SGLT2 inhibitor use associated with lower risk of cancer

9th June 2023

SGLT2 inhibitor drug use in patients with diabetes appears to reduce cancer risk, according to a retrospective analysis by Taiwanese researchers.

Epidemiological evidence suggests that diabetes increases the risk of cancer. It is thought the combination of hyper-insulinaemia, chronic inflammation and hyperglycaemia could increase the growth of tumours. Consequently, it may be possible to reduce this risk with anti-diabetic treatment. A recent meta-analysis of randomised clinical trials, suggests that SGLT2 inhibitor drugs could lower cancer risk compared to placebo. However, the extent to which these drugs might reduce the risk of cancer in practice is less clear.

The current study, published in the Journal of Diabetes and its Complications, retrospectively compared cancer development among SGLT2 inhibitor users. The team matched these patients with a group not prescribed these drugs. The primary outcome was cancer development and the analysis adjusted for several potential confounders.

SGLT2 inhibitor use and cancer risk

A cohort of 325,990 SGLT2 inhibitor users with mean age of 58.6 years (42.2% female) and 325,989 non-users was identified.

SGLT2 inhibitor users had a significantly lower cancer risk (adjusted hazard ratio, aHR = 0.79, 95% CI 0.76 – 0.83) than non-users. The risk of cancer was also higher among males (aHR = 1.35, 95% CI 1.30 – 1.41) and in patients aged 50-64 and older than 65 years.

Researchers also noticed that this risk reduction was dependent on the duration of SGLT2 inhibitor use. Short-term use (60-140 days) was actually linked to a higher cancer risk (aHR = 1.30, 95% CI 1.21 – 1.39).

In addition, while cancer risk was generally lower, there was a significant increased risk of pancreatic cancer (aHR = 1.51, 95% CI 1.22 – 1.87) which was consistent with the findings of a recent case study.

SGLT-2 inhibition lowers stroke risk in people with diabetes plus atrial fibrillation

1st June 2023

SGLT-2 inhibitor use in people with both diabetes and atrial fibrillation reduces the risk of ischaemic strokes, according to the results of a longitudinal follow‐up study.

Atrial fibrillation (AF) is the most common global cardiac arrhythmia, affecting over three million people. Having AF increases the risk of ischaemic stroke with this risk stratified by the CHA₂DS₂-VASc score. Fasting hyperglycaemia is a risk factor for AF although the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduces this risk.

The researchers considered whether SGLT-2 inhibitors could therefore reduce the risk of ischaemic stroke in diabetics with AF. Published in the Journal of the American Heart Association, the Taiwanese study followed a group of patients with both diabetes and AF who were prescribed either empagliflozin or dapagliflozin. These individuals were propensity matched to non-users and the incidence of ischaemic strokes documented over the next five years.

SGLT-2 inhibitor use and ischaemic stroke

A total of 6,614 patients, 801 prescribed one of the SGLT-2 inhibitors, had usable data for analysis.

After five years, 809 patients with diabetes and AF developed an ischaemic stroke. However, the rate was significantly lower among SGLT-2 inhibitor users (p = 0.021).

As expected, there was an increased risk of stroke per one-point increase CHA₂DS₂‐VASc score (hazard ratio, HR = 1.24, 95% CI 1.20 – 1.29, p < 0.001). Adjusting for the CHA₂DS₂‐VASc score lowered the stroke risk by 20% among SGLT-2 inhibitor users (HR= 0.80, 95% CI 0.64 – 0.99, p = 0.043).

The findings prompted the authors to suggest clinicians upgrade SGLT-2 inhibitors for glycaemic control, especially in those with co-existing AF.

Risk of high refractive error greatest among children with diabetic mothers

24th August 2021

An increased risk of high refractive error has been observed in children born to diabetic mothers, highlighting the need for early screening.

A refractive error represents a common eye disorder that prevents the eye from being able to focus images properly leading to blurred vision. There are several types of high refractive errors (HRE) including myopia (near-sightedness), hyperopia (far-sightedness), astigmatism (distorted vision) and presbyopia (difficulty in reading at arm’s length). The World Health Organisation has estimated that 153 million people worldwide have a visual impairment due to HRE. In children, the most common error is astigmatism, with one study finding a global prevalence of 14.9%. The cause of HRE remains uncertain although refractive changes are known to be associated changes in blood glucose levels and hence can be present in those with diabetes. In fact, there is some evidence that gestational diabetes can result in a three-fold increased probability of refractive errors compared to mothers without diabetes. In contrast, another study of refractive errors among diabetic and non-diabetic mothers found no significant differences in astigmatism between the two groups.

