Metformin use linked to lower risk of long Covid

12th June 2023

Metformin use by overweight or obese patients reduces the risk of developing long Covid by around 41%, according to the findings of a recent randomised, placebo-controlled trial.

Published in The Lancet Infectious Diseases, the study followed up on previous research which sought to determine whether the use of metformin, ivermectin or fluvoxamine prevented the primary outcome. These were the occurrence of hypoxemia, an emergency department visit, hospitalisation, or death associated with Covid-19. The researchers concluded that none of three drugs reduced the primary outcome.

For the follow-up study, the same researchers followed a subgroup of patients for 300 days to assess if any of the drugs would prevent long Covid. The participants were adults aged 30-85 years with overweight or obesity and with Covid symptoms for less than seven days. In the original trial, metformin was titrated up to a dose of 1,500 mg daily and the subsequent development of long Covid was physician diagnosed. The design of the original trial enabled a comparison of metformin use with a matching placebo and the findings of the current study largely relate to metformin.

Metformin use and long Covid

A total of 1,126 participants, 564 assigned to metformin and the remainder to matched placebo were included in the analysis. Overall, 8.3% of the cohort had developed long Covid by day 300.

The cumulative incidence of long Covid was 6.3% in the metformin group, but 10.4% (7.8-12.9) in those who received placebo (Hazard ratio, HR = 0.59, 95% CI 0.39 – 0.89 p = 0.012). In practice therefore, use of metformin reduced the absolute risk of developing long Covid by 4.1%. In other words, 24 people would need to take metformin to prevent one case of long Covid.

In the subgroup there were some interesting observations. The reduction in the risk of developing long Covid from using metformin was only significant if given less than three days from symptom onset (HR = 0.37, 95% CI 0.15 – 0.95). Similarly, the effect was also only significant in patients under 45 years of age, women and those with a body mass index greater than 30. Furthermore, metformin had no significant effect among those vaccinated against Covid-19.

Despite the positive findings, the researchers do acknowledge some limitations. Firstly, it is unclear if their findings would be generalisable to adults of a normal weight. Secondly, with a largely white population, whether metformin would still be effective for different ethnicities is unclear.

Combing glargine or liraglutide and metformin best for glycated haemoglobin target

3rd October 2022

Glargine or liraglutide with metformin were the most effective agents for achieving a glycated haemoglobin target in type 2 diabetics

Combining glargine or liraglutide with metformin is significantly, albeit modestly, more effective at maintaining a glycated haemoglobin target than either glimepiride or sitagliptin according to the findings of a 5-year study by the GRADE Study Research Group.

Data from 2017 suggest that approximately 462 million individuals were affected by type 2 diabetes (6.28% of the world’s population) and with over 1 million annual deaths attributable to the condition, making it the ninth leading cause of mortality.

The fact that improved blood-glucose control decreases the progression of diabetic microvascular disease as been known for many years and can be assessed using the level of glycated haemoglobin (HbA1c). In a recent meta-analysis it was concluded that the optimal HbA1c range for type 2 diabetes is 7.1-7.7% regardless of diabetes duration.

Moreover, the European Society of Cardiology Guidelines have suggested that glucose control to target a near-normal HbA1c (<7.0% or <53 mmol/mol) will decrease the frequency and severity of microvascular complications in patients with diabetes. Metformin is a recommended by the guidelines as a first-choice treatment in overweight patients with type 2 diabetes and without cardiovascular disease and in those at moderate cardiovascular risk.

However, if this fails to provide adequate diabetic control, there is a lack of clarity over which second treatment should be added to achieve control. This was the purpose of the GRADE study and designed to inform decisions about the clinical effectiveness of addition of four classes of diabetes medications to metformin.

Patients with type 2 diabetes were given metformin and during a 6 to 14 week run-in period, the dose of the drug was increased to at least 1000 mg daily but with a target dose of 2000 mg daily. Four medications could be added to metformin to maintain disease control: insulin glargine; glimepiride; liraglutide or sitagliptin and participants were randomised to one of these four treatments in addition to metformin.

The primary metabolic outcome was a metabolic failure, defined as a glycated haemoglobin of 7% or higher.

Glargine and diabetic control

A total of 5047 participants with a mean age of 57.2 years (63.6% male) and a mean body mass index of 34.3 were included in the study. Across the whole cohort, the mean duration of diabetes was 4.2 years and participants were followed for 5 years.

Over the 5-year follow-up period, 71% of the cohort had a primary metabolic outcome event, i.e., did not achieve the target glycated haemoglobin level of less than 7%. This was highest for those taking sitagliptin (77.4%), followed by glimepiride (72.4%), liraglutide (68.2%) and lowest for glargine (67.4%).

Using a global test of differences across groups, this finding was significant (p < 0.001). However, when comparing the rate/100 participant-years, the values for each of the drugs were broadly similar, ranging from 26.5% (glargine) to 38.1% (sitagliptin).

