Diabetologia

, Volume 56, Issue 4, pp 939–940 | Cite as

Metformin and mortality. Reply to Lund SS [letter]

Letter
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Keywords

Meta-analysis Metformin Neoplasms Systematic review 

Abbreviation

UKPDS

UK Prospective Diabetes Study

To the Editor: We thank Dr Lund for his comments [1] on our analysis of cancer incidence and mortality in randomised trials of metformin [2] and confirm that the Hyperinsulinaemia: the Outcome of its Metabolic Effects (HOME) trial [3] was excluded because it did not meet our sample size inclusion criterion.

Dr. Lund also calls attention to our sensitivity analysis of all-cause mortality, which excluded one trial, the UK Prospective Diabetes Study (UKPDS) trial of metformin in patients with sulfonylurea failure (UKPDS-S) [4], from the group of trials in which the comparator was placebo or usual care. This acknowledged post hoc sensitivity analysis was carried out because of the high heterogeneity in this group of studies (I2 = 50.8%), but Dr Lund correctly observes that we could equally conduct a sensitivity analysis to exclude the other large trial in this group of studies, the UKPDS trial of metformin in overweight patients (UKPDS-O). For completeness, we include here a table of relative risks for all-cause mortality, and corresponding confidence intervals and heterogeneity statistics, for all placebo- or usual-care-controlled trials, and excluding each trial in turn (Table 1). Exclusion of either UKPDS trial, but not any other trial in this group, reduces the I2 statistic for heterogeneity to 0.0%.
Table 1

Summary relative risks (RR), with 95% CIs and I2 statistics for heterogeneity, for all-cause mortality in trials randomising participants to receive metformin or placebo/usual care, across all trials and in sensitivity analyses excluding each trial in turn

Study omitted

RR (95% CI)

I2

None (main analysis)

0.91 (0.70, 1.18)

50.8%

Diabetes Prevention Program (DPP) [5]

0.90 (0.68, 1.17)

59.9%

Early Diabetes Intervention Trial (EDIT) [6]

0.91 (0.70, 1.20)

60.4%

Indian Diabetes Prevention Program (IDPP) [7]

0.91 (0.70, 1.19)

60.2%

Pfützner et al 2011 [8]

0.90 (0.69, 1.18)

60.6%

UKPDS trial in overweight patients (UKPDS-O) [4]

1.43 (0.95, 2.13)

0.0%

UKPDS trial in sulfonylurea failure (UKPDS-S) [4]

0.67 (0.49, 0.93)

0.0%

We believe that the remarks in our paper that the summary estimates ‘are dominated by the two large trials from the UKPDS group, which appear to show for metformin effects in opposite directions’ and that our analyses have limitations to be overcome by future randomised trials, remain justified. We re-emphasise our observation that the average follow-up for mortality in our analysis is just 2.8 years, and that our results for all-cause mortality in particular are unlikely to fully reflect the long-term effects of metformin.

Notes

Duality of interest

R. R. Holman has, in the last 12 months, received research support from Amylin, Bayer, Merck and Novartis; attended advisory boards with Amylin, Lilly, Merck, Novartis and Novo Nordisk; and given lectures supported by Bayer, Lilly, Merck and Novo Nordisk. R. J. Stevens and B. J. Cairns have no conflicts of interest associated with this letter.

Contribution statement

RJS, BJC and RRH were responsible for the conception and design of the manuscript, drafting the article and revising it. RJS carried out statistical analyses. All authors approved the version to be published. The authors are writing on behalf of the Metformin Trialists’ Collaboration.

References

  1. 1.
    Lund SS (2013) Metformin and mortality. Diabetologia. doi:10.1007/s00125-013-2843-y
  2. 2.
    Stevens RJ, Ali R, Bankhead CR et al (2012) Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia 55:2593–2603, Erratum 55:3399–3400PubMedCrossRefGoogle Scholar
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    Kooy A, de Jager J, Lehert P et al (2009) Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 169:616–625PubMedCrossRefGoogle Scholar
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    UK Prospective Diabetes Study Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865CrossRefGoogle Scholar
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    Knowler WC, Barrett-Connor E, Fowler SE et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403PubMedCrossRefGoogle Scholar
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    Holman RR, Blackwell L, Stratton IM, Manley SE, Tucker L, Frighi V (2003) Six-year results from the Early Diabetes Intervention Trial. Diabet Med 20:15, AbstractGoogle Scholar
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    Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V (2006) The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 49:289–297PubMedCrossRefGoogle Scholar
  8. 8.
    Pfützner A, Paz-Pacheco E, Allen E, Frederich R, Chen R (2011) Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metabol 13:567–576CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Primary Care Health SciencesUniversity of OxfordOxfordUK
  2. 2.Cancer Epidemiology UnitUniversity of OxfordOxfordUK
  3. 3.Diabetes Trials Unit, Oxford Centre for Diabetes Endocrinology and MetabolismUniversity of OxfordOxfordUK

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