metformin

Metformin in Pregnancy: Mixed Outcomes for Developing Brain

Posted by

0


Summary: A new study explored the effects of metformin, a common treatment for gestational diabetes, on offspring’s brain development in a mouse model. While metformin benefits pregnant mothers with gestational diabetes, its impact on the children’s brain development remains uncertain, with the study indicating no positive effects on the offspring.

The research reveals that metformin’s influence varies based on the mother’s metabolic state during pregnancy and highlights sex-specific changes in the offspring’s hypothalamic signaling. These findings underscore the complexity of prescribing metformin during pregnancy and the importance of considering the maternal metabolic condition before treatment.

Key Facts:

  1. Complex Effects of Metformin: Metformin treatment during pregnancy shows no clear benefits for offspring’s brain development, emphasizing the need to evaluate its use carefully.
  2. Mother’s Metabolic State Matters: The impact of metformin on offspring is significantly influenced by the mother’s metabolic health during pregnancy, suggesting tailored approaches to gestational diabetes treatment.
  3. Sex-Specific Brain Signaling Changes: The study identifies sex-specific alterations in hypothalamic AMPK signaling in offspring exposed to metformin, pointing to nuanced differences in treatment response.

Source: DZD

With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. Although it is known that the oral antidiabetic agent can cross the placental barrier, the impacts on the brain development of the child are largely unknown.

An interdisciplinary research team from the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) have now been able to demonstrate in a mouse model that although metformin has positive effects in pregnant animals, it does not in the offspring.

The results were published in the specialist journal Molecular Metabolism.

This shows a brain and pills.
This increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Current figures show that around one in six pregnant women worldwide are affected by a special form of diabetes known as gestational diabetes. According to the Robert Koch Institute, 63,000 women in Germany were affected by the disease in 2021, and the trend is increasing.

These numbers are alarming because excessively high blood sugar levels during pregnancy are associated with negative consequences for mother and child. This increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Long-Term Effect of Metformin on Offspring is Unclear
For several years, the placenta-crossing oral antidiabetic agent metformin has been increasingly gaining importance as an alternative to insulin administration when lifestyle changes show no success during the treatment of gestational diabetes.

However, there are currently only a few studies on the long-term effects of metformin on the health of offspring. It is known that metformin has an impact on the AMPK signaling pathway, which regulates the networking of nerve cells during brain development.

The interdisciplinary team of DIfE researchers led by Junior Research Group Leader Dr. Rachel Lippert therefore grappled with two central questions: Is metformin treatment only beneficial for the mother or also the child? And does metformin treatment lead to long-term negative physiological changes in the offspring, especially in connection with the development of neuronal circuits in the hypothalamus, a critical region in the regulation of energy homeostasis?

Mouse Models Shed some Light
To answer the key questions, the researchers used two mouse models to represent the main causes of gestational diabetes: severe obesity of the mother before pregnancy and excessive weight gain during pregnancy.

These metabolic states were achieved by means of different feeding patterns, with the mice receiving either a high-fat or control diet. The antidiabetic treatment of female mice and their offspring took place during the lactation period as this corresponds to the third trimester of a human pregnancy in terms of brain development.

Treatment involved insulin, metformin, or a placebo, whereby the dosage was based on standard human treatments. The research team collected data on the body weight of the mice, analyzed various metabolic parameters and hormones, and examined molecular signaling pathways in the hypothalamus.

Maternal Metabolic State is Crucial
“As a result of antidiabetic treatment in the early postnatal period, we were able to identify alterations in the weight gain and hormonal status of the offspring, which were critically dependent on the metabolic state of the mother,” explains Lippert.

Furthermore, sex-specific changes in hypothalamic AMPK signaling in response to metformin exposure were also observed. Together with the metformin-induced shift in the examined hormone levels, the results indicate that the maternal metabolic state must be taken into account before starting the treatment of gestational diabetes.

Focusing on Prevention
According to Rachel Lippert, treatment of gestational diabetes in future could entail developing a medication that is available for all and does not cross the placenta.

“Given the increasing prevalence, education about gestational diabetes and preventive measures are of vital importance. If we can find a way to manage lifestyle and diet more proactively, we are in a better position to exploit the potential of gestational diabetes treatment,” says Lippert.

Background Information
Metformin is an orally taken antidiabetic agent that lowers blood sugar levels by inhibiting glucose production in the liver and increasing the insulin sensitivity of the cells. It is often prescribed as a first-line treatment for people with type 2 diabetes.

Metformin is either used alone or in combination with other oral antidiabetic drugs or insulin preparations. The European Medicines Agency approved metformin for treatment during pregnancy in March 2022

Abstract

Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice

Objective

The incidence of gestational diabetes mellitus (GDM) and metabolic disorders during pregnancy are increasing globally. This has resulted in increased use of therapeutic interventions such as metformin to aid in glycemic control during pregnancy. Even though metformin can cross the placental barrier, its impact on offspring brain development remains poorly understood.

