 75 andindependently of health status. Furthermore,healthy behaviours remained predictive ofsurvival also among the very elderly and thosewith multiple morbidities. Of note, a meta-epidemiological study (8) of 16 meta-analysesincluding 305 randomised controlled trialswith 339,274 participants found a comparableeffectiveness of exercise and drug interven-tions on mortality outcomes in the secondaryprevention of cardiovascular diseases, and inprediabetes.

Therefore, we suggest that physiciansshould not mainly focus on drugs to treatconditions brought on by unhealthy behav-iours.

A. Donzelli,1 L. Mascitelli,2

M. R. Goldstein,3 F. Berrino41ASL di Milano, Milano, Italy

2Medical Service, Comando Brigataalpina “Julia”/Multinational Land

Force, Udine, Italy

3NCH Physician Goup, Naples, FL, USA4Department of Preventive and Predictive

Medicine, Fondazione IRCCS IstitutoNazionale dei Tumori, Milan, Italy

E-mail: lumasci@libero.it

References1 Carnethon MR, De Chavez PJ, Biggs ML et al. Asso-

ciation of weight status with mortality in adults with

incident diabetes. JAMA 2012; 308: 581–90.

2 Yamaoka K, Tango T. Efficacy of lifestyle education

to prevent type 2 diabetes: a meta-analysis of ran-

domized controlled trials. Diabetes Care 2005; 28:

2780–6.

3 Orozco LJ, Buchleitner AM, Gimenez-Perez G, Roqu�e

I Figuls M, Richter B, Mauricio D. Exercise or exer-

cise and diet for preventing type 2 diabetes mellitus.

Cochrane Database Syst Rev 2008; 3: CD003054.

4 Sumamo Schellenberg E, Dryden DM, Vandermeer B

et al. Lifestyle interventions for patients with and at

risk for type 2 diabetes. A systematic review and

meta-analysis. Ann Intern Med 2013; 159: 543–51.

5 The Look AHEAD Research Group. Cardiovascular

effects of intensive lifestyle intervention in type 2 dia-

betes. N Engl J Med 2013; 369: 145–54.

6 Pinsky PF, Miller A, Kramer BS et al. Evidence of a

Healthy Volunteer Effect in the Prostate, Lung, Colo-

rectal, and Ovarian Cancer Screening Trial. Am J Epi-

demiol 2007; 165: 874–81.

7 Rizzuto D, Orsini N, Qiu C, Wang HX, Fratiglioni L.

Lifestyle, social factors, and survival after age 75: pop-

ulation based study. BMJ 2012; 345: e5568.

8 Naci H, Ioannidis JP. Comparative effectiveness of

exercise and drug interventions on mortality out-

comes: metaepidemiological study. BMJ 2013; 347:

f5577.

Disclosure

None.

doi: 10.1111/ijcp.12383

LETTER

Do randomised studies of traditional Asian therapies generatedifferent results than non-randomised trials?

To the Editor:In clinical trials, randomisation is employedto minimise bias. When treatment groupsare allocated through an adequate randomprocedure, they are likely to be similar in all

quantifiable and unquantifiable aspects. Basedon this rationale, the randomised clinicaltrial (RCT) has become the gold standard fortesting the efficacy of therapeutic interven-tions.

Some experts have, however, suggestedthat randomisation may be misguided asnon-randomised studies (NRS) tend to gener-ate similar results as RCTs (1). This may betrue in certain, but not in all circumstances;

ª 2014 John Wiley & Sons LtdInt J Clin Pract, May 2014, 68, 5, 655–658 655

if RCTs of a given intervention have consis-tently demonstrated positive results, thistherapy is likely to be effective. Most NRSwould then show similarly positive findingsas RCTs. The situation is different forinterventions, which are not indisputablyeffective. Here, NRS might generate positiveresults because of selection bias, whileRCTs might yield negative findings. Weinvestigated whether RCTs and NRS oftraditional Asian treatments generate similarfindings.

To maximise consistency of the evalua-tion process, we confined our analysis toour own systematic reviews of both RCTs

and excluded systematic reviews includingless than four clinical studies. We calculatedthe percentages of RCTs and NRS withpositive results from each systematic reviewand generated a ratio of the two figures(Table 1).

Seventeen systematic reviews met ourinclusion criteria (2–18). Table 1 shows thatRCTs tend to produce different results fromNRS. If both generated similar findings, theratio would be close to 1. Yet, the ratio isconsistently higher; on average, it amounts to1.52. This seems to confirm our hypothesisthat NRS of interventions of uncertain effi-cacy yields positive results more frequently

than RCTs. However, it is based on only arelatively small sample of systematic reviewswhich were all conducted by us. This wasdone to increase the consistency of evaluatingthe primary data, but it might have intro-duced a systematic error. Thus, our resultsrequire independent confirmation.