In pairwise comparisons, the risk of the primary outcome was significantly lower with glargine than with sitagliptin (hazard ratio, HR = 0.71, 95% CI 0.64 – 0.78, p < 0.001). It was also lower for liraglutide compared with sitagliptin (HR = 0.69, 95% CI 0.63 – 0.76, p < 0.001).

The authors concluded that while all four treatments when added to metformin improved glycated haemoglobin, glargine and liraglutide were significantly, though modestly, more effective at achieving and maintaining target levels.

Citation
The GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes N Engl J Med 2022

Adjuvant metformin of no benefit in non-metastatic breast cancer

7th June 2022

Addition of metformin to standard chemotherapy for breast cancer did not produce a significant improvement of invasive disease-free survival

Adding metformin to standard breast cancer chemotherapy in women with non-metastatic, high-risk operable breast cancer, did not lead to a significant improvement of invasive disease-free survival. This was the conclusion of a randomised trial conducted by researchers in Canada, Switzerland and the UK.

Diabetic patients who develop cancer havea 40% higher mortality risk than non-diabetics. In addition, studies have suggested that type 2 diabetes may be associated with 10-20% excess relative risk of breast cancer.

The drug metformin is a biguanide that is used in the treatment of type 2 diabetes and works by decreasing gluconeogenesis and increases peripheral utilisation of glucose. In a 2015 meta-analysis of 11 studies, that compared the outcomes of breast cancer therapy in diabetes with and without metformin, the authors concluded that use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients.

However, this is not a consistent finding in the literature. For instance, another study of over 2,300 women with breast cancer, the authors concluded that their study failed to show an association between improved survival and increased cumulative metformin use in breast cancer patients who had recent-onset diabetes.

In contrast, a 2012 retrospective analysis, found that diabetic patients with breast cancer who received metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than those not receiving the drug.

However, the data in the above studies is derived from observational studies which are subject to several forms of bias. As a result, for the current study, the researchers focused specifically on metformin and undertook a randomised trial to determine whether the use of metformin in breast cancer patients without diabetes, positively impacted on treatment outcomes.

Adult women without diabetes who received standard therapy for a T1 to T3, No to N3, MO breast cancer were recruited and stratified as either oestrogen and/or progesterone receptor positive (ER/PgR +) or negative (ER/PgR -).

Enrolled participants were then randomised 1:1, to 850 mg of metformin once daily or matching placebo for 4 weeks. The dose was then increased to twice daily for 5 years. Patients were followed-up at 6 and 12 months and then annually.

The primary endpoint of the trial was invasive disease-free survival. Secondary outcomes included overall survival and the incidence rates for death.

Metformin and invasive disease-free survival

A total of 3649 women with a mean age of 52.4 years of whom, 2533 were ER/PgR + were recruited. However, futility was declared for the ER/PgR- group and so the analysis was restricted to the 2533 women who were ER/PgR +.

After a median follow-up of 96.2 months, 18.4% of women had invasive disease-free survival (234 in the metformin group vs 231 in the placebo arm), giving an incidence rate of 2.78 per 100 patient-years in the metformin group and 2.74 in the placebo group (hazard ratio, HR = 1.01, 95% CI 0.84 – 1.21, p = 0.93). Similarly, the risk of death was not significantly different (HR = 1.10, 95% CI 0.86 – 1.41, p = 0.47).

Although futility was declared for those with ER/PgR-, among the patients who were followed up for a median of 94.1 months, there was also no difference in the level of invasive disease-free survival (HR = 1.01, 95% CI 0.79 – 1.30, p = .082). There were also no significant differences in any of the secondary outcomes.

The authors concluded that despite the evidence from observational studies, use of adjunctive metformin did not improve invasive disease-free survival in women with breast cancer.

Citation
Goodwin PJ et al. Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial JAMA 2022

SGLT-2 inhibitors and metformin have similar cardiovascular outcomes in type 2 diabetes

31st May 2022

SGLT-2 inhibitors and metformin have similar CV outcomes in type 2 diabetes though SGLT-2 inhibitors slightly lower heart failure mortality

SGLT-2 inhibitors and metformin when initiated for patients with type 2 diabetes have been shown to have the same cardiovascular outcomes such as myocardial infarction, stroke and death although use of SFLT-2 inhibitors is associated with a slightly lower risk of both hospitalisation and death due to heart failure.

These were the key findings from a cohort study analysis by a team based at Harvard University, Boston, USA.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) such as empagliflozin, although primarily used in the management of type 2 diabetes, have also been shown to reduce cardiovascular events when added to standard care.

In addition, evidence from the UK Prospective Diabetes Study showed that patients assigned to metformin had risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death and 36% for all-cause mortality.

Thus, although SGLT-2 inhibitors and metformin are primarily diabetic treatments, it is apparent that both are associated with cardiovascular benefits in diabetic patients. Furthermore, using SGLT-2 inhibitors and metformin as a first-line combination therapy for patients with type 2 diabetes has been suggested as a cost-effective strategy for the management of both type2 diabetes and cardiovascular disease.