As metformin promotes AMPK signaling, which plays a key role in axonal growth during development, we hypothesized that it may have an impact on hypothalamic signaling and the formation of neuronal projections in the hypothalamus, the key regulator of energy homeostasis. We further hypothesized that this is dependent on the metabolic and nutritional status of the mother at the time of metformin intervention.

Using mouse models of maternal overnutrition, we aimed to assess the effects of metformin exposure on offspring physiology and hypothalamic neuronal circuits during key periods of development.

Methods

Female C57BL/6N mice received either a control diet or a high-fat diet (HFD) during pregnancy and lactation periods. A subset of dams was fed a HFD exclusively during the lactation. Anti-diabetic treatments were given during the first postnatal weeks. Body weights of male and female offspring were monitored daily until weaning.

Circulating metabolic factors and molecular changes in the hypothalamus were assessed at postnatal day 16 using ELISA and Western Blot, respectively. Hypothalamic innervation was assessed by immunostaining at postnatal days 16 and 21.

Results

We identified alterations in weight gain and circulating hormones in male and female offspring induced by anti-diabetic treatment during the early postnatal period, which were critically dependent on the maternal metabolic state.

Furthermore, hypothalamic agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neuronal innervation outcomes in response to anti-diabetic treatment were also modulated by maternal metabolic state. We also identified sex-specific changes in hypothalamic AMPK signaling in response to metformin exposure.

Conclusion

We demonstrate a unique interaction between anti-diabetic treatment and maternal metabolic state, resulting in sex-specific effects on offspring brain development and physiological outcomes.

Overall, based on our findings, no positive effect of metformin intervention was observed in the offspring, despite ameliorating effects on maternal metabolic outcomes. In fact, the metabolic state of the mother drives the most dramatic differences in offspring physiology and metformin had no rescuing effect.

Our results therefore highlight the need for a deeper understanding of how maternal metabolic state (excessive weight gain versus stable weight during GDM treatment) affects the developing offspring.

Further, these results emphasize that the interventions to treat alterations in maternal metabolism during pregnancy need to be reassessed from the perspective of the offspring physiology.

Is Metformin a ‘Drug for All Diseases’?

Posted by

0


As a front-line treatment for type 2 diabetes, metformin is among the most widely prescribed drugs in the United States. In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.

But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.

Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.

The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.

“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told Medscape Medical News.

“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”

Cardiovascular Outcomes

Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, Colorado, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.

Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.

“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”

Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.

“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Schwartz said.

“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Schwartz added. “Perhaps the old dog can learn some new tricks.”

Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.

Reducing Cancer Risks

Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.

The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.

“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.

Research is underway in other tumor types, including oral and endometrial, and brain cancers.

Preventing Alzheimer’s Disease

Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer’s disease.

The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.

“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.

Similar studies are underway in Europe and Asia.

Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug’s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”

Off-Label Uses

Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.

Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.

For the most part, metformin is considered a safe drug, but it is not risk-free, Jain cautioned.

“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.

“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”

Meet Metformin – and It’s Anti-Aging Superpowers

Posted by

0


supplement

To be sure, a healthy diet, physical activity and stress management are still, and for the foreseeable future, the best insurance we can get to support a long, vigorous life. But researchers are continuing to chip away at the biological mechanisms that explain how and why we age, and account for the physiological changes that make us “old,” and ultimately lead to our demise. If we now know a good bit about this biology – I’ve written about a number of these topics — a question naturally comes up. Aren’t we at a point where we can develop treatments that attack aging head-on? And the answer is (sorry, if this doesn’t completely satisfy), we seem to be getting very close by the day. In fact, we may have already done so on a few fronts, but only now are we starting to put the pieces together.

One treatment that’s somewhat unintentionally made the biggest longevity splash is the widely-prescribed medication metformin, which was first discovered, in its natural form, in the 1920s, first synthesized and prescribed (in France) in the late ‘50s, and readily available in the U.S. since 1995. Though for decades, its primary job has been to help millions of people manage their type 2 diabetes, in addition, metformin may be the key to slowing the aging process for millions more. Here’s what you need to know:

A longer, healthier life may be metformin’s superpower.

Metformin is the most commonly prescribed drug to treat type 2 diabetes. It’s generic and hence relatively cheap, and it’s remarkably good at making the body more sensitive to insulin — it helps diabetics clear glucose from the bloodstream with the less-than-normal amounts of insulin their bodies produce. None of this should be news. But bolder claims for the therapeutic power of metformin have been advanced, especially by one influential researcher, Dr. Nir Barzelai at the Albert Einstein College of Medicine. He took his inspiration from studies that showed that older type 2 diabetics taking metformin lived longer than a comparison group, not diabetic, not taking metformin. Further positive results from animal research bolstered his theory that the therapeutic effect of the drug went beyond blood sugar control, beyond even the reduction in cardiovascular disease that you might expect. (Diabetics have a much higher risk of heart attack and stroke.) He surmised that the drug was altering some basic mechanisms of aging, molecules like mTOR and AMK, that regulate, at a deep level, how the body operates. 

Reprogramming the human machine.

