Ketogenic diet linked to higher LDL cholesterol and increased risk of adverse cardiac events

16th March 2023

A ketogenic diet was found to be associated with increased levels of LDL cholesterol and double the risk of an adverse cardiovascular event.

In a study presented at the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023, researchers described how following a ketogenic diet, involving consumption of very low amounts of carbohydrates and high amounts of fats, appeared to increase levels of LDL cholesterol and the risk of an adverse cardiovascular event.

A ketogenic diet, also referred to as a low carbohydrate, high fat (LCHF) diet, contains high amounts of fat (55-60%), 30-35% protein and 5-10% carbohydrate.

Overall, it seems that a ketogenic diet plays appears to play a significant therapeutic role in various cardiometabolic diseases and there is certainly evidence of a benefit when used as an intervention for overweight patients with type 2 diabetes.

However, despite these advantages, others have raised concerns that a ketogenic diet has the potential to exacerbate or cause hypercholesterolaemia in patients with or without underlying genetic hyperlipidaemia.

Nevertheless, whether a ketogenic diet over time gives rise to adverse cardiovascular events is unclear given the absence of long-term data.

The study presented at ACC/WCC tried to answer this question and researchers used information from data held in the UK Biobank and identified individuals meeting their their definition of a ketogenic diet diet, i.e. no more than 25% of total daily calories from carbohydrates and more than 45% from fat. 

These individuals were then matched to a group who self-reported eating a normal diet.

The main outcome of the study was the effect of a ketogenic diet on serum lipids whereas a secondary outcome was the composite incidence of adverse cardiovascular events (e.g., angina, myocardial infarction, coronary artery disease, ischaemic stroke, peripheral arterial disease, or coronary/carotid revascularisation.)

Ketogenic diet outcomes

A total of 305 participants eating a ketogenic diet diet were matched with 1,220 eating a standard diet. The mean age of the sample was 54, some 73% were women and the mean body mass index (BMI) of 27.7 compared to 26.7 on the standard diet.

After an average follow-up of 11.8 years, a ketogenic diet gave rise to higher LDL cholesterol levels compared to a standard diet (3.80 vs 3.64 mmol/L, p = 0.004). There was also a significantly higher level of apolipoprotein B (1.09 vs 1.04 g/L, p < 0.001).

However, after adjustment for cardiovascular risk factors, such as diabetes, hypertension, obesity and smoking, researchers found that 9.8% of those on a ketogenic diet and 4.3% on a standard diet experienced an adverse cardiovascular event (adjusted hazard ratio, aHR = 2.18, 95% CI 1.39 – 3.43, p < 0.001).

Despite these findings, the authors did acknowledge the limitations of their study in that the information was self-reported and based on a single time-point. They also noted how not everyone responds to a ketogenic diet in the same way.

Source
‘Keto-Like’ Diet May Be Linked to Higher Risk of Heart Disease, Cardiac Events. ACC Anywhere.

RCT finds bempedoic acid reduces cardiovascular adverse events for statin-intolerant patients

13th March 2023

Bempedoic acid has been found to significantly reduce major adverse cardiovascular events among patients intolerant of statin therapy

Bempedoic acid (BPA) use in patients at high risk for cardiovascular disease or who are statin intolerant, significantly reduced the incidence of major adverse cardiovascular events compared to placebo according to the findings of a large, randomised, double-blind, placebo-controlled trial by an international research group.

Treatment with statin drugs is a recommended as part of the therapeutic strategy for the management of patients with atherosclerotic cardiovascular disease or in those at a high risk of such disease. Nevertheless, not all patients can tolerate a statin and it is estimated that between 7 and 29% of patients complain of statin-associated muscle symptoms. One alternative treatment to reduce LDL cholesterol for statin-intolerant patients is BPA which, like statins, reduces hepatic cholesterol synthesis and raises LDL receptor expression. The drug is an ATP citrate lyase inhibitor and targets cholesterol synthesis upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the enzyme targeted by statins and has a lower incidence of muscle-related adverse effects. Currently studies have revealed that bempedoic acid is able to significantly reduce LDL cholesterol levels although whether this also translates into a reduction of adverse cardiovascular outcomes is unknown.

In the current study, researchers randomised patients who were either unwilling or unable to take statins, (i.e., were statin intolerant) and/or were at a high risk of cardiovascular disease, to oral bempedoic acid, 180 mg daily or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, i.e., death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or coronary revascularisation.

Bempedoic acid and adverse cardiovascular events

A total of 13,970 patients with a mean age of 65.5 years (48.3 % female) were randomised to bempedoic acid (6,992) or placebo and followed for a median of 40.6 months.

The primary outcome occurred in 11.7% of those assigned to BPA and 13.3% of placebo patients and this difference was statistically significant (Hazard ratio, HR = 0.87, 95% CI 0.79 – 0.96, p = 0.004).

Significant differences favouring bempedoic acid were also found for fatal or non-fatal myocardial infarction (HR = 0.77, p = 0.002) and coronary revascularisation (HR = 0.81, p = 0.001) but not for fatal and non-fatal strokes.

The authors concluded that for statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events.

Citation
Nissen SE et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Eng J Med 2023

Blood pressure medicine dosing time does not affect adverse CV outcomes

20th October 2022

Blood pressure medication can be taken in the evening or morning as the time of administration does not affect cardiovascular outcomes

Blood pressure medicine can be taken in the morning or evening since the administration time has no effect on adverse cardiovascular outcomes according to the findings of a randomised trial by a team of UK researchers.

