Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis
Introduction
Ageing is characterised by progressive damage at a cellular and organ level as prevention and repair mechanisms begin to break down (Finkel and Holbrook, 2000, Garinis et al., 2008, Mitchell, 2008). Diseases of ageing – such as cardiovascular disease (CVD), kidney failure and cancer – are the result of the accumulation of this damage and ultimately responsible for organisms dying of old age. With the ageing population of the developed world the extension of healthspan – the period that an individual is functional and free of chronic diseases (Barzilai et al., 2016) – has been identified as an important goal both for the minimisation of human suffering and to enable healthcare systems to cope.
One drug which has been subjected to significant research as a geroprotective factor is the insulin sensitiser metformin. Metformin has been shown to extend the lifespans of model organisms (including mice and C. elegans (Anisimov et al., 2011, Anisimov et al., 2010a, Cabreiro et al., 2013)) and a number of potential mechanisms for its effects have been discussed, including decreased insulin and IGF-1 signalling (Liu et al., 2011), inhibition of mTOR (Kickstein et al., 2010, Nair et al., 2014), reducing the levels of reactive oxygen species (ROS)(Batandier et al., 2006; Zheng et al., 2012), lowering inflammation (Saisho, 2015), reducing DNA damage (Algire et al., 2012; Na et al., 2013), and the activation of AMP-activated protein kinase (AMPK)(Zhou et al., 2001). Its effect on AMPK has received particular attention as it models the intracellular mechanisms of caloric restriction (Gillespie et al., 2016, Lee and Min, 2013) – another intervention which has been found to be capable of extending the lifespans of animal models – but which is not feasible for widespread implementation in humans (Roth and Ingram, 2016). This, among other factors, has led to metformin being described as a caloric restriction mimetic (CRM) (Gillespie et al., 2016, Lee and Min, 2013, Roth and Ingram, 2016).
One aspect of metformin which makes it particularly promising for development as a geroprotective agent is that it is already being widely used in humans for a different purpose. As an insulin sensitiser metformin is a first line therapy for diabetes (Nathan et al., 2006). Through this use its potential for adverse effects and contraindications have been well characterised, and it has been found to have a broad safety profile (Rojas and Gomes, 2013) which would make it significantly quicker and easier to implement as an intervention for ageing than a previously unutilised drug.
Due to the widespread application of metformin for the management of diabetes, a large amount of data has already been collected on its effects on mortality and diseases of ageing. However, extrapolation of this research evidence to the general population is invariably confounded by the fact that the people who are currently receiving metformin have diabetes and are taking it for the treatment thereof. As such, any benefits seen could be due to improvements in diabetes control. Two analytic strategies have been attempted to overcome this limitation and gain some insight as to whether metformin could be used to improve the healthspan of the general population.
The first strategy is the comparison of the outcomes of diabetics taking metformin to the general or non-diabetic population (Bannister et al., 2014). This approach reasons that as diabetics are on average less healthy than non-diabetics, superior outcomes in the metformin/diabetic group should be a consequence of beneficial effects of metformin overcoming their generally worse health status. A weakness of this strategy is that people taking metformin could be observed to have worse or the same outcomes as non-diabetics in the presence of an actual beneficial effect of metformin due to it being masked by the detrimental effects of diabetes. The second strategy is to compare diabetics taking metformin to diabetics managing their diabetes through other means while statistically controlling for the effects of the different therapies on diabetes management (i.e. HbA1c or diabetes related doctor visits (Lin et al., 2015)). This strategy reasons that any difference in outcomes seen after adjusting for the relative effects on disease management can be attributed to metformin’s activity beyond diabetes control, and are therefore generalisable. This strategy’s weaknesses are that statistical adjustment is an imperfect process – it is always possible that residual confounding remains that could cause any differences observed − and that other antidiabetic drugs could cause harms which in comparison would appear to be beneficial effects by metformin.
However, although additional controlled, experimental research will need to be carried out, there exists a wealth of observational data that can offer evidence on whether metformin could be applied as a geroprotective agent in humans. As such, this systematic review and meta-analysis has been undertaken to identify and synthesise all studies where the effects of metformin on all-cause mortality or diseases of ageing have been compared to the general or non-diabetic population or to diabetics managing their diabetes through other means with adjustment for disease control. Numerous systematic reviews have been carried out which nominally address this review’s outcomes of interest, however those which investigate the association between metformin and all-cause mortality do so in the context of severe diseases in addition to diabetes (usually various forms of cancer) (Coyle et al., 2016, Gash et al., 2017, Li et al., 2017, Meng et al., 2017, Tang et al., 2017, Zhou et al., 2017a) and their results therefore cannot be generalised, while those that investigate the incidence of diseases of ageing do so without attempting to adjust for diabetes control (Liu et al., 2017, Ma et al., 2017, Pladevall et al., 2016, Tang et al., 2017, Zhou et al., 2017b). As such, the question of whether metformin could act as a geroprotective agent in humans has yet to be addressed in a systematic review.
Section snippets
Objective
This systematic review aimed to identify and synthesise all research on the effect of metformin on all-cause mortality and diseases of ageing which had the potential to give evidence on whether it could be used as a geroprotective factor to extend life and healthspan in the general population. It followed an a priori protocol pre-registered with PROSPERO (CRD42016036098).
Population
Studies on all-cause mortality were eligible for inclusion if they reported on adults with a minimum age of 40 years or a
Results
The initial search identified a total of 21,027 studies, which was reduced to 19,408 following the removal of duplicates. Following title/abstract screening, 260 studies were included for full-text review. Of these, 207 were excluded and 53 were included. Full search details and reasons for exclusion are given in Fig. 1. Overall, 13 included studies reported data on all-cause mortality while 49 reported on diseases of ageing.
Discussion
This systematic review has shown through meta-analysis that diabetics taking metformin have a lower rate of all-cause mortality than non-diabetic people and the general population. Our results suggest that metformin could be an effective intervention to extend the lifespans of people who do not have diabetes. This is supported by additional meta-analyses showing that diabetics taking metformin had lower rates of all-cause mortality than diabetics receiving other therapies after adjusting for
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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