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There are a lot of conflicting messages on high fructose corn syrup. In popular media, it is frequently demonized as a hidden danger or silent killer that should be avoided at all costs.

From 5 Reasons Why High Fructose Corn Syrup Will Kill You:

When used in moderation it is a major cause of heart disease, obesity, cancer, dementia, liver failure, tooth decay, and more.

As you'd expect, the corn industry argues otherwise and says HCFS is as safe as table sugar. Besides industry responses, though, there are some studies that found little ill effects, such as this one: Health implications of fructose consumption: A review of recent data, Rizkalla SW (2010).

Is there enough high-quality evidence to determine if high fructose corn syrup is, in fact, dangerous?

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Definition:

The term "high fructose corn syrup" is not a good descriptor of its composition, but the term was mandated to distinguish the newly developed fructose-containing corn syrup from traditional all-glucose corn syrups. Factors that may account for the different effects of fructose alone or a mixture of fructose and glucose could be its gastrointestinal effects and absorption characteristics. (5)

The Problem

Today we have too much access to energy that we don't need. This leads to the problem of obesity when people consume too many calories, pointing towards higher risks of cardiovascular diseases.

The Possible Culprit

High Fructose Corn Syrup (HFCS) contributes to this problem because when consumed, it does not stimulate the pancreas to produce insulin. In animal models, it even induces insulin resistance, leading to diabetes (1).

"the long-term consumption of diets high in fat and fructose is likely to lead to increased energy intake, weight gain, and obesity" (1).

Additionally, when ingested by itself, fructose is poorly absorbed from the gastrointestinal tract, and it is almost entirely cleared by the liver since it's absorbed through a different system than glucose. This puts more work on the liver. (2)

Furthermore, HFCS

"did not suppress circulating ghrelin, a major appetite-stimulating hormone" - (2)

So even though you're taking in a massive amount of energy and overworking your liver, you don't feel full, which causes you to keep eating and drinking.

For runners and other endurance athletes, this is ideal. They can store up massive amounts of energy without the need to stuff themselves until their stomachs are nearly exploding. For people who burn a massive amount of energy on a regular basis, HFCS comes as a good source for replenishing and preparing that energy for usage, but for everyone else who doesn't burn high levels of calories, this indicates a high influx of potential energy without anywhere to go.

The Counter

This short-term study notes,

"There were no differences in energy or macronutrient intake on day 2. The only appetite variable that differed between sweeteners was desire to eat" (4)

Another study notes that most of the testing has been done on rats, whereas in humans,

for people with insulin resistance, diets with 50 grams or more per day (high consumption) may result in elevated triglycerides, but there is no effect with normal levels of fructose consumption. (5)

The Caution

Fructose is poorly absorbed from the digestive tract when it is consumed alone, but absorption improves when fructose is consumed in combination with glucose and amino acids. In addition, the principal sweetener in soft drinks in the US, HFCS, is not pure fructose but a mixture of fructose (55%) and glucose (45%). HFCS is predominately present as HFCS-55 (55% fructose, 41% glucose, and 4% glucose polymers) or HFCS-42 (42% fructose, 53% glucose and 5% glucose polymers) (5).

Studies on humans hasn't been substantial enough to develop hard evidence. In fact, one of the studies indicates that fructose increased appetites while another claimed it inhibited appetite!

If there's one thing that seems highly possible right now, it's that high fructose corn syrup gives energy, whether you need it or not. Since most people don't, that contributes to possible obesity (3).

Sources:

(1) Fructose, weight gain, and the insulin resistance syndrome

(2) How bad is Fructose?

(3) A sweet problem: Princeton researchers find that high-fructose corn syrup prompts considerably more weight gain

(4) Effects of high-fructose corn syrup and sucrose consumption on circulating glucose, insulin, leptin, and ghrelin and on appetite in normal-weight women.

(5) Health implications of fructose consumption: A review of recent data

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Fructose does not stimulate production of incretin, which results in sweeteners with a high fructose content being metabolized differently.

People taking GLP-1 agonists should avoid high levels of fructose, including the obvious - high fructose corn syrup.

ref: https://www.physiology.org/doi/pdf/10.1152/ajpendo.00446.2012 Burmeister, et al., Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose] Am J Physiol Endocrinol Metab 304: E677–E685, 2013; doi:10.1152/ajpendo.00446.2012

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