When we’re young, our bodies are programmed to get bigger and stronger and to reach sexual maturity. After our prime reproductive years, evolution doesn’t care what happens to us (we’ve already passed our genes down to the next generation, or had the chance to), and that same pro-growth strategy slowly poisons us. We get less good at taking out the trash that builds up inside the cells (autophagy); energy-burning generates more waste (“free radicals”); cells get damaged and hang around, gumming up the works; inflammation keeps increasing. Barzelai, and others, suspect that metformin is dialing down growth and dialing up cell maintenance, which would account for the metformin group seeming to suffer from less disease across the board and, on average, living longer. In other words, it might be helping the drug-takers become more like the centenarians he had famously studied. Not only did the centenarians live much longer than average, but more significantly, they stayed healthy for decades longer, until they hit some internal age limit and then died relatively quickly, i.e., the end that most of us would choose. Could metformin be the ticket, or a ticket, for the rest of us who weren’t born with those fortunate genes? 

Shouldn’t we know the answer by now? 

The answer is yes. Barzilai has had a research trial ready to go for some years now, a study that will look at two groups of 1,500 older subjects, one on metformin, one not, nobody diabetic, to see if the drug group, on average, develops the common “diseases of aging” (heart disease, dementia, cancer) more slowly than the non-drug group over the course of six years. The NIH has given its tentative blessing but, frustratingly, the funding is still not in place. As virtually everyone in the anti-aging field has pointed out, the medical establishment is so locked into the traditional mindset of researching diseases one by one that the idea of treating the aging process, the thing that underlies all the severe chronic diseases, gives them the willies. Even in the case of metformin which has successfully been prescribed for one condition, diabetes, for over sixty years and has an excellent safety record. 

Cause for optimism. 

Admittedly, some of the older studies that suggested that metformin slowed down disease, for diabetics and non-diabetics alike, had design flaws and we simply don’t know how or if the positive results from the animal research will translate to humans. Still, the research landscape is, at the least, promising. One meta-analysis of over fifty studies found that diabetics on metformin had fewer deaths, from any disease, than non-diabetics not taking the drug. In one pilot study of a group of people with mild cognitive impairment, taking metformin for only eight weeks was associated with better cognitive performance. Another study found a 51% decrease in the risk of cognitive impairment, with the biggest benefit seen in patients who’d been on the drug for more than six years. The metformin-cancer connection is far from pinned down but one large meta-analysis (a study of the existing studies) found that people with diabetes on metformin suffered 34% fewer cancer deaths than would otherwise have been predicted. 

Metformin and the microbiome can play well together.

“Healthy gut, healthy life,” that’s a message I’ve been delivering to my patients and readers for years. So, I’m particularly gratified by research that suggests that one way metformin improves health is through the gut microbiome. Specifically, taking the drug is associated with higher levels of a particular bacteria, Akkermansia muciniphila, which can do a number of fine things inside the gut, including helping to build up the lining of the gut wall, to prevent inflammation-promoting “leaky gut.” Some of the work has been done on animals – metformin has been shown to have an anti-inflammatory effect on mice with ulcerative colitis and, in another study, it improved cognitive performance by aged mice by reducing inflammation. In a human study, the researchers found evidence to suggest that the drug’s effect on the microbiome contributed to its ability to tamp down blood sugar levels – so there’s likely a fair amount of good news associated with this decades old medication.

Nothing is perfect.

As interesting and promising as metformin is, it does have its downsides. GI side-effects like nausea are common but for most people, they’re temporary. The drug can also interfere with the absorption of B-12. That could be more serious since B-12 levels decrease with age anyway, leaving some seniors fatigued and/or suffering from brain fog. If you’re on metformin, have your levels checked. It also may be the case that taking metformin blunts some of the body’s positive adaptation to healthier physical activity and diet, so more effort may be required to get results. However, these minor drawbacks don’t come close to off-setting the significant benefits of metformin if you’re type 2 diabetic (in which case, you’re probably already on it) and, if you’re pre-diabetic, you may want to have a conversation with your doctor about the pros and cons of metformin therapy. As for the rest of us, stay tuned. 

The future of metformin.

The research that’s in the pipeline could tell us that metformin is poised to be the first all-purpose, broadly embraced anti-aging drug, which has been tested over decades, is generally well-tolerated, widely available and inexpensive. Even if the blue-sky anti-aging scenario doesn’t quite unfold, the roughly half of adult Americans who are pre-diabetic may still benefit from metformin. But the drug’s greatest contribution, as its most ardent boosters freely admit, is to open the minds of the medical establishment to the limitations of its “whack-a-mole” approach to treating disease and open the door to a new generation of anti-aging drugs that will prove to be more effective than metformin itself. 

