Time to revisit the true role of metformin in type 2 diabetes mellitus

KEYWORDS:

• Metformin
• type 2 diabetes
• cardiovascular disease
• insulin resistance
• inflammation

Those who cannot remember the past are condemned to repeat it.

– George Santayana

Guidelines issued by the European Society of Cardiology (ESC) and the European Society for the Study of Diabetes (EASD) were last released regarding the treatment of diabetes, prediabetes, and cardiovascular disease in 2019 [1]. These new guidelines not only highlight data with regard to pathophysiology but also in terms of new treatment options for type 2 diabetes mellitus (T2DM). Specifically, the recent introduction of glucagon-like peptide 1 (GLP-1) agonists and oral sodium glucose cotransport 2 (SGLT2) inhibitors are greatly emphasized [2–5].

We certainly embrace these new guidelines with great enthusiasm as they provide recommendations on new emerging therapies; particularly, as the prevalence of DM continues to increase across the world. In fact, based on the latest results from the International Diabetes Federation Diabetes Atlas, under half a billion people are currently living with DM across the globe, estimates that are projected to increase by 25% in 2030 and 51% in 2045 [6].

Data have linked the development of CVD in T2DM to a complex combination of various traditional and non-traditional risk factors [7]. Additionally, since the seminal work of Haffner and associates from 1998, T2DM is now seen as a true coronary artery disease (CAD) risk equivalent [8]. Currently, T2DM is a well-recognized trigger that accelerates atherothrombosis, leading to the development of CAD, peripheral vascular disease, and stroke [9].

One of the main harbingers of T2DM is insulin resistance [10]. Insulin resistance could be defined as the subnormal glucose response to endogenous and/or exogenous insulin. It most commonly occurs in association with obesity but may result from multiple other underlying causes such as: insulin antibodies, pregnancy, stress induced and medications [11]. This metabolic imbalance develops in multiple organs involving the skeletal muscle, liver, adipose tissue, and the heart [10].

Aside from the initial compensatory response of insulin resistance of increasing beta-cell insulin production that results in hyperinsulinemia; we are more interested in the domino cascade complications that ensue such as hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperuricemia, elevated inflammatory markers, endothelial dysfunction, and promotion of a prothrombotic state [10]. However, if we simply focused on hyperglycemia and linked it to the development of T2DM and eventual CVD complications, we might have a good starting point [12].

The presence of hyperglycemia has not only been an invaluable measure to diagnose DM but also very useful in guiding treatment [13–17]. Notwithstanding, hyperglycemia has also become more common given its robust association with obesity [18,19]. Certainly, this becomes critically important given the well-recognized additive abnormalities shared by both obesity and T2DM as it relates to the development of long-term adverse CVD complications [20–24].

If we circle back to the 2019 ESC/EASD guidelines, it is important to keep in mind the main recommendations. First, CVD prevention through the institution of healthy lifestyle interventions. Second, the importance of addressing effective goals of therapy with regard to lipid management. Third, recognition that metformin is no longer recognized as a first-line therapy in the management of DM patients. Instead, glucose-lowering treatments should include the use of GLP-1RAs or SGLT2 inhibitors for patients with either T2DM and CVD or patients with very high CVD risk, with the intention of reducing CV events. Fourth, given the robust data with regard to heart failure, SGLT2 inhibitors are recommended to lower heart failure hospital admissions. Alternatively, metformin should be considered in DM patients with HF if eGFR >30 mL/min/1.73 m². Despite the neutral effect GLP1-RAs and DPP4 inhibitors might have on the risk of HF, their use might still be considered. Furthermore, insulin treatment in HF may be considered, while the DPP4 inhibitor saxagliptin in is not recommended in HF as well as thiazolidinediones. Finally, while aspirin is no longer required for primary prevention in patients with T2DM at moderate CV risk; RAAS blockers are now preferred over beta-blockers/diuretics in pre-DM patients, and the maximum tolerated dose of a stain plus ezetimibe, or PCSK9 inhibitor is recommended in DM individuals with high LDL-c levels [1].

Although we are fully supportive and in complete agreement with these recommended guidelines, as they stand firm, moving in the right direction, we are somewhat taken by surprise by the complete dismissal of metformin as first-line therapy for T2DM. This dismissal was justified by the trial-based evidence from UKPDS that metformin is not as strong as the new novel drugs tested in recent cardiovascular outcomes trials (CVOTs). In the recent CVOTs, a majority of patients received metformin before and concurrently with the newer drug under test. However, because metformin was similarly present in both groups, the active and placebo, it is thought that it is unlikely to explain the beneficial effects of the newer drugs under test. Thus, the choice of drug to reduce cardiovascular events in patients with T2DM should be prioritized based on the presence of cardiovascular disease and its risk factors.

We ought to remember the metformin legacy that dates to 1957 since its introduction. This biguanide derivative has been extremely useful in treating T2DM for decades [25]. Although this Editorial in not intended to review the pharmacology of either metformin or any other oral hypoglycemic agent, our intent is to recognize the importance of metformin as a still useful medication. Aside from the fact that metformin it is rarely associated with hypoglyemia even when the risks of hypoglycemia except for cases in which individuals perform high-intensity strenuous physical activity or indulge in prolonged fasting [26–28].

