Will PREDIMED and the Lyon Diet Heart Study be the last nutrition cardiovascular outcome trials?

For Cardiovascular Diabetology’s 20th anniversary, we’ve asked the authors of the journal’s most influential articles to comment on their findings from today’s perspective and how the articles may have advanced science and influenced their careers. In this blog Amy McKenzie and colleagues discuss nutritional approaches to reduce heart disease risk in type 2 diabetes, as tested in their trial.

Type 2 diabetes (T2D) has been called a cardiovascular disease for good reason. The risk of cardiovascular disease is 2-4 times greater in people with T2D, and cardiovascular reasons are the number one cause of death among those with the disease.

Lowering blood sugar, however, seems to reduce risk. The UK Prospective Diabetes Study showed that every 1% lower HbA1c reduced the risk of heart attack by 14%, and although differences in HbA1c between the intensive and standard treatment groups were lost after the first year, the reduction in risk of heart attack and death persisted for 10 years, indicating a lasting effect of short-term improved blood glucose in patients with newly diagnosed diabetes. However, lowering glucose too much with medication, to the point of severe hypoglycemic (low blood sugar) events, could have negative effects.

Fortunately, diabetes treatment has come a long way. GLP-1 receptor agonists and SGLT2 inhibitors deliver improved blood glucose control with a low risk of hypoglycemia and a reduced risk of cardiovascular events. And now, significant evidence exists that nutritional approaches, like a ketogenic diet, reverse diabetes (i.e., the process of lowering glucose and deprescribing medications), or even put diabetes into remission by returning blood glucose to prediabetic levels without the need for medication.

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Taken together, evidence suggests that improved glucose outcomes and diabetes remission from nutritional approaches could also favorably impact cardiovascular disease and events. The lower carbohydrate and higher fat Mediterranean diet is the only nutritional approach with evidence of a reduced risk of actual cardiovascular events (like a heart attack or stroke) or deaths related to a cardiovascular cause in both primary and secondary prevention, coming from the PREDIMED and Lyon Diet Heart studies, respectively.

Data from studies on very low carbohydrate diets resulting in nutritional ketosis, like ours published in Cardiovascular Diabetology, currently rely on surrogate markers of cardiovascular risk. While the majority of markers improve, some studies observe an increase in LDL-C, which has been a cornerstone of cardiovascular risk management.

Although LDL is considered causal in atherosclerosis and cannot be ignored in clinical practice, it also can’t solely inform risk assessment, as LDL-C can often be discordant with the number of LDL particles. In fact, calculated risk scores to help clinicians judge risk often don’t include LDL-C, but instead rely on several other markers of risk like total cholesterol, HDL-C, and blood pressure.

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The process of atherosclerosis is gradient driven, and measures reflective of the number of particles, like LDL particle number and ApoB, and non-HDL-C are better markers of risk than LDL-C and are included in practice guidelines. These markers are typically not changed by a ketogenic diet, as we observed. We also found that the thickness of the carotid artery wall, another marker of atherosclerosis, was unaffected.

Even when LDL-C lowering is achieved through statin treatment, residual risk can remain from high triglycerides, low HDL-C, and more small LDL particles. This constellation of characteristics is referred to as the atherogenic lipoprotein profile (ALP), and it is the most common dyslipidemia in patients with T2D. The ALP was normalized in a significant proportion of patients advised to consume a very low carbohydrate diet over 2 years in this research study. Other risk factors for cardiovascular disease like obesity and inflammation improved; most patients lowered HbA1c and some put diabetes in remission.

Our research shows that very low carbohydrate diets including nutritional ketosis can result in a plethora of improvements in cardiovascular risk factors. This, coupled with no change in LDL particle number and carotid intima media thickness, suggests cardiovascular safety alongside the reversal of T2D to lower blood glucose levels, even to the point of remission.

Our research shows that very low carbohydrate diets including nutritional ketosis can result in a plethora of improvements in cardiovascular risk factors.

The impact of nutritional ketosis on cardiovascular outcomes like heart attack, stroke, and hospitalization or death from a cardiovascular cause, however, remains an open question. The evidence certainly points in the right direction, and this coupled with the reversal of diabetes seems like a win-win.

Imagine a 10-year trial among newly diagnosed patients with T2D using ketogenic nutrition therapy for intensive therapy, and what we could learn about primary prevention. Imagine a trial in patients hospitalized for heart failure started on ketogenic nutrition therapy and what we could learn about the risk of readmission.

So, are we willing to let PREDIMED and the Lyon Diet Heart Study be the last cardiovascular outcome trials in nutrition? Or are we ready to put this intervention of a very low carbohydrate diet including nutritional ketosis with sustained, long-term benefits to the test?

Our patients deserve to know.

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