Small Prolonged Reductions in LDL, BP Substantially Reduce CV Risk

September 17, 2019

PARIS — Lifelong lowering of low-density lipoprotein cholesterol (LDL) and systolic blood pressure have independent, additive, and dose-dependent effects on cardiovascular risk, resulting in larger reductions in events than have been seen before, a new study using Mendelian randomization has found. 

"While we already know that lowering LDL and systolic blood pressure results in lower cardiovascular events, this study shows that the benefits increase over time and prolonged exposure to lower LDL and systolic blood pressure levels can substantially reduce the likelihood of having cardiovascular disease throughout one's life," lead investigator Brian Ference, MD, University of Cambridge, UK, told theheart.org | Medscape Cardiology

Because the benefits increase over time, even a small difference in LDL and systolic blood pressure was seen to have a substantial effect on reducing cardiovascular disease over a lifetime, Ference noted.  

"These small differences can easily be achieved with lifestyle changes," he said. "For example, a reduction of 0.3 mmol/L in LDL and 5 mmHg in systolic blood pressure — which can be achieved by following the DASH diet — if sustained over time would translate into a 50% reduction in lifetime risk of cardiovascular disease. With larger reductions in LDL and blood pressure sustained over a lifetime we could even eliminate cardiovascular disease."

Ference said their results drum home the importance of having sustained lipid and blood pressure reductions over the long term.

"How this is achieved is not so important. The best diet, lifestyle, exercise program for any person is the one that achieves the greatest reductions in LDL and systolic blood pressure but — more importantly — it is the one they will adhere to for life," said Ference.

"Our message for primary care doctors is try and keep LDL and systolic blood pressure as low as possible for as long as possible. Small reductions are still beneficial if sustained over the long term, so make sure your patients are taking their meds and keep up the lifestyle advice," he continued.

"Tell your patients about these benefits and give them small goals to aim for in terms of their LDL and systolic blood pressure to keep them motivated," Ference added. "Patients need to hear that they can change the trajectory of their cardiovascular disease risk by sticking to that process."

The study was presented here at the European Society of Cardiology (ESC) Congress 2019 and simultaneously published online September 2 in JAMA.  

Nature's Randomized Trial

The current study used Mendelian randomization, basically "nature's version of a randomized trial," based on the numerous genetic variants that determine reduced levels of LDL and systolic blood pressure.

There are 100 different known gene variants associated with lower levels of LDL and 61 different gene variants associated with lower systolic blood pressure, Ference said.

He and his colleagues analyzed these gene variants in 438,000 individuals in the UK Biobank, a database of volunteers who have given blood for DNA analysis. The biobank also has links to detailed medical history and follow-up over time.

Scores based on the genetic programming for lower LDL levels and systolic blood pressure were calculated for each patient based on the number and power of each gene variant they carried. Cardiovascular outcomes (coronary death/MI/revascularization) were then compared in patients with scores above or below the median for the LDL scores and blood pressure scores.

As would be expected in a randomized trial, apart from LDL and systolic blood pressure, all of the other baseline characteristics in the four groups (high LDL, low LDL, high blood pressure, low blood pressure) were the same.

The average age of individuals included was 65 years. "As genes are allocated at birth, this is the equivalent of having a randomized trial of LDL lowering or systolic blood pressure lowering with a follow up of 65 years," Ference commented.  

Results showed that individuals with a genetic propensity to lower LDL levels (those with an LDL lowering genetic score above the median) had a reduction in LDL levels of 15 mg/dL compared to those with scores below the median. This was associated with a 26% reduction in lifetime risk of coronary events (OR, 0.74; P < .001) and translates into a 54% reduction in coronary events for each 1 mmol/L (38.7 mg/dL) reduction in LDL.

For systolic blood pressure, those genetically programmed to have lower systolic pressure (ie, a systolic blood pressure lowering score above the median) had a systolic pressure of 3 mmHg less than those with scores below the median. This was associated with a 17% lower risk of a major coronary event (OR, 0.83; P < .001) and translates into a 45% reduction in coronary events for every 10 mmHg reduction in systolic pressure. 

People genetically programmed to have both lower LDL and lower systolic pressure had a 39% reduction in coronary events (OR, 0.61; P < .001). This translates into a 78% reduction in major coronary events for every 1 mmol/L reduction in LDL together with a 10 mmHg reduction in systolic blood pressure, Ference noted, including a 75% reduction in MI and a 68% reduction in cardiovascular death.  

"Our results show that exposure to any combination of reduced LDL and reduced systolic blood pressure gives a dose-dependent reduction in major cardiovascular events. In addition, the benefits of lowering LDL and systolic blood pressure together are independent and additive and dose-dependent," he concluded.

Discussing the study at the ESC Hotline session, Jemma Hopewell, PhD, University of Oxford, UK, said the results extend findings from previous observational and randomized studies.

Previous studies have shown reductions in cardiovascular events of about 25% to 30% with a 1 mmol/L reduction in LDL over 5 to 10 years, while this Mendelian randomized study increases that reduction to 54% when the 1 mmol/L reduction in LDL is extended over 50 to 60 years, she noted.

"So we are seeing a pattern of larger event reductions with longer exposure to lower LDL, and the same thing is seen with systolic blood pressure and the combination of both LDL and blood pressure," she said.

However, Hopewell pointed out it is not known if these results based on genetic scores apply to the same differences achieved with medication use.

European Society of Cardiology (ESC) Congress 2019, World Congress of Cardiology. Presented September 2, 2019.

JAMA. Published online September 2, 2019. Full text

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