New Insights Into the Genetics of Glycemic Response to Metformin 

Posted by

0


Metformin is one of the most commonly prescribed medications in the world, with 25 million prescriptions in England in the last year alone (data are from https://openprescribing.net) for a population of 56 million people. Metformin has been in clinical use for >60 years, yet despite this, or probably because of this, the mechanism(s) for how metformin lowers glucose remains unclear. Population genetic studies have transformed our understanding of the etiology of most common and rare diseases. It follows that population pharmacogenetic studies should provide insight into variation in glycemic response to metformin, which can be attributed to variation in pharmacokinetics and pharmacodynamics of the medication. This might allow us to better understand how metformin works, enabling more targeted drug treatments or the identification of who is likely to respond or not respond.

Unlike common disease and trait genetics, where it is now not uncommon to see genetic studies of more than 1 million people, pharmacogenetic studies in general are much smaller, are less powered, and have had limited success when considering common diseases and medications. It should be noted that this is not the case for genetics of rare disease, severe adverse drug reactions, drug metabolism, and anticancer treatments, where pharmacogenetics is increasingly making its way into clinical care. For metformin, there have been three genome-wide association studies (GWAS) published to date reporting on HbA1c change in people with type 2 diabetes (1–3), with additional GWAS reporting on the genetic interaction with metformin and diabetes prevention (4) and acute response to metformin in people without diabetes (5). Of these, only the loci at NPAT/ATM and SCL2A2 have been replicated.

In this issue of Diabetes Care, Wu et al. (6) report a further GWAS of glycemic response to metformin. The discovery GWAS used data from 447 African Americans, with replication undertaken in 353 African Americans and 466 European Americans. A genome-wide variant, rs143276236, in gene ARFGEF3, replicated in the African American cohort but not in the European American population. This is the first GWAS to focus discovery on an African American population, with previous metformin GWAS being predominantly in populations of White European or mixed ethnicity. This, of course, is important to ensure precision medicine findings are not limited to the European population and may identify ancestry-specific variants that would not be detected in a White European population. The variant identified is an intronic single nucleotide polymorphism (SNP) in a gene, ARFGEF3, that has a plausible connection to glucose metabolism, as it is expressed in α-cells and β-cells and its knockout in mice is associated with increased insulin granule content and increased insulin secretion. The mechanism whereby rs143276236 alters metformin response is unclear and follow-on mechanistic studies are needed, but this study, like the previous GWAS, provides potential novel insights into how metformin works to lower glucose in humans.

One area highlighted by this study that has important implications for pharmacogenetic studies is the challenge of defining a phenotype of drug response in diabetes studies. The focus here is specifically on glycemic response in patients with type 2 diabetes rather than acute response or prevention of diabetes. As outlined in Fig. 1, the U.K. Prospective Diabetes Study (UKPDS) and subsequent studies, like A Diabetes Outcome Progression Trial (ADOPT) (7) and Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (8), show that when a new medication is started there is a reduction in HbA1c to a nadir between 6 and 12 months and then an inexorable deterioration in glycemic control that reflects the underlying diabetes disease progression, resulting in what is commonly referred to as the “Nike tick.” The most-used measure of drug response is to simply measure the change from a pretreatment value to an on-treatment value measured at or close to the HbA1c nadir (∼6–12 months) and to adjust for the baseline HbA1c in a regression model. This method has merit because it captures the short-term response, which is only minimally confounded by underlying disease progression, and it is a simple definition that can be applied across populations. However, it is far from perfect: it will be confounded by lifestyle change at the time of medication initiation, which may well be marked for metformin, because it is often started at or close to diabetes diagnosis and will be affected by regression to the mean (9). Another approach would be to model time to failure of a medication, although it is difficult to disentangle drug effect from underlying disease progression. Probably the best approach, if sufficient data are available longitudinally, is to use a linear mixed model with many HbA1c measures before and after medication initiation, as used by McGurnaghan et al. (10) for modeling dapagliflozin response. In the study by Wu et al. (6), two on-treatment HbA1c measures are used at least 120 days apart, and the closest such pair to metformin initiation was used. This definition was largely determined by the lack of pretreatment HbA1c measures but does show how, even without pretreatment measures, a measure of drug response can be derived from observational data. Supplementary Fig. 9 in their article nicely demonstrates how, as the window used to define metformin response shifts away from the initiation of metformin, the drug effect is attenuated, with much of the informative data coming from those patients with the first HbA1c measure before 146 days after starting metformin, which explains why the overall HbA1c reduction seen with metformin is low. The potential merits of this approach are that it may be less affected by regression to the mean caused by a randomly increased baseline measure. Importantly, Wu et al. (6) go on to investigate the interaction between drug dose (exposure) and HbA1c change and report a significant interaction for rs143276236 and metformin exposure; the SNP effect was only observed in those receiving >425 mg/day of metformin. The use of such an interaction analysis provides strong support that the SNP is working to alter metformin response, and its effect is not independent of metformin.

An illustration of how HbA1c changes over time with initiation of new treatment. Each letter depicts different definitions of drug response: A, difference between pretreatment HbA1c and on-treatment HbA1c at 6–12 months; B, the approach used by Wu et al. (6), which relied on the difference between two on-treatment HbA1c values at least 120 days apart and closest to initiation of medication; C, time to failure of medication, defined as initiation of next medication or a threshold HbA1c reached; and D, a linear mixed model allowing for within-person slope prior to medication initiation.

