Could Aspartame Increase the Risk of Heart Disease? A Deep Dive into the Latest Research

In a previous article, we explored recent research on erythritol, a widely used sugar alcohol found in many low-carb and sugar-free products. That study raised concerns about erythritol’s potential to increase blood clot formation, promote platelet aggregation, and mimic pathways associated with sickle cell disease. These findings suggested that, while erythritol has been favored for its low glycemic impact, it may not be metabolically inert and could pose cardiovascular risks, particularly for individuals already at risk of thrombosis or metabolic disease.

Now, we turn our attention to another common low-calorie sweetener—Aspartame (951 or E951).

Aspartame, one of the most widely used artificial sweeteners, has long been a subject of debate regarding its health effects. While regulatory agencies worldwide have deemed it safe for human consumption within recommended limits, emerging research continues to raise concerns about its potential metabolic and cardiovascular impacts.

A groundbreaking 2025 study by Wu et al., published in Cell Metabolism, investigates the connection between aspartame consumption and atherosclerosis, a leading cause of cardiovascular disease (CVD). The study’s findings suggest that aspartame exacerbates atherosclerosis through an insulin-triggered inflammatory mechanism, shedding new light on the metabolic effects of this commonly used sweetener.

This article breaks down the study’s key findings, explains the proposed mechanism linking aspartame to heart disease, and contextualizes these findings within the broader landscape of metabolic health research.

Additionally, we incorporate insights from Dr. Nick Norwitz, PhD (Oxford), MD (Harvard), to further explore the implications of this study.

Aspartame and Heart Disease: What We Know So Far

Aspartame is an artificial sweetener approximately 200 times sweeter than sucrose (table sugar) and is widely used in diet sodas, sugar-free gums, and a variety of low-calorie food products. Despite its near-zero caloric content, concerns have been raised about its potential role in metabolic disorders such as insulin resistance, obesity, and cardiovascular disease. Several epidemiological studies have suggested a possible association between artificial sweeteners and an increased risk of heart disease. However, these observational studies do not establish causation. Given the impracticality of conducting long-term human randomized controlled trials (RCTs) on heart disease progression, researchers have turned to animal models to explore potential mechanisms of harm.

The new study by Wu et al. (2025) aimed to investigate whether aspartame consumption directly contributes to atherosclerosis and, if so, to uncover the molecular mechanisms driving this process.

Study Method: How Was the Research Conducted?

To explore the effects of aspartame on metabolic and cardiovascular health, researchers in the Wu et al. (2025) study conducted experiments using both animal models (mice and monkeys) and molecular analyses. The study aimed to determine whether aspartame consumption contributes to atherosclerosis (plaque buildup in arteries), insulin resistance, and inflammation.

🔬 Study Design:

✔ Mice Model: Researchers fed genetically susceptible mice a diet containing 0.15% aspartame, an amount equivalent to consuming three Diet Cokes per day in humans. A control group was maintained on an aspartame-free diet. Researchers monitored the development of atherosclerosis, insulin levels, and inflammatory markers over time.

✔ Monkeys Model: To assess the effects in primates, a group of monkeys was given aspartame over an extended period. Researchers measured insulin secretion, insulin resistance, and markers of vascular inflammation.

✔ Molecular Analysis: The study investigated the mechanism linking aspartame, insulin resistance, and inflammation by analyzing gene expression in vascular endothelial cells. They identified the role of the CX3CL1-CX3CR1 inflammatory pathway, which facilitates immune cell infiltration into blood vessels, accelerating plaque buildup.

Key Findings: How Aspartame May Contribute to Atherosclerosis

The Wu et al. (2025) study systematically evaluated the metabolic and cardiovascular effects of aspartame in both mice and monkeys, offering new insights into its potential role in promoting insulin resistance, inflammation, and atherosclerosis. Below, we break down the study’s key findings in greater detail, relying on both experimental data and molecular mechanisms identified in the research.

1. Aspartame Consumption Increases Atherosclerotic Plaque Formation

One of the most significant findings of the study was the dose-dependent increase in atherosclerotic plaque formation in aspartame-fed mice. Compared to the control group, the mice that consumed aspartame equivalent to three Diet Cokes per day developed larger and more advanced arterial plaques, indicating a potential link between aspartame consumption and cardiovascular disease risk.

