Intended for healthcare professionals

CCBYNC Open access

Rapid response to:

Research

Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study

BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f5577 (Published 01 October 2013) Cite this as: BMJ 2013;347:f5577

Rapid Response:

Re: Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study

Naci H, et al investigated to determine the comparative effectiveness of exercise versus
drug interventions on mortality outcomes. They included 16 (four exercise and 12 drug) meta-analyses and included 305 randomised controlled trials with 339 274 participants. They observed that no statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09 and exercise v antiplatelets 0.10). Diuretics were more effective than exercise in heart failure (exercise vs diuretics 4.11). They concluded that although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.1

This study points the importance of therapeutic life style changes compared with drugs intervention. All physicians should think about this message in time of many drugs being prescribed while elderly population is increasing fast and life expectancy is longer. In this regard, statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are very important and so, most frequently prescibed to prevent cardiovascular events in patients with high risk or even low risk of vascular disease by reducing low density lipoprotein cholesterol.2,3 Therefore, The 2013 American guidelines recommend to use high-intensity statin therapy and extend to use in more people.4 However, European worried about the potential side effects of statins in a large fraction of population for a life-long period.5 This is true to Asian people including Korean and Japanese in whom cholesterol levels and the prevalence of cardiovascular disease are still lower albeit both are increasing now.

Unwanted effects of statins have been neglected over the decade and nowadays, these off-target effects are being focused. Statin treatment are associated with deterioration of glucose homeostasis and increased risk of diabetes mellitus.6-8 Experimental and clinical studies have suggested these off-target effects are dose-dependent.9-13 A very recent study reported that after adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new-onset diabetes (hazard ratio 1.23 and 1.32, respectively).14 Most recently, renal insult by statin treatment has been suggested in contrast to the previous studies showing the renoprotective effect.15 These off-target effects are also dose-dependent. The use of high potency statins was associated with an increased rate of diagnosis for acute kidney injury in hospital admissions compared with low potency statins.

With current evidence, it is difficult to weigh the possible adverse renometabolic effects of statin on overall mortality in a quantitative manner. In the primary prevention studies, the use of statins is controversial: favoring3 or not favoring16,17 statins. According to a current meta-analysis on this issue, as compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events.12 This data support that lipid lowering effect of statins outweighs adverse renometabolic effect of statins. Of note, it would be prudent to consider current cardiorenometabolic status and natural histroy of diseases in each individual when choosing statin therapy for optimal individual patient health over the long-term. Indeed, therapeutic life style changes may be potentially as effective as many drug interventions on the secondary prevention of coronary heart disease, stroke, heart failure, and prediabetes.1

Funding: None, Disclosures: None

REFERENCES
1. Naci H, Ioannidis JPA. Comparative effectiveness of exercise and drug
interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f5577

2. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.

3. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.

4. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013, doi: 10.1161/01.cir.0000437738.63853.7a.

5. http://us5.campaign-archive2.com/?u=5722525cab46445583feb00fd&id=4c6ab38...

6. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins. Atherosclerosis 2011;215:1-8.

7. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167: 1696-1702.

8. Lim S, Sakuma I, Quon M, Koh KK. Differential metabolic actions of specific statins: clinical and therapeutic considerations. Antioxid Redox Signal 2013 Aug 7. [Epub ahead of print]

9. Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells. Br J Pharmacol 1999;126:1205-13.

10. Koh KK, Quon MJ, Han SH, et al. Simvastatin improves flow-mediated dilation but

reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes

Care 2008;31:776-82.

11. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol 2010;55:1209-16.

12. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64.

13. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013;346:f2610.

14. Shen L, Shah BR, Reyes EM, Thomas L, Wojdyla D, Diem P, et al. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ 2013;347:f6745.

15. Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, Teare GF, Raymond CB, et al; Canadian Network for Observational Drug Effect Studies. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ 2013;346:f880.

16. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 2012;172:144-52.

17. Goldstein MR, Mascitelli L. Do statins cause diabetes? Curr Diab Rep 2013;13:381-90.

Competing interests: No competing interests

30 December 2013
Kwang K. Koh
Cardiologist
Gachon University Gil Medical Center
1198 Kuwol-dong, Namdong-gu, Incheon, Korea