Post #28: Are Sugar Substitutes (Artificial Sweeteners) Effective or Harmful for Long Term Health?

Today’s post (#28) is on understanding the effectiveness of sugar substitutes for long term weight loss, blood sugar control, and other health benefits. Over the years, I have seen enough ads for the various artificial sweeteners (Equal, Splenda, Sweet’N Low, etc.) as well as been bombarded by reels / videos from social media influencers touting the benefits of the more naturally occurring sweeteners like Stevia, and I wanted to do my own literature research to determine if it was worth actually experimenting with it.?

Most of my literature research takes about one to two weeks before I move on to the experimental phase. Some topics end up being given the green light quickly (e.g. cold water showers), some get the red light equally quickly (unlike Bryan Johnson I have decided against asking my son for a liter of his blood plasma - BTW, for those that are dying to know, he concluded that it didn’t show any improvement), but this topic of sugar substitutes has probably required the most research (even more than the research involved in my post on the Galleri cancer screening test). The deeper I got into it, the more I realized how much is still not clearly understood about the long term implications of these sugar substitutes in spite of years of research. Here I will share my learnings and conclusions, which I think you will still find quite intriguing, fun and hopefully helpful if you consume artificial sweeteners in your tea, coffee or food or have ever considered doing it. While the post is on the longer side, you can easily skip sections and only read the ones that you want to know more about.

Sugar substitutes: why there were developed and how they work

Let’s start with why sugar substitutes were developed. We’ve all heard that sugar is bad for us. Long-term sugar consumption, in the form of table sugar (sucrose), high fructose corn syrup, etc. can lead to weight gain and elevated risk for many of the most deadly chronic diseases, including metabolic syndrome and type 2 diabetes, cardiovascular disease, Alzheimer’s, dementia, and certain types of cancers. However, just because we know something is bad for us doesn’t stop us from doing it, especially in this case, because … sugar just tastes so good. So the promise of a product that could give you the pleasure but not the pain sounded amazing. This is what led to the development of Saccharin as early as the 1890s and the subsequent launch of other compounds that you may have heard of, such as Aspartame, Sucralose, Erythritol, Stevia, Allulose, etc.?

How these compounds work is they bind to the sweet receptors on our tongues even more densely than regular table sugar does, thereby giving a 100X to 1000X increase in the perception of sweetness. This means that for the same perception of sweetness in the brain, one has to consume much smaller amounts of these compounds, which in turn means consumption of zero to very low calories compared to table sugar. On a fun note, the artificial sweetener packets seem to carry as much quantity as table sugar but given that you don’t need as much of it as per my previous statement, it is more of a marketing gimmick; most of it is a filler that doesn’t add any value.

It all sounds great so why isn’t there a clear conclusion after so many years?

The reason there has been so much research but is still inconclusive is because doing long-term controlled trials on humans on a topic like this has proven to be very difficult .That is because there are various sugar substitutes today in almost everything you eat or drink and therefore harder to figure out two distinct groups of subjects to compare and contrast. While there are a number of short term studies, those can be misleading because imagine what a short term study on the effects of smoking would have demonstrated: pretty good at keeping your weight down and little to no impact on your lungs. There have been some controlled studies done on animal models but unfortunately (or fortunately) humans are not mice and while those studies can provide some initial insights, they cannot be assumed to automatically apply to humans. Finally, each of the compounds I have mentioned previously may have different levels of impact and most studies have lumped them together so the results aren’t conclusive about the effectiveness of any one of them. That said, there have been many observational studies done on people over reasonably long periods of time and although they aren’t as conclusive because they aren’t controlled, they do begin to provide longer term perspectives that are practically more insightful.

What do these long term observational studies suggest? (you can skip this section if you don’t want to get into the research studies)

Before we reach any conclusions, let’s just look at results from various studies. Peter Attia and his team have done an excellent job analyzing data from hundreds of studies, thereby saving me countless hours. In the rest of this article, I will attribute in quotation marks the comments I picked up from Peter Attia’s research and provide my simplified analysis next to it.?