🔍 Key Data:

✔ Increased Plaque Size: Mice that were fed aspartame showed significantly larger atherosclerotic plaques compared to those in the control group. The severity of plaque buildup correlated with higher doses of aspartame, demonstrating a dose-dependent effect.

✔ Presence of Inflammatory Markers: In the mice given aspartame, researchers observed a greater presence of macrophages within arterial plaques. Macrophages are immune cells that contribute to vascular inflammation, and their increased presence indicates greater inflammatory stress on the arteries.

✔ Effects Observed in Monkeys: The study also found that monkeys consuming aspartame displayed an increase in insulin levels, which is a major contributor to metabolic dysfunction. Elevated insulin can promote vascular inflammation, which can accelerate the development of plaque in the arteries, as seen in atherosclerosis.

🗣 Dr. Norwitz’s Perspective:

"What’s striking about these findings is that the effect was dose-dependent—meaning the more aspartame consumed, the worse the plaque formation became. This suggests that habitual consumption of aspartame, even in moderate amounts, could potentially contribute to cardiovascular disease risk."

2. Aspartame Increases Insulin Levels and Insulin Resistance

Perhaps one of the most concerning aspects of the study was the unexpected metabolic response to aspartame consumption. The researchers observed that aspartame triggered significant insulin secretion, leading to heightened insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including Type 2 diabetes and cardiovascular disease.

🔍 Key Data:

✔ Dose-Dependent Insulin Spikes in Mice: Mice that consumed aspartame showed a clear dose-dependent increase in insulin levels, meaning higher aspartame intake led to greater insulin spikes. This suggests that aspartame may not be metabolically "neutral" as previously assumed.

✔ Insulin Spikes in Monkeys: Similar results were observed in monkeys, where aspartame intake led to a significant and rapid rise in insulin secretion. The fact that these effects were replicated in primates raises concerns about potential human implications.

✔ Aspartame vs. Sugar: The researchers compared aspartame-induced insulin resistance to that caused by sucrose (table sugar). Surprisingly, the insulin resistance triggered by aspartame was even greater than that caused by sugar—challenging the assumption that only sugar leads to insulin resistance.

🗣 Dr. Norwitz’s Perspective:

"This finding is particularly concerning because we typically associate insulin resistance with sugar, not artificial sweeteners. If aspartame is causing insulin resistance comparable to or worse than sugar, it could have serious metabolic implications. Given that insulin resistance is a known driver of heart disease, this study raises red flags about the metabolic safety of aspartame."

3. Aspartame Triggers Endothelial Inflammation via the CX3CL1-CX3CR1 Pathway

A major breakthrough in the Wu et al. (2025) study was the identification of a novel molecular mechanism explaining how aspartame contributes to inflammation and atherosclerosis. The researchers discovered that aspartame-induced insulin spikes stimulate an inflammatory signaling pathway, specifically CX3CL1-CX3CR1, which promotes immune cell infiltration into blood vessel walls.

🔍 Key Mechanism:

✔ Aspartame Consumption Increases Insulin Secretion: The study demonstrated that aspartame stimulates insulin production, which activates inflammatory pathways in blood vessels.

✔ CX3CL1 Upregulation: High insulin levels upregulate CX3CL1, a chemokine (immune signaling molecule) that plays a crucial role in recruiting inflammatory immune cells to blood vessel walls.

✔ Macrophage Infiltration and Plaque Development: Increased CX3CL1 levels attract macrophages to blood vessels, promoting endothelial inflammation and contributing to plaque formation.

✔ Increased Adhesion Molecules in Arterial Walls: The study found that aspartame consumption led to higher expression of adhesion molecules in endothelial cells. These adhesion molecules act like “molecular Velcro”, making it easier for immune cells to stick to blood vessels and trigger inflammation.

🗣 Dr. Norwitz’s Perspective:

"This is the first time we have seen evidence that aspartame triggers inflammatory pathways that accelerate atherosclerosis. The CX3CL1-CX3CR1 pathway is a known driver of immune cell recruitment into arteries, which means that aspartame may not be a ‘neutral’ sweetener—it might actually contribute to the progression of heart disease."

