Metformin and cardiorenal outcomes in diabetes: A reappraisal

Abstract

The guidance issued to the pharmaceutical industry by the US Food and Drug Administration in 2008 has led to the publication of a series of randomized, controlled cardiovascular outcomes trials with newer therapeutic classes of glucose-lowering medications. Several of these trials, which evaluated the newer therapeutic classes of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, have reported a reduced incidence of major adverse cardiovascular and/or renal outcomes, usually relative to placebo and standard of care. Metformin was the first glucose-lowering agent reported to improve cardiovascular outcomes in the UK Prospective Diabetes Study (UKPDS) and thus became the foundation of standard care. However, as this clinical trial reported more than 20 years ago, differences from current standards of trial design and evaluation complicate comparison of the cardiovascular profiles of older and newer agents. Our article revisits the evidence for cardiovascular protection with metformin and reviews its effects on the kidney. K E Y W O R D Satherosclerotic cardiovascular disease, cardiovascular outcomes, chronic kidney disease, glucose-lowering therapy, metformin

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT)

“…This hypothesis was corroborated by the ORIGIN study which showed that reduction in blood glucose levels per se did not reduce cardiovascular events in the studied population ( 30 ). However, as mentioned previously, the randomized data on metformin treatment in patients with documented cardiovascular disease are scarce and there is a definite need for more randomized data ( 9 ).…”

“…This is partly because the metformin substudy of the UKPDS trial compared conventional therapy with metformin in 753 patients in a nested study design and that few patients were on randomized therapy after 5 years. ( 8 , 9 ) and there has been no randomized outcome trials to assess the effect of metformin on cardiovascular events. Furthermore, and most importantly, the recent large randomized clinical trials of sodium glucose co-transporter 2 (SGLT2)-inhibitors ( 10 ) and glucagon like peptide 1 (GLP1)-analogues ( 11 ) have provided strong evidence of a beneficial clinical effect of these newer drug classes.…”

Where Does Metformin Stand in Modern Day Management of Type 2 Diabetes?

“…One main criticism is that UKPDS only comprised of individuals with a new diagnosis of T2D not based on a tight criteria (fasting blood glucose range from 6.1 to 15.0 mmol/L) who were not at particularly high risk of CVD in the first place [26]. It is important to remember that the inclusion of obese individuals in UKPDS is consistent with general T2D population and is more representative of the current diabetes population.…”

“…The history of CVOTs can broadly be categorised into pre-2008 and post-2008 periods after the US Food and Drug Administration (FDA) introduced the new guidelines for cardiovascular evaluation of GLTs largely focussed around the composite end-point of Major Adverse Cardiovascular Events (MACE) following the discovery of increased adverse cardiovascular events associated with rosiglitazone use [38,39]. Hence, considerable caution is required when comparing older and newer trials, which are more standardised in design and amenable to meta-analysis [26]. It is also worth noting that the modern CVOTs are relatively short trials recruiting mostly high-risk individuals who are unrepresentative of the general population.…”

“…In summary, the results of these reviews are inconclusive in respect to the cardiovascular impact of metformin. It was acknowledged that a lot of this uncertainty was due to lack of a large randomised double-blind, placebo controlled trial with dedicated MACE end-points [45], lack of long-term evaluations [26] and the unexplained deleterious effect of the combination of metformin plus SU from the UKPDS data [25,46]. Additionally, differences in patient characteristics, study designs and duration could provide an explanation for the discrepancies observed.…”