“An analysis of data from the San Antonio Heart Study showed that the positive relationship between artificial sweetener consumption and weight-related metrics (change in BMI and incidence of overweight/obesity over the 10-year observation period) was dose-dependent (n=3,682), even after adjusting for baseline BMI and other confounding factors such as smoking and exercise habits.” This suggests that the more artificial sweeteners they used, the higher their BMI over a 10-year period, not lower, even after accounting for other factors that could have influenced the conclusion. Not a great start for the long-term effects of artificial sweeteners.

“Some animal studies have shown that sugar substitutes can cause rodents to overeat and consequently gain weight, but interestingly, others suggest that low-calorie sweeteners may induce weight gain even without triggering increased total calorie intake. A study in rats showed that diets sweetened with saccharin or aspartame – but not diets sweetened with sucrose – resulted in weight gain despite comparable total caloric intake across groups. Similarly, a study in mice found that animals given a saccharin solution gained more weight than controls given water despite consuming approximately 14% fewer total calories.” This suggests that for some reason (that I will discuss in a subsequent section), even though the animals consumed the same number of calories across both the artificial sweetener fed group and the regular sugar fed group, the former had long term weight gain. A different study showed that the group of rodents that were on sugar substitutes ended up naturally consuming more calories (why this happens is discussed later) and therefore gained weight. A third study showed weight gain despite consuming fewer calories.?

“A 2021 meta-analysis of prospective cohort studies assessing the relationship between artificial sweetener consumption and diabetes incidence reported an overall 13% increase (95%CI: 1.03-1.25) in type 2 diabetes risk for every additional serving of an artificially sweetened beverage per day. Though heterogeneity across studies was high, risk was found to increase in a dose-dependent manner. Further, a recent study revealed that rats supplemented with a mix of aspartame and sucralose for 12 weeks exhibited increased hemoglobin A1c (HbA1c) and HOMA-IR (a metric of insulin resistance) at the end of the intervention period relative to both normal-diet controls and to animals supplemented with sucrose.” This was again not good news with an increase in HbA1c levels for those that consumed drinks that contained artificial sweeteners. However, the silver lining here seems to be that the individuals who were consuming drinks that had sucrose and were substituting them with drinks sweetened by sugar substitutes, they did definitely see a short term improvement in both weight loss as well as HbA1c. On the other hand, if you are used to drinking water and you choose to switch to a Diet Coke, that is going to make matters worse.

Doesn’t sound very encouraging. Why do the results not match the hype?

I am glad you asked, but while there are simple logical mechanisms that are suspected behind these observations, there unfortunately isn’t a universally accepted answer on these conclusions. Here are the things that are theorized as being at work:

1. Impact of sugar substitutes on the gut microbiome

In a past post, I have written about the role that our microbiome plays in our short and long-term health. Specifically, our gut or digestive tract houses trillions of bacteria, where they interact with the food we consume and influence a number of things such as how we digest that food, how our immune system reacts to it, how it impacts our hormones, and in general how it seems to determine our health risk for diseases such as Alzheimer’s, diabetes, heart health and cancers. Some of these gut bacteria are associated with positive health conditions while others with negative health conditions; this is a relatively new research area and findings are evolving rapidly so keep an eye on this space.

Humans may not be able to metabolize most sugar substitutes, but these compounds can nevertheless have profound impacts on our gut microbiome, which in turn can lead to long-term metabolic effects. “A landmark study by Suez et al. in 2014 provided definitive evidence that indeed, non-nutritive sweeteners caused alterations in the mouse microbiome which secondarily drove the development of glucose intolerance.” This was the first comprehensive study that suggested that consuming artificial sweeteners (the focus in this study was on saccharin, aspartame, and sucralose) caused the rodents to become glucose intolerant and with altered microbiome compositions, while those on the regular table sugar (sucrose control group) and the water-treated control groups did not exhibit either of these effects. Even more interestingly, when these mice were given antibiotics which destroy the gut microbiome, it eliminated the glucose intolerance, indicating that effects on glycemic control were caused specifically by the effects of the sugar substitutes on the microbiome. A follow up study in humans showed the above conclusions to hold but even more fascinating was the fact that when the gut microbiome of humans with blood sugar issues was transferred to germ-free mice unexposed to artificial sweeteners, these animals subsequently developed the same glycemic issues as the humans they received the microbiome transplant from. These results strongly support the idea that non-nutritive sweeteners cause microbiome changes which in turn cause derangements in glucose metabolism. On a side note, if you plan to take any antibiotic treatment, combine it with a renewed focus on eating lots of veggies and healthy foods to help with the rebuild of your good bacterial colonies.