Implications for Cardiovascular and Metabolic Health

The findings from the Wu et al. (2025) study provide new evidence that aspartame may not be as metabolically neutral as once believed. Instead, it appears to:

✅ Promote arterial plaque formation, increasing the risk of cardiovascular disease.
✅ Trigger insulin spikes and worsen insulin resistance, making it comparable to (or worse than) sugar in terms of metabolic impact.
✅ Stimulate inflammatory pathways that exacerbate atherosclerosis, particularly through the CX3CL1-CX3CR1 immune signaling mechanism.

For those who consume aspartame-containing products regularly, these findings suggest a need for caution, particularly for individuals with:

⚠ Type 1 or Type 2 Diabetes (where insulin resistance can exacerbate complications).
⚠ Existing cardiovascular disease risk factors (such as hypertension, obesity, or high cholesterol).
⚠ A family history of heart disease.

Given that aspartame is widely used in diet sodas, sugar-free products, and even some low-carb food options, this study raises important considerations for those following a Therapeutic Carbohydrate Reduction (TCR) approach. Individuals choosing low-carb, sugar-free foods should carefully evaluate the sweeteners they consume and consider alternatives that may have less impact on metabolic and cardiovascular health.

Considerations for Those Following TCR for T1D and Metabolic Health

For individuals following Therapeutic Carbohydrate Reduction (TCR) to manage Type 1 Diabetes (T1D) or improve metabolic health, the findings of this study raise important and thought-provoking questions. The primary goal of TCR in T1D management is to achieve stable, normal blood glucose levels, reduce insulin requirements, and improve long-term health outcomes. Many individuals with T1D opt for diet, low-carb, or low-calorie foods to minimize blood sugar fluctuations—many of which contain aspartame as a sugar substitute.

However, the latest Wu et al. (2025) study suggests aspartame may contribute to insulin resistance, vascular inflammation, and atherosclerosis through insulin-triggered pathways. But does this risk extend to individuals with T1D, who do not naturally secrete insulin and must inject insulin as needed?

This brings us to an important and nuanced debate:

✅ If aspartame does not directly raise blood glucose levels in someone with T1D, and they do not naturally secrete insulin, would they still experience the same risks as individuals without T1D?

✅ Does injected insulin behave the same way as naturally secreted insulin in relation to the inflammatory and atherosclerotic pathways observed in the study?

✅ Could individuals with T1D still be at risk due to other mechanisms beyond insulin secretion, such as gut microbiome alterations, endothelial inflammation, or oxidative stress?

Given these uncertainties, should individuals with T1D avoid aspartame altogether, or is its consumption justifiable in their specific case?

📌 We will explore these critical questions in a subsequent article, Part 2, analyzing both sides of the debate before providing a clear recommendation for those with Type 1 Diabetes.

Potential Alternatives

For those looking to reduce or eliminate aspartame from their diet, the following low- or zero-calorie sweeteners may offer metabolically favorable alternatives:

✔ Monk Fruit Extract – Another plant-derived sweetener with no known impact on blood glucose or insulin resistance.
✔ Allulose – A rare sugar with promising metabolic benefits, shown to reduce oxidative stress and improve mitochondrial function in recent research.

Given that aspartame has been a common ingredient in diet sodas, sugar-free desserts, and protein products, individuals may wish to examine food labels more closely and make informed choices about their intake.

Aspartame, known by its additive code E951, is a widely used artificial sweetener found in numerous food and beverage products. When reviewing ingredient labels, especially in regions like the European Union where additive codes are commonly used, it's important to recognize that E951 denotes the presence of aspartame.

Here is a list of popular products that often contain aspartame (E951):

• Diet Soft Drinks: Many low-calorie or "diet" sodas use aspartame as a sugar substitute. Brands such as Diet Coke, Pepsi Max, and Coca-Cola Zero Sugar are known to contain aspartame.

• Sugar-Free Chewing Gum: Aspartame is commonly used in sugarless gums to provide sweetness without added calories. Products like Extra, Orbit, and Trident often list aspartame among their ingredients.