We conclude that the two trial designsgenerate findings which differ systematically.As randomisation minimises selection bias, itseems safe to assume that RCTs are lessbiased than NRS. In other words, the findingsof NRS are more likely to be false positivethan those of RCTs. This suggestion isnot purely supported by our findings; more

Table 1 Systematic reviews of Asian traditional therapies

Intervention

(reference) Condition

Number of

included RCTs

Number of

included NRS

Directions of

results of RCTs

Directions of

results of NRS

% positive

NRS:RCTs (ratio)

Acupuncture (2) Erectile dysfunction 2 2 1 positive

1 negative

2 positive 100:50 (2)

Acupuncture (3) Uraemic pruritus 3 3 3 positive 3 positive 100:100 (1)

Cupping (4) Stroke 3 2 3 positive 2 positive 100:100 (1)

Guasha (5) Musculoskeletal pain 5 2 1 positive

4 negative

1 positive

1 negative

50:20 (2.5)

Moxibustion (6) Type 2 diabetes 4 1 4 positive 1 positive 100:100 (1)

Qigong (7) Cancer 4 5 2 positive

1 negative

1 unclear

5 positive

0 negative

0 unclear

100:50 (2)

Qigong (8) Movement disorders 3 1 2 positive

1 negative

1 positive 100:66.6 (1.5)

Qigong (9) Type 2 diabetes 3 6 3 positive 4 positive

2 negative

50:100 (0.5)

Tai Chi (10) Breast cancer 3 4 1 positive

2 negative

3 positive

1 unclear

75:33.3 (2.5)

Tai Chi (11) Cancer 3 1 2 positive

1 negative

1 positive

0 negative

100:66.6 (1.5)

Tai Chi (12) Osteoarthritis 5 7 4 positive

1 negative

6 positive

0 negative

1 unclear

93:80 (1.16)

Tai Chi (13) Osteoporosis 5 2 2 positive

3 negative

1 positive

1 negative

50:40 (1.3)

Tai Chi (14) Parkinson’s disease 3 4 1 positive

2 negative

0 unclear

3 positive

0 negative

1 unclear

75:33.3 (2.5)

Tai Chi (15) Rheumatoid arthritis 2 3 2 positive 3 positive 100:100 (1)

Tai Chi (16) Type 2 diabetes 1 3 0 positive

0 negative

1 unclear

2 positive

0 negative

1 unclear

67:0

(∞)

Tai Chi (17) Type 2 diabetes 8 2 3 positive

5 negative

1 positive

1 negative

50:37 (1.4)

Yoga (18) Menopausal symptoms 3 4 0 positive

3 negative

4 positive

0 negative

100:0 (∞)

Average ratio 1.52*

*Two SRs with an infinite value for the ratio were excluded. RCTs, randomised clinical trials; NRS, non-randomised studies. Positive = suggesting effectiveness of

experimental treatment for at least one outcome measure; negative = not suggesting effectiveness of experimental treatment.

ª 2014 John Wiley & Sons LtdInt J Clin Pract, May 2014, 68, 5, 655–658

656 Letters

importantly, it is also sustained by simplecommon sense about the nature of selectionbias.

E. Ernst,,1 M. S. Lee,21Complementary Medicine, Peninsula Medical

School, University of Exeter, Exeter, UK2Medical Research Division, Korea Instituteof Oriental Medicine, Daejeon, South Korea

E-mail: E.Ernst@exeter.ac.uk

References1 Concato J, Shah N, Horwitz RI. Randomized, con-

trolled trials, observational studies, and the hierarchy

of research designs. N Engl J Med 2000; 342: 1887–92.

2 Lee MS, Shin BC, Ernst E. Acupuncture for treating

erectile dysfunction: a systematic review. BJU Int

2009; 104: 366–70.

3 Kim KH, Lee MS, Choi S-M, Ernst E. Acupuncture

for Treating Uremic Pruritus in Patients with End--

Stage Renal Disease: a Systematic Review. J Pain

Symptom Manage 2010; 40: 117–25.

4 Lee MS, Choi TY, Shin BC et al. Cupping for stroke

rehabilitation: a systematic review. J Neurol Sci

2010; 294: 70–3.

5 Lee MS, Choi TY, Kim JI, Choi SM. Using Guasha

to treat musculoskeletal pain: a systematic review of

controlled clinical trials. Chin Med 2010; 5: 5.

6 Kim TH, Choi TY, Shin BC, Lee MS. Moxibus-

tion for managing type 2 diabetes mellitus: a

systematic review. Chin J Integr Med 2011; 17:

575–9.

7 Lee MS, Chen KW, Sancier KM, Ernst E. Qigong

for cancer treatment: a systematic review of

controlled clinical trials. Acta Oncol 2007; 46:

717–22.

8 Lee MS, Ernst E. Qigong for Movement Disor-

ders: a Systematic Review. Mov Disord 2009; 24:

301–3.

9 Lee MS, Chen KW, Choi TY, Ernst E. Qigong for

type 2 diabetes care: a systematic review. Comple-

ment Ther Med 2009; 17: 236–42.