The challenges of defining drug response are largely overcome by randomized controlled trials (RCTs), where the randomization removes the baseline differences and the ability to assess the genetic effect in an interaction with treatment allocation ensures that findings truly reflect a pharmacogenetic effect. To date, limited RCT trial data with genotyping have been made available to researchers, but this is changing. A recent pharmacogenetic study of glycemic response to glucagon-like peptide 1 receptor agonists included data from the Harmony trials (albiglutide) and the Assessment of Weekly Administration of LY2189265 (dulaglutide) in Diabetes (AWARD) studies (11), and the pharmacogenetic study of GRADE (8) is ongoing. These open the possibility of undertaking metanalysis of GWAS for RCTs of newer medications where genetic data are available, but these are likely to still be underpowered (only tens of thousands of individuals) and do not help us with older medications like metformin and sulfonylureas. With increasing availability of large biobanks, we should be able to supplement RCTs with large cohorts (potentially reaching up to 100,000 individuals) where drug response is defined from electronic medical record data that capture longitudinal drug exposure, HbA1c, BMI, and other covariates. Hopefully the complementary meta-analyses of RCTs and large real-world data from biobanks will allow us to move diabetes pharmacogenetics closer to diabetes disease genetics, finding many robust replicated variants that inform on drug mechanisms and support a precision approach to diabetes care.

Does Metformin Lower Risk for Long COVID?

Posted by

0


Study participants who received metformin for outpatient therapy of COVID-19 had lower rates of long COVID than those who received placebo.

Various antiviral therapies can reduce COVID-19 progression in high-risk outpatients, but none have been definitively shown to reduce symptoms or signs persisting after acute infection (i.e., long COVID). In a randomized trial, investigators now report the effect of metformin on incidence of long COVID. Participants were overweight or obese adults with COVID-19 symptoms for <7 days. They were assigned to receive metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. This analysis focused on 1126 participants (median age, 45; 56% women, 55% had received COVID-19 vaccination) who received metformin or matched placebo.

Findings are as follows:

  • 93 participants (8.3%) reported that a medical provider had made a diagnosis of long COVID by day 300.
  • Cumulative incidence of long COVID was 6.3% (metformin) and 10.4% (placebo), a difference translating to a 41% reduction with metformin.
  • Neither ivermectin nor fluvoxamine reduced incidence of long COVID.

Comment

The data in this study are intriguing, but I do not find them definitive enough to recommend using metformin to prevent long COVID. A key challenge in assessing the effects of treatment on long COVID is lack of consensus on how to diagnose the condition; indeed, in this study the diagnosis was not based on specific criteria but was made at the discretion of the participant’s medical provider. Recent progress in defining long COVID is based on a prospective study in the RECOVER cohort (JAMA 2023; 329:1934. opens in new tab). One of the highest research priorities is to apply consensus definitions to prospectively assess whether (and which) therapies will prevent long COVID.

Popular diabetes drugs compared in large trial

Posted by

0


At a Glance

  • A comparison of four common drugs for treating type 2 diabetes showed that two outperformed the others in maintaining target blood sugar levels.
  • The findings offer new insights for the long-term management of type 2 diabetes.

Black female doctor giving an elderly male patient pills

Researchers tested four common secondary drugs for treating type 2 diabetes.

Diabetes affects more than 37 million Americans. Up to about 95% of them have type 2 diabetes, in which their body doesn’t make or use insulin well. This can impair the ability to keep levels of blood sugar (also called blood glucose) in a safe range. When blood glucose gets too high, it can cause complications such as nerve, kidney, eye, and heart-related conditions.

A drug called metformin has long been the considered the first-line medication for type 2 diabetes. Health care professionals generally recommend metformin combined with diet and exercise as the best early approach to diabetes care. If blood glucose becomes difficult to control over time, a second medication is often added. But there had been no consensus regarding which medications might best be added to metformin to keep blood glucose levels in check. And it had been unclear which drugs might best protect against common side effects, such as cardiovascular disease.

To find answers, NIH supported a large clinical trial to directly compare four drugs often used in combination with metformin to treat type 2 diabetes. The trial was conducted at 36 study centers nationwide. Findings were described in a pair of papers that appeared in the New England Journal of Medicine on September 22, 2022.

The trial enrolled more than 5,000 people with type 2 diabetes who were already taking metformin. They were from diverse racial and ethnic backgrounds. Participants were randomly placed into one of four treatment groups. Three groups took metformin plus a medicine that increased insulin levels: sitagliptin, liraglutide, or glimepiride. The fourth group took metformin and insulin glargine U-100, a long-acting insulin.

After about five years of follow-up, the researchers found that all four drugs improved blood glucose levels when added to metformin. But those taking metformin plus liraglutide or the long-acting insulin achieved and maintained their target blood levels for the longest time. They had about six months more time with blood glucose levels in the target range compared with those taking sitagliptin, the least effective in maintaining target levels. The effects of treatment did not differ with age, sex, race, or ethnicity.

