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Take a look at a selection of our recent media coverage:

Using nitrate and PDE5 inhibitors together not associated with a higher incidence of adverse CV events

27th April 2022

Despite a contra-indication, the combined use of nitrate and PDE5 inhibitors does not appear to be linked to more adverse CV events

Using nitrates and phosphodiesterase type 5 (PDE5) inhibitors together does not seem to increase the risk of adverse cardiovascular (CV) outcomes, even though concomitant use of drugs from either class is contra-indicated. This was the key finding of a retrospective analysis by a team from the Research Division, Department of Cardiology, Herlev and Gentofte Hospital, Hellerup, Denmark.

Organic nitrates, which are vasodilators, are traditionally used for the treatment of angina and heart failure. Phosphodiesterase type 5 (PDE5) inhibitors are used for the treatment of erectile dysfunction but are also vasodilators and thus when taken together with nitrates, a synergistic effect occurs, enhancing the hypotensive effect of nitrates. Moreover, in one study, co-administration of sildenafil (a PDE5 inhibitor) with either isosorbide mononitrate of glyceryl trinitrate produced significantly greater reductions in blood pressure than from either nitrate alone thereby confirming the possible adverse effect of using these drugs together. In fact, in the summary of product characteristics for sildenafil, it states that ‘sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.’

In a 2019 review it was found that the global prevalence of erectile dysfunction was high, ranging from between 3 and 76.5%. Whilst the use of a nitrate and PDE5 inhibitors is a known contra-indication, given how erectile dysfunction is a common problem, the Danish researchers believed it likely that the two classes of drugs might be co-prescribed. They set out to examine not only the extent of co-prescription of these drugs but also whether there was any evidence from a real-world setting, that this combination was associated with an increased level of adverse cardiovascular events. Using a Danish national registry, the team identified male patients aged 30 to 85 years of age with a history of ischaemic heart disease and continued prescriptions for nitrates as well as a new prescription for a PDE5 inhibitor. They considered two composite outcomes; one including cardiac arrest, shock, ischaemic stroke and a second which included angina, syncope and a diagnosis of an adverse drug-related event. These outcomes were primarily assessed within 14 days of PDE5 inhibitor exposure although 7, 21 and 28 days were also used because the exact time of PDE5 inhibitor use after filling a prescription was always going to be uncertain.

Nitrates and PDE5 inhibitors and adverse cardiovascular outcomes

A total of 249,541 men with ischaemic heart disease were identified, of whom 42,073, with a median age of 70 years, were prescribed oral nitrates. Between 2000 and 2018, the average yearly prescription rate for PDE5 inhibitors in those taking oral nitrates, increased from 0.9 to 19.7 per 100 persons per year.

In the subgroup of men prescribed oral nitrates, there were 16,948 cases of cardiac arrest, shock, myocardial infarction, ischaemic stroke or acute coronary arteriography during the follow-up period. However, there was no significant association between co-prescription of nitrates and PDE5 inhibitors (odds ratio, OR = 0.58, 95% CI 0.28 – 1.13) for a 14-day exposure window. Similarly, for the second outcome, there was also no significant increased risk (OR = 0.73, 95% CI 0.40 – 1.32) during a 14-day exposure window. There were also no significant differences for 7, 21 and 28-day exposure windows.

Based on these findings, the authors concluded that despite the known contra-indication, there was no apparent increased risk of adverse cardiovascular events from co-prescription of nitrates and PDE5 inhibitors.

Citation
Holt A et al. Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease. A Case-Crossover Study Ann Intern Med 2022

Early glycaemic control in type 2 diabetes reduces subsequent adverse CV outcomes

22nd April 2022

Early glycaemic control in type 2 diabetes reduces the incidence of adverse cardiovascular outcomes in the first year after diagnosis

Early glycaemic control in patients with type 2 diabetes leads to a reduction in the incidence of adverse cardiovascular outcomes according to the findings of a retrospective analysis by a team from the Department of Clinical & Experimental Medicine, University of Surrey, UK.

Patients with diabetes are deemed to be at a higher risk of death and adverse cardiovascular outcomes than those without the condition. Furthermore, poor control of diabetes defined by an increased level of glycated haemoglobin levels (HbA1c) is also a risk factor for myocardial infarction (MI). In fact, one study found that each 1% higher HbA1c was associated with an 18% greater risk of MI. In addition, the HbA1c levels 3 months post-diabetes diagnosis, has been found to be a strong predictor of subsequent mortality.

However, there is some uncertainty over whether tight glycaemic control in patients with a high HbA1c after diagnosis is associated with a subsequent reduction in adverse cardiovascular outcomes. For the present study, the UK researchers examined the effect of changes in HbA1c levels in the first year after a diagnosis of type 2 diabetes and how this impacted on the incidence of cardiovascular events. A further consideration was the effect of glycaemic variability on cardiovascular events as there is some evidence to show that having consistent glycaemic control reduces the risk of vascular events and death in type 2 diabetes.

The team reviewed the records of adults with a diagnosis of type 2 diabetes and an HbA1c level recorded at diagnosis and after 1 year and with an additional five measurements recorded over time. The HbA1c values were categorised into three groups: group A (HbA1c < 7.5%), group B (HbA1c 7.5% – 9.0%) and group C (HbA1c > 9.0%). The team then recorded the individual patient’s group status at the end of the first year, for instance, a status of A to A, meant that the person’s levels remained in group A, a C to A status meant that values transitioned from C to A during the first year and so on. A glycaemic variability score was also calculated, based on the number of times the HbA1c reading differed by more than 0.5% and the results categorised into 5 groups, depending on the level of variability (e.g., 0 – 20, 21 – 40 up to 81 – 100). The primary outcome of interest was the first occurrence of a major adverse cardiovascular event (MACE) which included myocardial infarction, coronary intervention, stroke, amputation/limb revascularisation.

Early glycaemic control and MACE

A total of 26,180 individuals with type 2 diabetes and a mean age of 68.7 years (43.9% female) were identified and included in the analysis.

The proportion of individuals categorised as A to A was 48%, whereas only 1.5% were categorised as C to A. A total of 2,300 MACE events occurred in the 26,180 individuals with type 2 diabetes and the median time to the first MACE was 635 days. Compared to those in the A to A group after the first year, individuals who transitioned from C to A had a significantly reduced risk of MACE (hazard ratio, HR = 0.75, 95% CI 0.60 – 0.94, p = 0.014). In addition, individuals who displayed the greater glycaemic variability (81 – 100) also had the highest risk for MACE (HR = 1.51, 95% CI 1.11 – 2.06, p = 0.0096) compared to those in the lowest (0 – 20) group.

The authors concluded that both transitioning to an HbA1c <7.5% within the first year after a type 2 diabetes diagnosis and lack of substantial glycaemic variability were both associated with reduced MACE events.

Citation
Whyte MB et al. Early and ongoing stable glycaemic control is associated with a reduction in major adverse cardiovascular events (MACE) in people with type 2 diabetes: primary care cohort study Diabetes Obes Metab 2022