10 Lee MS, Choi T-Y, Ernst E. Tai chi for breast cancer

patients: a systematic review. Breast Cancer Res

Treat 2010; 120: 309–16.

11 Lee MS, Pittler MH, Ernst E. Is tai chi an effective

adjunct in cancer care? A systematic review of con-

trolled clinical trials. Support Care Cancer 2007; 15:

597–601.

12 Lee MS, Pittler MH, Ernst E. Tai chi for osteoarthri-

tis: a systematic review. Clin Rheumatol 2008; 27:

211–8.

13 Lee MS, Pittler MH, Shin BC, Ernst E. Tai chi for

osteoporosis: a systematic review. Osteoporos Int

2008; 19: 139–46.

14 Lee MS, Lam P, Ernst E. Effectiveness of tai chi for

Parkinson’s disease: a critical review. Parkinsonism

Relat Disord 2008; 14: 589–94.

15 Lee MS, Pittler MH, Ernst E. Tai chi for rheumatoid

arthritis: systematic review. Rheumatology 2007; 46:

1648–51.

16 Lee MS, Pittler MH, Kim MS, Ernst E. Tai chi for

Type 2 diabetes: a systematic review. Diabet Med

2008; 25: 240–1.

17 Lee M, Choi T-Y, Lim H-J, Ernst E. Tai chi for

management of type 2 diabetes mellitus: a system-

atic review. Chin J Integr Med 2011; 17: 789–93.

18 Lee MS, Kim JI, Ha JY et al. Yoga for menopausal

symptoms: a systematic review. Menopause 2009; 16:

602–8.

Disclosures

The authors have declared that no competinginterests exist.

doi: 10.1111/ijcp.12417

LETTER

Depression, anxiety and reduced quality of life in predialysis:differences across the CKD stages?

To the Editor:Recently, we read with great interest the arti-cle by Lee et al. entitled ‘Association ofdepression and anxiety with reduced qualityof life in patients with predialysis chronic kid-ney disease’ published in April 2013 in TheInternational Journal of Clinical Practice (1).As the authors said, depression and anxietywere related to impaired quality of life(QOL), and the prevalence of anxiety anddepression did not differ significantly acrossthe chronic kidney disease (CKD) stages.However, the QOL between different stages inadvanced CKD remain unclear in this article.Previous longitudinal studies showed thatserum creatinine or estimated glomerular fil-tration rate (eGFR) was associated with QOL.The Modification in Diet in Renal DiseaseStudy in a cohort of patients with moderateto severe CKD found decreased renal functionwas associated with psychological distress andimpaired health-related QOL (2). Okubo’saccount of a 3-year follow-up study in Japanshowed that the health-related QOL at stages4–5 were significantly lower than at stages 1–2 (3). Nevertheless, few cross-sectional studiesmeasured QOL between different stages of

moderate to advanced CKD although suffi-cient data are available to evaluate. Althoughpsychological distress is a mirror of decreasedQOL, the specific status of QOL is importantfor planning proper treatment strategies. Sowe suggest that QOL between different CKDstages should be mentioned in the study.

The authors indicated that there were noassociation between depression or anxiety andthe stages of CKD. However, patients withCKD face several challenges that increase thelikelihood of developing anxiety or depres-sion. As these challenges change with thedecreasing renal function, the managementmay not invariable. These challenges includespecific symptoms caused by CKD or thepatient’s treatment; diet prescription andwater restriction; fear of disability, morbidityand shortened life span; worry about the bur-den on family and so on (4,5). Theoretically,therapies for anxiety and depression includemedications on CKD or specific symptomscaused by CKD; reduced-doses of anxiolyticsand antidepressants adjusted by eGFR; properpsychological therapy and alternative medi-cine (5). Surprisingly, only few data exist onthe effective and safety of these therapies.

Further research may emphasise on how toimprove depression and anxiety and enhanceQOL in patients with different stages of CKD.

Another considerable question is that theabbreviated version of the World HealthOrganization Quality of Life assessmentinstrument (WHOQOL-BREF) was used toassess the patients’ subjective QOL. WHO-QOL-BREF is a generic instrument andwidely used in patients with CKD. However,the use of a disease-specific instrument alongwith the generic instrument selected in eachcase is recommended by the majority ofexperts. The specific instrument is more effec-tive than the generic instrument, and the gen-eric instrument allows different diseases orpatients and general population to be com-pared (6–8). There is not a specific instru-ment for non-dialytic therapy. Nevertheless,patients with predialysis CKD also have highprevalence of psychological and physicalimpairment, and the early detection andactive interventions are in urgent need. Alongwith better understanding of the problemswith advanced CKD patients, the time todevelop a new specific instrument for predial-ysis CKD population has truly arrived.

ª 2014 John Wiley & Sons LtdInt J Clin Pract, May 2014, 68, 5, 655–658

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