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When the history of sugar is written, 2016 may go down as the year its image turned. Sure, we always knew those sweet white crystals could rot teeth and cause people to pack on the pounds. Obesity and diabetes were already national emergencies, with the latter representing 10% of U.S. health care costs in recent years.

But now an increasing number of researchers and a buzzy book, The Case Against Sugar, have also begun linking our favorite natural sweetener to such dreaded conditions as heart disease, Alzheimer’s, and cancer. (Those conclusions are far from universally accepted to this point.) Adding a dark undercurrent, revelations in the fall suggested that the sugar industry paid Harvard scientists in the 1960s to trivialize its role in coronary problems and instead play up saturated fat as the culprit—which helped shape the direction of nutrition research to this day.

 “Sugar is the new tobacco” in the minds of the public, says David Turner, a global food and drink analyst at market research firm Mintel.

And a public health war has followed. A handful of cities have responded with taxes on sugary drinks, and next year the Food and Drug Administration will start requiring companies to reveal the amount of added sugars on product packaging.

 That’s the problem for Big Food: It’s built on the stuff. Some 74% of packaged foods and beverages in the U.S. contain some form of sweetener, according to a recent study in The Lancet, making it a more than $100 billion market. Companies “use hedonic substances, and sugar is the most ubiquitous hedonic substance,” says Robert Lustig, a professor at the University of California at San Francisco’s School of Medicine and a leading critical voice on the topic. That’s an academic way of saying that food companies know customers crave a sugar rush.

All of this has infused new urgency in the multi-decade quest to find low-calorie sweeteners. And it’s occurring just as the incumbent alternatives face ever more skepticism. According to Mintel, 39% of consumers think it’s best to avoid products containing artificial ingredients like aspartame and saccharin because of perceptions of health risks. Sales of such substitutes fell 13% between 2011 and 2016.

That brings us to the final factor that is pressing heavily on packaged food companies: the ever-more-ravenous appetite for “natural,” unprocessed products. “Health and wellness used to be synonymous with reduced caloric intake,” says Bernstein analyst Ali Dibadj. By that standard, as he puts it, referring to the iconic early diet cola, “Tab used to be damn healthy.” No longer…

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