With some uncertainty over the relationship between HRE errors and diabetes, a team led by researchers from the Department of Clinical Epidemiology, Aarhus University, Denmark, undertook a population-based cohort study using Danish national registers. Mothers were considered to have diabetes if they were diagnosed either before or during their pregnancy. Their primary outcome of interest was high refractive errors in offspring and secondary outcomes were the specific types of refractive errors that developed over a 25-year follow-up period. The team used regression analysis to model the association between prenatal diabetes exposure and high refractive errors, adjusting for several factors including maternal age, smoking status, calendar period of delivery.

Findings
During the 25-year follow-up, there were 553 children of mothers with diabetes and 19,695 children of mothers without diabetes, diagnosed with a HRE. The children exposed to maternal had a 39% increased risk of having a HRE compared to those without diabetes (adjusted hazard ratio, aHR = 1.39, 95% CI 1.28 – 1.51, p < 0.001). This risk was significantly increased, compared to mothers without diabetes, for all forms of pre-gestational diabetes e.g., type 1 (aHR = 1.32), type 2 (aHR = 1.68) and gestational diabetes (aHR = 1.37). The risks for each type of HRE were also increased, e.g., hypermetropia (HR = 1.37), myopia (HR = 1.34) and astigmatism (HR = 1.58). In addition, the risks of HRE were higher in children of mothers who had at least one diabetic complications (aHR = 1.76) and higher still, in the presence of two or more complications (aHR = 2.24).
In trying to account for these elevated risks, the authors suggested the among diabetic mothers, it was possible that increased plasma glucose levels could result in foetal hyperglycaemia or that an increased oxidative stress and inflammatory response from the ensuing hyperglycaemia could have damaged the optical nerves. They concluded that given these finding, early ophthalmological screening should be undertaken in the children of mothers with diabetes.

Citation
Du J et al. Association of maternal diabetes during pregnancy with high refractive error in offspring: a nationwide population-based cohort study. Diabetologia 2021

Metformin use in diabetes protective against COVID-19-related mortality

18th January 2021

While type 2 diabetes has become a recognised risk factor for a worse prognosis in patients with COVID-19, less is known about how anti-diabetic treatments impact upon mortality.

It has become recognised that increasing age and a higher number of co-morbidities such as hypertension, obesity and diabetes are associated with higher levels of mortality among those infected with COVID-19.

Given that the prevalence of diabetes is often very high among this ethnic group, a team from the Hugh Kaul Precision Medicine Institute, University of Alabama, US, sought to determine the effects of different anti-diabetic treatments on mortality among an ethnically diverse population infected with COVID-19. The team retrospectively reviewed all electronic health records of subjects consecutively tested for COVID-19 between February and June 2020 at a single tertiary hospital in their area. In an effort to make the results more generalisable, the researchers included all patients within the five month period with the only exclusion criterion being a lack of available outcome data. The team sought to focus their attention on the diabetic treatments and in particular, insulin and metformin because these were the most commonly prescribed and there were too few patients prescribed other medicines to provide a meaningful statistical analysis. The primary outcome for the study was overall mortality and the researchers used logistic regression to explore the association between mortality and known risk factors and diabetic treatments.

Findings
There were 604 patients who tested positive for COVID-19 during the study period. The majority of those testing positive (43%) were aged 50 to 70 years and just over half (51.5%) were Black Africans, giving a highly significant odds of testing positive compared to those of white ethnicity (odds ratio, OR = 2.6 95% CI 2.19–3.10, p < 0.001). Overall mortality among those testing positive for COVID-19 was 11% and the presence of diabetes dramatically increased the risk of mortality (OR = 3.62 95% CI 2.11–6.2, p < 0.001). In fact, 67% of all deaths occurred among those with diabetes. Focusing on diabetic treatments, the researchers observed that use of metformin reduced the odds of dying by 62% (OR = 0.38 95% CI 0.17–0.87, p = 0.0221) although no such effect was seen with insulin. Moreover, after adjusting for the covariates age, race, sex, obesity and hypertension status, the odds ratio remained significant (OR = 0.33 95% CI 0.13–0.84, p = 0.0210). The researchers also observed that neither BMI or HBA1C levels were lower in those taking metformin thus discounting these as explanatory factors.

The authors noted that while the presence of type 2 diabetes was associated with an increased mortality risk in those with COVID-19 (as reported in other studies) there appeared to be a protective effect among diabetic patients treated with metformin although they were unable to explain their findings and called for more research to understand how metformin conferred these effects.

Citation
Crouse AB et al. Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. Front Endocrinol 2021.