However, what remains uncertain, is the relative cardiovascular benefits of using either a SGLT-2 inhibitor or metformin as mono-therapy in patients with type 2 diabetes.

In the present study, the US team used information held within two large commercial health insurance databases to compare the incidence of cardiovascular events when either treatment was initiated as mono-therapy.

The researchers focused on adults (> 18 years of age) with a diagnosis of type 2 diabetes and those who had new prescription for SGLT-2 inhibitors or metformin. Individuals were followed-up until the occurrence of a study outcome, death or discontinuation of treatment.

There were two primary outcomes of interest; a composite of acute myocardial infarction, stroke or all-cause mortality (referred to as ‘mortality’) and a composite of hospitalisation for heart failure or all-cause mortality (HHF).

For secondary outcomes, the authors individually assessed the effect of either treatment on different components of the two composites. Individuals were propensity-matched 1:2 (SGLT-2i: metformin).

SGLT-2 inhibitors and metformin

A total of 8,613 first-time SGLT-2i patients were matched to 17,226 metformin users, with a mean age of 60 years (approximately 51% male). Individuals prescribed SGLT-2i were followed for a mean of 10.7 months and metformin users for 12.2 months.

The risk of the composite mortality outcome was not significantly different between the two treatments (hazard ratio, HR = 0.96, 95% CI 0.77 – 1.19). However, SGLT-2i inhibitor use was associated with a lower risk of HHF (HR = 0.80, 95% CI 0.66 – 0.97).

When each of the outcomes were analysed separately, only hospitalisation for heart failure was significantly lower (HR = 0.78, 95% CI 0.62 – 0.97) in those prescribed a SGLT-2i.

Based on these findings, the authors concluded that first-line treatment of type 2 diabetes with SGLT-2i or metformin was associated with a similar risk of adverse cardiovascular outcomes although SGLT-2i use was linked to a lower risk of hospitalisation and mortality due to heart failure. However, they called for a randomised trial to provide more robust evidence to confirm these findings.

Citation
Shin JH et al. Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium–Glucose Cotransporter-2 Inhibitors Versus Metformin. A Cohort Study Ann Intern Med 2022

Preconception paternal metformin use linked to major birth defects

7th April 2022

Metformin use by fathers approximately three months prior to conception appears to increase the risk of developing genital birth defects

Metformin use by fathers with diabetes, three months before conception, is linked to an increased risk of birth defects among their offspring. This was the main finding of a study by Danish researchers from the Department of Epidemiology, Biostatistics and Bio-demography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Denmark.

It is already known that diabetic men have a significantly higher percentage of sperm with nuclear DNA damage and which is a factor associated with compromised fertility and increased miscarriage rates.

Furthermore, other research suggests that there is a relationship between male and female diabetes and fecundity (i.e. their ability to produce live offspring) and that early evaluation and treatment may be warranted for diabetics prior to attempting to conceive.

However, as well as men, data also shows that among pregnant women with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects in their offspring.

In men, the entire spermatogenic process is thought to require approximately 74 days and for the present study, the Danish team looked at fathers who had a prescription for any diabetic medication, including insulin, metformin and sulfonylureas, during the three months before conception, which they termed the sperm development period (sDev).

Since diabetes is known to affect sperm, their primary interest was to examine if the use of diabetic medicines might prevent damage to paternal sperm. They used a national patient registry to extract individual-level data and excluded mothers who were diabetic and using diabetic medication at any time prior to birth.

The primary outcome of interest was the diagnosis of 1 or more major birth defects in the first year of life. The authors calculated odds ratios and adjusted for several factors birth year, paternal age, income, education, maternal age and smoking status.

Metformin use and birth defects

A total of 1,116,779 offspring were included in the analysis, of whom, 3.3% had one or more birth defects. A total of 7,029 offspring were exposed to paternal diabetic medication including insulins (5,298), metformin (1,451) and sulfonylureas (647). The main birth defects observed among metformin-exposed offspring were genital defects, all of which occurred in boys.

In regression analysis, the adjusted odds ratio (aOR) for birth defects during the sDev period for insulins was 0.98 (95% CI 0.85 – 1.14), 1.40 (95% CI 1.08 – 1.82, p = 0.012) for metformin and 1.34 (95% CI 0.94 – 1.92) for sulfonylureas.

Interestingly, the frequency of birth defects varied among paternal metformin users at different time points in comparison to the sDev period. For example, longer than 1 year before the sDev, the frequency was 4% but this increased to 4.4% one year before sDev before peaking at 5.2% during sDev.

Moreover, the frequency declined thereafter to 3.3% more than one year after sDev. However, the birth defect frequency was non-significant and no higher than non-metformin users, at all time points other than during sDev.

The authors concluded that preconception use of metformin is associated with major birth defects, particularly genital birth defects in boys, although added that further work was required to confirm these findings.

Citation
Wensink MJ et al. Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring. A Nationwide Cohort Study Ann Intern Med 2022.