However, none of the combinations overwhelmingly outperformed the others. Although average blood sugar levels decreased during the study, nearly three of four participants were unable to maintain the blood glucose target over the study period. This underscores the difficulty for many patients with type 2 diabetes to maintain recommended targets.

The study also looked at the drugs’ effects on developing diabetes-related cardiovascular disease and other conditions. Although the differences were small, participants in the liraglutide group were least likely to experience any cardiovascular disease. However, gastrointestinal symptoms were more common with liraglutide than with the other groups. Severe hypoglycemia, or low blood glucose, was generally uncommon, but affected more participants assigned to glimepiride.

“This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes,” says the study’s project scientist, Dr. Henry Burch of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. “This is an integral step toward precision medicine for diabetes care, as these results can now be used in the decision-making process for each individual patient in light of their levels of glucose control, how well the medications are tolerated, and the person’s other health considerations.”

Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer

Posted by

0


Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Introduction

Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with lower overall cancer risk in epidemiologic studies conducted in patients with diabetes.1,2 Meta-analyses of these studies have inconsistently identified lower risk of some types of cancer when individuals receive metformin.3–14 It has been suggested that data from observational studies of metformin and cancer risk seem largely unreliable, studies using designs least likely to be affected by bias (notably selection and time-related biases) being most likely to yield results that did not support a causal effect of metformin on cancer risk.15–17 The Diabetes Prevention Program trial, which randomly assigned adults with prediabetes to metformin, a lifestyle-based weight loss intervention or placebo, reported no effect of metformin versus placebo on cancer mortality at 21-year follow-up (hazard ratio [HR], 1.04; 95% CI, 0.72 to 1.52; P = .83).18

Current understanding of metformin action includes systemic effects resulting from reduced insulin signaling through PI3K/RAS pathways and cancer cell direct effects (notably LKB1–mediated activation of AMPK, a negative regulator of PI3K/Akt/mTOR signaling and protein synthesis). Some preclinical research suggests that metformin may lower cancer risk; however, translation to the clinical setting is not straightforward.19,20

Here, we report the effect of metformin versus placebo on new invasive cancers in MA.32, a phase III adjuvant randomized trial of metformin versus placebo in high-risk T1-3, N0-2, M0 breast cancer. We have previously reported the absence of an effect of metformin on invasive disease-free survival (IDFS) or overall survival in hormone receptor–positive or hormone receptor–negative breast cancer.21 Exploratory analyses suggested beneficial effects in human epidermal growth factor receptor 2 (HER2)–positive breast cancer, notably in those with at least one C allele of the rs11212617 single-nucleotide polymorphism (SNP), a SNP associated with enhanced glycemic response and higher metformin blood levels in patients with diabetes.

Discussion

The MA.32 trial provided a unique opportunity to examine the effects of metformin on the risk of developing new primary invasive cancers in a population without diabetes. Metformin did not affect the risk of new contralateral breast cancer, any invasive cancer, cancers outside of the breast, obesity, or tobacco-associated cancers. Point estimates of risk were all above 1, making it unlikely that additional power would have identified a clinically important reduction in risk. Furthermore, metformin did not reduce cancer risk in subgroups defined by BMI, metabolic factors (insulin, HOMA, leptin, hsCRP), smoking history, or rs11212617 SNP status, factors that could potentially be associated with metformin benefit.

It is unclear whether our results are generalizable to populations with diabetes or prediabetes. Because of its beneficial physiologic effect, it is possible that metformin could reduce cancer risk in populations experiencing hyperglycemia, hyperinsulinemia, or inflammation. However, results of the Diabetes Prevention Program18 and critical appraisals of the observational studies in populations with diabetes1–17 discussed above raise concern about metformin benefit.

These findings do not support the use of metformin to reduce risk of new primary cancers in patients without diabetes who have high-risk breast cancer.

Is metformin safe?

Posted by

0


 

Diabetes cases have been steadily increasing worldwide. Metformin has been the gold standard first agent for many people to try first with all the drawbacks patients experience.

There are lots of medicines available for people with diabetes. Some, like insulin, are widely available but also quite expensive. Some are relatively unknown to the general public and known only to experts and physicians.

One, however, is primarily known to the public at large. This diabetes drug is one of the most popular medicines for people with diabetes.

What is Metformin and What Does It Do?

What is metformin HCL?

Metformin hydrochloride or metformin HCL is one of the most common types available in the market. As a diabetes drug, it could be administered to both adults and children for long-term treatment of diabetes. Its generic version is widely available worldwide, making it one of the more accessible diabetes drugs.

Experts estimate that more than 120 million people are taking this to manage and control their diabetes.

Metformin drug class

This diabetes medicine belongs to the anti-diabetes drug class. Specifically, it belongs to drug class biguanides. Biguanides belong to the class called non-sulfonylureas, one class of drugs used for treating diabetes type-2 diabetes and PCOS(polycystic ovarian syndrome).

Non-sulfonylureas like biguanides work by inhibiting the liver from producing too much glucose. It also helps in the body’s insulin response by lowering insulin resistance. Finally, it helps tissues to absorb glucose from the bloodstream.