With this introduction, it is now important to bring to the forefront of our discussion two elements we consider invaluable. First is the indisputable CVD protection offered by metformin regardless of its minimal effect on glucose levels [29–32]. In fact, these beneficial effects have been linked to the well-known effects metformin has on lipids, blood pressure, and coronary artery disease with a reduction in the incidence of myocardial infarction [33–39]. Second, not only metformin was shown to be better than first- and second-generation sulfonylureas with regard to CVD outcomes [40,41] but also, the combined use of the thiazolidinedione, pioglitazone, with metformin showed significant slowing of atherosclerotic injury [42]. Unfortunately, pioglitazone has been largely marginalized by its association to heart failure and past concerns regarding bladder cancer [43].

Regarding metformin, we echo the famous quote from Sir Arthur Conan Doyle when he said, ‘When you have eliminated all which is impossible, then whatever remains, however improbable, must be the truth.’

Let us not forget that metformin use has been linked to activation of the AMP-activated protein kinase phosphorylation, which in turn reduces oxidative stress and hence reduces the production of inflammatory cytokines while increasing the activity of endothelial nitric oxide synthase activity [39]. All of which are important CVD protective mechanisms attributed to the use of metformin [22–39].

On a separate note, we should not be so prompt on dismissing the use of metformin in the overall management of T2DM despite the overwhelming excitement that GLP-1 agonists and SGLT2 inhibitors bring to the battleground [3–5]. We have accumulated decades of data on the use of metformin that by now should have solidified its use; particularly as it relates to its powerful anti-inflammatory features among diabetics with a very positive profile in terms of CVD benefits [29–39].

It is this anti-inflammatory component that should spark some positive momentum with regard to the use of metformin based on recent data linking dysfunctional immune responses because of dysregulated T-cell function causing adverse CVD events among T2DM. As it turns out, in a recent systematic review, both metformin and aspirin were shown to ameliorate T-cell mediated inflammation by different mechanisms [44]. These investigators suggested that metformin could probably mediate critical pathways and targets in the inflammatory cascade including the rapamycin (mTOR), STAT5, and adenosine-monophosphate-activated protein kinase (AMPK) signaling pathways [44]. We believe that these findings should revive our interest in drugs that have been used for such a long time and are suddenly dismissed as not useful based on these results that might reinvigorate enthusiasm for re-instituting metformin and aspirin as drugs to be used in the management of T2DM patients to mitigate CVD-related complications.

We should be mindful that we have a trove of information from treating patients with antidiabetic medications for decades. We have conducted large randomized clinical trials

that have given us great insight into the impact of antidiabetic medications and their natural side effects of hypoglycemia and weight gain on cardiovascular outcomes over time [45–47].

Perhaps, the real question we should be asking ourselves is which drug impacts the most glucose dysregulation and progression of atherosclerotic injury in T2DM patients rather than which antidiabetic medication goes first, second, or third. The answer to this burning question is that the only antidiabetic medications proven to reduce CVD are metformin, GLP-1 agonists, and SGLT-2 Inhibitors [48,49].

In terms of mechanisms, metformin reduces endogenously derived exposure to glucose through reduction of hepatic gluconeogenesis. GLP-1 agonists reduce exogenous glucose by reducing the amount consumed as well as reducing endogenous exposure through glucagon regulation. SGLT-2 inhibitors reduce glucose exposure by increasing their urinary excretion glucose. None of these agents have any effect on either fasting insulin levels or glucose deposition in peripheral tissues. In contrast, the use of insulin, sulfonylureas, and thiazolidinediones aside from not reducing CVD events have been suggested to increase CVD risks due to the resultant hypoglycemia, edema, and weight gain associated with their use [45–47,50].

Furthermore, all these agents increase tissue deposition of glucose peripherally. So, should we only be using metformin, GLP-1’s, and SGLT-2 inhibitors? Should we steer clear of insulin, beta-cell stimulators, and thiazolidinediones? The answer is no. All current treatment options are reasonable alternatives if we control glucose load, which ultimately drives glucose deposition into the peripheral tissues. Unfortunately, if we concentrate our efforts on a treatment regimen not addressing the overall glucose supply and the imbalance created toward peripheral glucose deposition, then hypoglycemia and weight gain become negative consequences that ultimately will account for poor CVD outcomes.

As a practical example, let us consider the effect of bariatric surgery, the ultimate regulator of glucose load. Despite ongoing debate on this topic, current evidence points out to the effect of this metabolic surgery in increasing endogenous GLP-1 signaling, a primary pathway considered by many to the postsurgical weight loss and improvements in glucose metabolism seen in these patients [51]. No surprise, bariatric surgery is a potent intervention to reduce cardiovascular events [51].

In summary, when faced with the problem of hyperglycemia, we must be prudent to ask not only how much the intervention lowers blood glucose but also in what manner have we reduced it. While GLP-1 and SGLT-2 inhibitors are potent supply-side antidiabetic medications and excellent first-line agents, it must not be lost that Metformin is one of few supply side antidiabetic medications. In the reality of clinical practice where cost and access are formidable factors, we must not forget that we have three agents that favorably impact the glucose load side of the equation and have favorable cardiovascular outcomes.

Metformin is one of the oldest and most prescribed antihyperglycemic agents for T2DM patients due to its availability, safety, cost, and effectiveness in reducing hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death [39,52–58]. There are also recent studies that suggest metformin may have effects beyond those related to lowering of blood glucose levels; therefore, we do believe that metformin should be continued to be used as a first-line agent in patients with T2DM.

Declaration of Funding

This manuscript received no funding.

Declaration of financial/other relationships

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.