2. Effect of sugar substitutes on the brain

Artificial sweeteners often fail to control body weight and metabolic health because they are less satisfying than sugar. Unlike sucrose, they do not strongly activate the brain's reward circuitry, leading to no significant decrease in hunger or calorie intake. Mice given a choice between artificially sweetened water and sugar-sweetened water of comparable levels of sweetness have been shown to consume both at equivalent rates initially, but within 24 hours, they shift toward a striking preference for the sugar-sweetened option.

While sugar substitutes taste as sweet to the tongue as does sucrose, once the sugar enters our gut, the cells lining the interior of the small intestine can detect regular sucrose but isn’t as effective at detecting the artificial sweeteners (for those that are curious, this is due to a protein called SGLT-1 that the glucose binds to but not the artificial sweetener compounds). In addition, in response to a calorie load, the gut releases certain hormones, (including GLP-1 which is used in Ozempic), signaling satiety and promoting cessation of eating. Release of these hormone levels increase in response to consumption of sucrose but often remain unchanged in response to artificially sweetened solutions. This means that no matter how much we replace sucrose with low-calorie sugar substitutes, they will never satisfy our sugar cravings nor will it help us feel full. Consequently, it’s easy to imagine how these substitutes might in fact lead to increased calorie consumption and the subsequent glucose-related issues.?

Another interesting effect when we taste sweetness is that our brain triggers what is termed as a cephalic phase response (CPR) to prepare the body for incoming glucose. This is how our brains have evolved over time to proactively prepare our bodies to deal with an upcoming issue. E.g. When we see any form of danger, our cortisol levels shoot up so it will help with the release of glucose to help us run away faster (fight or flight response); similarly, just before we wake up every morning, our fasting glucose levels increase as does our blood pressure to deal with the increased upcoming stress on the body. So when our tongue tastes any sweet foods, the CPR processes kick in, releasing hormones like GLP-1 and insulin to prepare for the incoming glucose spike. These responses help optimize nutrient use and maintain metabolic balance by preventing drastic blood sugar spikes. However, since artificial sweeteners do not provide glucose even though they tasted as sweet to the tongue, it disrupts these processes, leading to issues like hypoglycemia due to the pre-release of insulin without subsequent glucose absorption. This discrepancy may cause the brain to dampen CPRs for all sweet tastes, compromising the body's ability to maintain metabolic balance and regulate energy balance.?

Ok so what’s the conclusion: are they good or bad for me?

Given the absence of long-term randomized controlled trials on humans, clear conclusions are difficult to draw but there seems to be a bias towards the following that I have taken away:

1. In general, I have always preferred to stick to things that are naturally occurring, and then have them in moderation rather than go for things that sound like a magical solution but haven’t been tested enough. The only place I have resorted to using anything artificial, and that too only to supplement my natural intake, has been protein powders for reasons I have elaborated in a few other posts. For now, the research doesn’t provide a compelling argument to use sugar substitutes.
2. Having said that, I would consider them if I found myself consuming a lot of sugary drinks, such as Coke or Pepsi, or if I am used to consuming tea or coffee with regular sugar. In those cases, I would consider replacing the sodas with the diet version of those drinks that contain these sugar substitutes or use artificial sweeteners in my tea or coffee. There are potential issues with the diet versions of the sodas, but it is a matter of choosing the lesser of the two evils. Even here, I would avoid using them for any longer than absolutely necessary to kick-start any weight loss or HbA1c reversals.
3. If I was in a situation where I decided to use a sugar substitute for the short term, I would consider Allulose, monk fruit extract, and maybe Stevia given their ability to communicate with the brain like table sugar does, and therefore get addressed by the body more similar to regular sugar.?
4. The FDA has cleared a few different sugar substitutes with limited daily intakes but even the Mayo Clinic website suggests “In general, it is safest to take in small amounts of sugar substitutes. And it's best to use sugar substitutes for a short time, or just every once in a while. So try to cut back if you use them a few times a day.”

Hope that is helpful. I would love to hear from any of you that have had practical experience using sugar substitutes of any kind in the short or long term and what impact it has had, if any, on your health. And as always, any feedback on any aspect of the posts is welcome and appreciated.

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