They are in the form of tablets, however, cannot be used in treating type-1 diabetes. Type-1 diabetes is caused by poor insulin production, and this medication is not intended to address that issue.

Chemical Composition

The chemical composition of this diabetes drug is C4H11N5. It means that it has four molecules of carbon, eleven of hydrogen, and five of nitrogen. It is an organic compound, and organic compounds are vital to the survival of any organism here on earth.

The chemical composition allows for better absorption of glucose in the cells. Glucose itself is an organic compound mostly made of carbon molecules. Nitrogen and hydrogen within help facilitate the transfer of glucose from the bloodstream into the cells and tissues.

The synthesis of those chemicals allows it also to become a diabetic agent. They can lower blood sugar levels in the body. All in all, those things mentioned make it ideal as a treatment for diabetes. Is metformin free of side effects? Definitely no. We will dwell on that later in this article.

What Are the Forms?

It is usually in the form of tablets or pills. They are produced by numerous pharmaceutical companies worldwide. The most common is the regular one, also known as “immediate release.”

The regular ones comes in three doses: 500 mg, 850 mg, and 1000 mg. They are the ones available worldwide and are widely used.

Aside from regular tablets and pills, there is also the “extended-release”, the so-called extended version. As a medication, the “extended-release” is available in 500 mg and needs to be taken only once a day. This can be taken only by adults.

Aside from tablets and pills, there is also a version of liquid. However, all regular forms is available only as tablets and pills. Only the “extended-release” is available as an oral solution.

Who Should Take Metformin?

Those who have diabetes and PCOS can take this drug. In fact, many consider it to be one of the best initial treatments for those who are recently diagnosed with diabetes and/or PCOS.

Some doctors even prescribe this medication to those suffering from prediabetes, which is what they call borderline cases. These are people who, despite changes in lifestyle and eating habits, do not improve and are in danger of suffering from full-blown diabetes.  As diabetic drug it could be prescribed to those people as a preventive measure. At the end of today PCOS, prediabetes and diabetes are connected to each other. They are all related to insulin resistance most of the time

One reason for the popularity of this drug among physicians is that it largely works on metabolic functions. It is unlike other diabetic drugs which induce the pancreas to produce more insulin.

What exactly does it do to the body?

It increases the body’s receptivity to insulin. By doing so, it allows the body to absorb more glucose, without increasing the production of either insulin or glucose.

That is why most doctors prefer this drug. Depending on the need, they will administer doses of 500 mg, 850 mg, or  1000 mg.

The dosage and doses will depend on the doctor’s discretion. It will also depend on how advanced the diabetes is in a particular patient and how much they can tolerate at a time. Overall, however, most doctors usually want to improve insulin sensitivity before prescribing any other diabetes pills. Hence, they prescribe this for most patients first.

Who Should Not Take Metformin?

Those who have not consulted their doctors and have no diabetes should not take this whether in tablets or pills. There is some risk involved, as with most diabetic drugs.

The doctors will eventually know which medicines their patients must take. For our general knowledge, though, as a diabetes drug this is strictly not for those with severe kidney or liver issues. This may cause problems for those health issues, putting the lives of people with diabetes at significant risk.

We mentioned that this is also prescribed to some who have prediabetes. People who have prediabetes but are over 60, however, do not have to take this. Those who are suffering from diabetic ketoacidosis must also not take this drug.

Can Pregnant Women Take Metformin?

Taking this drug during pregnancy is entirely safe unless the pregnant woman has advanced kidney or liver problems. On the other hand, discussing with your Diabetes doctor prior to starting taking this drug is the best.

Actually, this helps patients who have PCOS become pregnant and maintain healthy blood sugar levels during pregnancy as well.

How Should this Drug be Taken?

This is taken orally. The dosage, of course, will depend upon the patient’s need and the doctor’s orders. Usually, tablets are administered once, twice, or even three times a day.

One who has diabetes can have a dosage as high as 2000 mg per day. Meaning they have to take the diabetic drug  1000 mg twice a day. Others, however, are usually administered 1000 mg, taking the 500 mg twice a day. Starting the dose low and gradually increasing the dose help tolerate this significantly. Also taking this after meals lowers the side effects.

Important reminder: do not double up your intake if you ever missed or skip your dosage. It will cause some side effects like an upset stomach.

Is Glimepiride a Safer Sulfonylurea for Type 2 Diabetes?

Posted by

0


People with type 2 diabetes treated with metformin plus a sulfonylurea with high affinity for cardiac mitochondrial adenosine triphosphate–sensitive potassium (mitoKATP) channels, such as glyburide and glipizide, had a significant, adjusted 18% higher relative rate of major adverse cardiovascular events (MACE) compared with matched patients who received a low-affinity sulfonylurea, such as glimepiride, in an observational study of more than 50,000 matched pairs of patients in Taiwan.

The increased MACE risk primarily was associated with hospitalization for myocardial infarction, and the risk was greatest during the first 90 days of treatment and with a high dose of a sulfonylurea with high mitoKATP channel affinity, write Meng-Ting Wang, PhD, and associates in a report recently published in JAMA Network Open.