Among the risk factors for cardiovascular disease, high blood pressure (BP) is associated with the strongest evidence for causation and prevention of age-related increases in blood pressure would eliminate a large proportion of the population burden of BP-related CVD. Blood pressure in normotensive individuals follows a diurnal rhythm, dipping during the night-time followed by an increase in the morning.

Moreover, there is also marked diurnal variation in the onset time of cardiovascular events, with the peak being exhibited in early morning. An important issue for patients therefore is what would be the best time to take their blood pressure medicine to reduce the risk of an adverse cardiovascular event. In a 2010 randomised, cross-over trial, the authors reported that among hypertensive patients whose BP was controlled, the timing of blood pressure medication administration (either morning or evening) did not affect mean 24-hour or clinic blood pressure levels.

Nevertheless, the MAPEC study found that bedtime administration provided better BP control and a reduced risk of cardiovascular morbidity and mortality risk compared to morning dosing. In 2022, an International Society of Hypertension position paper that was endorsed by World Hypertension League and European Society of Hypertension, concluded that preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice.

Despite this, the Hygia Chronotherapy Trial which again assessed the relative benefits of night versus morning administration of blood pressure medicine, concluded that the former was more effective at BP control and for reducing cardiovascular events.

Though the Hygia trial contained nearly 20,000 participants, concerns have been expressed over its findings. In trying to settle the argument over the best time for blood pressure medicine administration, the UK team established the Treatment in Morning versus Evening (TIME) study.

TIME was an open-label, blinded endpoint-controlled superiority trial and participants were randomised 1:1 to morning (6 to 10 am) or evening (8 – 12 pm) dosing of their antihypertensives. The primary endpoint was a composite cardiovascular outcome of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke whereas the secondary outcomes were the individual components of the primary outcome.

Blood pressure medicine dosing and cardiovascular outcomes

A total of 21,104 individuals with a mean age of 65.1 years (42.5% female) were enrolled and followed for a median of 5.2 years and of whom, 10.503 were assigned to evening dosing. The mean systolic blood pressures were broadly similar (135 mmHg in the evening group vs 134.8 in the morning group) as were the diastolic pressures (79.1 vs 78.8 mmHg).

The primary outcome occurred in 3.4% of those assigned to evening dosing and 3.7% of the morning group and this difference was not significant (Hazard ratio, HR = 0.95, 95% CI 0.83 – 1.10, p = 0.53). Similarly, there were no significant differences for any of the secondary endpoints.

The authors concluded that there was little difference in adverse cardiovascular outcomes when blood pressure medicines were taken in either the evening or morning.

Citation
Mackenzie IS et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet 2022

Cocoa flavanol supplement fails to reduce cardiovascular events

5th July 2022

An RCT has found that a cocoa flavanol supplement failed to reduce the incidence of adverse cardiovascular events compared to placebo

The use of a cocoa flavanol supplement in older patients free of cardiovascular disease or cancer, failed to reduce the incidence of adverse cardiovascular events compared to placebo according the findings of a randomised, controlled trial by a the COSMOS research group.

Cocoa contains a number of flavan-3-ols and which have been reported to exhibit several health beneficial effects that occur via an antioxidant, anti-carcinogen, cardio-preventive, antimicrobial, anti-viral, and neuro-protective effects. In addition, the presence within cocoa of methylxanthines enhances the beneficial vascular effects commonly ascribed to cocoa flavanol intake.

Much of the research on the cardiovascular benefits of cocoa has centred on the consumption of chocolate and a 2020 meta-analysis concluded that it could have a small inverse association with coronary heart disease and stroke but cautioned how this was based on low credibility evidence.

Nevertheless, several, small scale studies have shown even among healthy individuals how regular intake of cocoa flavanols improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular.

While small scale studies appear to show that there are benefits cocoa, there have been no large-scale trials assessing the benefits of a cocoa flavanol supplement in comparison to a placebo.

For the present study, the US team undertook a randomised, placebo-controlled trial, which they termed the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). The trial was designed to test whether a cocoa flavanol supplement and a multivitamin could prevent cardiovascular disease among older adults.

Individuals were randomly assigned to one of four arms; active cocoa ((500 mg flavanols/day) and a multivitamin; active cocoa and placebo vitamin; active multivitamin and placebo or finally two placebos.

The primary outcome was a composite of total cardiovascular outcomes which had several outcomes e.g., incident myocardial infarction, coronary revascularisation, cardiovascular mortality and hospitalisation for unstable angina. The secondary outcomes included a total of CVD and all-cause mortality and the individual components of the composite primary outcome.

Cocoa flavanol supplement and cardiovascular outcomes

A total of 21,442 individuals with a mean age of 72.1 years (59.1% female) were randomised and followed-up for a median of 3.6 years. During the follow-up, 410 participants taking the cocoa supplement and 456 taking placebo experienced a cardiovascular event and this difference was not statistically significant (hazard ratio, HR = 0.90, 95% CI 0.78 – 1.02, p = 0.11).

For the secondary outcome of cardiovascular death, there was a significant reduction among those assigned to the cocoa flavanol supplement (HR = 0.73, 95% CI 0.54 – 0.98) but the difference for each of the other secondary outcomes was non-significant.

In addition, while the number of deaths was slightly lower among those taking the cocoa supplement compared to placebo (353 vs 397), this difference was non-significant.

The authors concluded while there were no apparent differences in the primary outcome, additional research was needed to further clarify if a cocoa flavanol supplement could reduce cardiovascular events.

Citation
Sesso HD et al. Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial Am J Clin Nutr 2022

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