• Flavored Milk Drinks: Some flavored milk beverages, especially those labeled as "light" or "sugar-free," may contain aspartame. It's advisable to check the ingredient list for E951 or the term "aspartame."

• Powdered Drink Mixes: Beverage mixes designed to be added to water, particularly those marketed as low-calorie or sugar-free, frequently use aspartame. Brands offering flavored drink powders often include aspartame as a sweetening agent.

• Tabletop Sweeteners: Aspartame is available as a tabletop sweetener under various brand names, including Equal, NutraSweet, and Canderel. These products are used to sweeten beverages and foods as a sugar alternative.

• Sugar-Free Candies and Desserts: Many sugar-free or reduced-sugar candies, gelatin desserts, and puddings utilize aspartame to achieve sweetness without the added sugar.
Products like Jell-O Sugar-Free Gelatin are examples where aspartame is used.

• Yogurts: Certain "light" or "diet" yogurts incorporate aspartame to reduce calorie content while maintaining sweetness. Brands may label these products as low-calorie or sugar-free.

• Pharmaceuticals and Supplements: Aspartame is sometimes used as a sweetener in chewable tablets, sugar-free syrups, and powdered supplements to improve palatability. It's essential to read the ingredient list of medications and supplements, especially for those monitoring aspartame intake.

When reviewing product labels, especially in regions where additive codes are prevalent, look for 951, E951 or the term "aspartame" to identify its presence.

Final Thoughts: Should You Avoid Aspartame?

The Wu et al. (2025) study presents compelling experimental evidence that aspartame may contribute to atherosclerosis, insulin resistance, and vascular inflammation—raising concerns about its long-term safety, particularly for individuals at risk of metabolic or cardiovascular disease. While these findings do not necessarily mean that occasional consumption will lead to immediate harm, they do suggest that frequent and habitual intake of aspartame could have long-term implications for metabolic health.

Assessing the Risk: What We Know from the Study

✔ Atherosclerosis Progression: The study identified a dose-dependent increase in arterial plaque formation in aspartame-fed mice, with higher levels of consumption correlating to greater vascular damage. This suggests that chronic exposure could contribute to the progression of cardiovascular disease.

✔ Insulin Resistance and Metabolic Effects: The research demonstrated that aspartame consumption led to elevated insulin secretion and increased insulin resistance, with effects that were comparable to or worse than sugar in both mice and monkeys. Given that insulin resistance is a precursor to diabetes and cardiovascular disease, these findings suggest potential metabolic consequences for long-term users.

✔ Inflammatory Pathways and Endothelial Dysfunction: The study identified a novel inflammatory mechanism in which aspartame-induced insulin spikes upregulated CX3CL1, a chemokine involved in immune cell recruitment. This mechanism increased the infiltration of inflammatory cells into blood vessels, further promoting vascular inflammation and plaque formation.

While these findings were primarily based on animal models, the insulin-resistance effects in primates suggest that these mechanisms may be relevant to humans, particularly for individuals with preexisting metabolic conditions.

🚀 What Do You Think?

The Wu et al. (2025) study contributes to a growing body of research suggesting that artificial sweeteners may not be metabolically inert. While further human studies are needed, the potential risks of aspartame—including insulin resistance, inflammation, and vascular dysfunction—raise important questions about its long-term safety.

Will these findings change how you feel about aspartame?

Are you considering switching to alternative sweeteners?

Let us know your thoughts!

REFERENCES

Wu, W., Sui, W., Chen, S., Guo, Z., Jing, X., Wang, X., Wang, Q., Yu, X., Xiong, W., Ji, J., Yang, L., Zhang, Y., Jiang, W., Yu, G., Liu, S., Tao, W., Zhao, C., Zhang, Y., Chen, Y., & Zhang, C. (2025). Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. Cell Metabolism. https://doi.org/10.1016/j.cmet.2025.01.006

Nick Norwitz. (2025, February 23). Pour Decisions: Why I Won’t Touch This Common Ingredient. YouTube. https://www.youtube.com/watch?v=5oWAVPz0ffE