These findings suggest that “the high-affinity blockage of cardiac mitoKATP channels may act as an important determinant of sulfonylurea-related adverse cardiovascular events in patients with type 2 diabetes,” conclude the authors, who are affiliated with several institutions in Taipei, Taiwan.

The findings both confirm and refine a long-standing suspicion that at least some agents in the sulfonylurea class may increase risk for cardiovascular disease events, although evidence for this adverse effect is largely considered inconclusive.

In part because of safety concerns like this ― as well as other relative shortcomings of sulfonylureas, such as weight gain and relatively higher rates of hypoglycemia — the drug class has dropped from secondary to tertiary agents in the hierarchy of antidiabetic drugs in some sets of treatment recommendations. Despite this, sulfonlyurea use persists, especially in lower-income countries but also in the United States, owing to the affordability of agents in this class.

For example, glimepiride sells at many US pharmacies for as little as $20 for as much as a 6-month supply, less than 1% of the full retail cost of many agents now favored for treating patients with type 2 diabetes, such as the sodium-glucose cotransporter 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) agonists.

De-emphasizing Sulfonylureas

“This study is part of an ongoing series of observations suggesting some of the challenges of sulfonylureas in the management of diabetes,” commented Robert A. Gabbay, MD, PhD, chief scientific and medical officer for the American Diabetes Association (ADA).

The findings “suggest there may even be differences between specific sulfonylurea analogs,” Gabbay said in an interview. He also highlighted that the ADA’s annual Standards of Care in Diabetes―2023 management recommendations, as well as in recent prior editions, “de-emphasize” use of sulfonylureas “in favor of others that show cardiovascular benefits,” such as metformin, the SGLT2 inhibitors, and the GLP-1 agonists.

“Currently, two opposing opinions are present in the literature. Some people consider that there is almost no more place for sulfonylureas when taking into account alternative new medications that showed advantages compared with older agents,” wrote André J. Scheen, MD, PhD, in an assessment of sulfonylureas published in 2021.

“Others make a plea for maintaining a right place of sulfonylureas in the therapeutic armamentarium of type 2 diabetes, especially in countries with limited resources,” noted Scheen, professor and head of the Division of Diabetes, Nutrition, and Metabolic Disorders at the Academic Hospital of Liège, Belgium.

Low-Affinity Sulfonylureas Predominate in Taiwan

The new JAMA Network Open study used data from more than 670,000 people in the Taiwan Diabetes Mellitus Health Database from 2006–2017, which included essentially all people in Taiwan who were newly diagnosed with diabetes during that period. This cohort included more than 280,000 adults who received sulfonylurea as second-line treatment after metformin; nearly 248,000 of these people qualified for the analysis, mostly because at least 1 year of data were available for them.

The study cohort included about 193,000 on a low-affinity sulfonylurea, glimepiride, or gliclazide (the latter is not approved for US marketing) and 54,411 on a high-affinity sulfonylurea, glyburide, or glipizide. These four agents constitute more than 99% of the sulfonylureas prescribed for use with metformin for these Taiwanese adults during the study period.

These numbers indicate that in Taiwan during the 12 years studied, more than three quarters of people with diabetes who received a sulfonylurea added on top of metformin were on a low-affinity sulfonylurea associated with a lower risk for MACE.

The main analysis focused on 53,714 matched pairs of people from this study set, with one member of the pair on a low-affinity agent matched with someone on a high-affinity agent. The analysis also adjusted for demographic and clinical characteristics to further reduce the possible influence of confounding not resolved by matching.

The primary endpoint of MACE included cardiovascular death, hospitalization for myocardial infarction, and hospitalization for ischemic stroke during an average follow-up of about 10 or 14 months, depending on treatment subgroup.

The analysis showed that treatment with a high-affinity sulfonylurea was significantly linked with an 18% higher rate of MACE compared with those treated with a low-affinity sulfonylurea. This was primarily driven by a significant 34% relative increase in the rate of myocardial infarction among those who received a high-affinity agent. All-cause death in the high-affinity subgroup was a significant 27% higher among those who were taking a high-affinity agent compared with those taking a low-affinity agent. Plus, the rate of severe hypoglycemia was a significant 82% greater with high-affinity sulfonylureas compared with low-affinity agents.

The same team of researchers had previously reported largely similar findings in 2022 in Diabetes Care based on fewer people with type 2 diabetes in Taiwan, using close to 34,000 matched pairs of patients.

First-Line Therapy in T2D: Has Metformin Been ‘Dethroned’?

Posted by

0


Initially approved by the US Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular Outcome Trials Transform Standard of Care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc– and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio [HR], 0.47; 95% CI, 0.37-0.59; P = .01) when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.

Individualizing Care to Attain Cardiorenal-Metabolic Goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s (ADA) 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology (AACE) Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (eg, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min/1.73 m2, and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.

Optimizing Guideline-Directed Medical Therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (eg, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.