Obesity Trends, Anti-Obesity Drugs, and the Future of CKD Care
A few weeks ago, the New York Times amplified a recent study in the journal Lancet, which reported forecasts of rates of overweight (body mass index or BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2), projecting that a third of adolescents and some two-thirds of adults age 25 or older (some 213 million adults) will have overweight or obesity by 2050. The drivers of this alarming trend are complex, and made even more so by the well-known limitations on BMI as a measure which reliably distinguishes future risks of co-morbidity and death from normal variations on body morphology, colored by the pervasive scourge of “fat-stigma” which impedes sober empirical analysis and patient-focused diagnosis and management of a condition which actually conveys future health risks, rather than perpetuating a durable prejudice which actively impedes the delivery of sound medical care.
Our measurements of obesity are too simple, and there is a clear social cost to this oversimplification which warrants scrutiny. But, as the overall prevalence of overweight and obesity increases substantially, and as some of that increase in obesity rates translates to future risks for obesity related health complications like cardiovascular disease and chronic kidney disease, one point seems clear: Short of systemic and dramatic (even draconian) public health interventions which attenuate “risky” obesity, obesity-related complications like diabetes and chronic kidney disease are unlikely to fade as a growing challenge to public health.
And so, for good reason, glucagon-like peptide-1 agonists (GLP-1A) like semaglutide and tirzepatide are generating a lot of attention. GLP-1As have demonstrated significant weight loss and improvements in rates of heart attack and stroke. The recent results of the FLOW trial and the SELECT trial have rightly continued to draw attention to the promise of GLP-1A, and their effects in extending the quality and quantity of life in patients with chronic kidney disease.
In the United States, there are currently 30 million patients with CKD and only 500,000 patients with ESKD. The imbalance is because the vast majority of patients with CKD die (mostly from cardiovascular causes) before they progress to ESKD. Therapies that slow CKD progression typically also improve cardiovascular mortality. Hence, a patient with CKD on one of these medications may avoid a premature cardiovascular death and realize slowed chronic kidney disease progression.
In a world where many of the 30 million patients with CKD in the U.S. are taking one or more of these medications, if only 1% of these patients with CKD avoid a cardiovascular death and live long enough to develop ESKD, the number of current dialysis patients would increase by more than 50%. If the number of U.S. adults with overweight or obesity increases to > 200 million, and similar trends in the adolescent population are realized, the downstream future estimates of individuals with obesity and CKD may be substantially higher. Our public health infrastructure must be prepared to address the health needs of more patients with advanced kidney disease, including strategies which should prominently include expanded access to all modes of organ replacement like transplantation or dialysis.
Two studies of semaglutide in different populations of patients with CKD, the FLOW trial and the SELECT trial, offer additional clues about the impact of these medications on the CKD and ESKD populations. The FLOW trial looked at the effects of semaglutide in patients with advanced CKD at high risk of both cardiovascular mortality and rapid progression of CKD to ESKD over two years of follow up. In that study, cardiovascular mortality was reduced from 9.6% in the placebo group to 7.0% in the semaglutide group. For kidney disease progression, semaglutide reduced kidney-specific events from 14.4% in the placebo group to 12.0% in the treatment group. While the absolute numbers seem small on the surface, underscoring the point that GLP-1A medications can slow CKD progression but they don’t “cure” CKD, semaglutide is a welcome and important addition to what has otherwise been a stagnant therapy pipeline for effective drugs to reduce the progression of CKD.
There are also a striking percentage of patients prescribed GLP-1A drugs that discontinue them soon after they are prescribed. A recent study from a pharmacy benefits firm reported that less than 25% of patients prescribed Ozempic or Wegovy for weight loss were still taking the medications two years later. (Older GLP-1A medications fared worse with < 10% adherence at two years). If the majority of patients prescribed these medications actually stop them after a year or two, and given the widely recognized phenomenon of weight regain after discontinuing these drugs, we should all wonder whether patients who start and stop these medications are realizing any long-term health benefits at all. After all, the phenomenon of “weight cycling” (defined as losing and regaining ≥ 10% of total body weight) can actually increase the risks of new onset hypertension and diabetes, an observation which may be due a persistent reduction in resting metabolic rate after significant weight loss. Longitudinal studies of contestants on a reality TV show focused on extreme weight loss illustrate a complex relationship between severe calorie restriction, high physical activity, and propensity for weight gain. In these cases, dramatic reductions in weight loss resulted in metabolic adaptations which persistently reduced resting metabolic rate.
An expected increase in resting metabolic rate after weight loss didn’t happen, such that very low caloric intake was required to compensate for a persistently lower resting metabolic weight. Some (but not all) had a striking propensity for weight regain even with sustained rates of high physical activity, and those that did keep the weight off had to do so by maintaining the highest rates of physical activity. The effects of weight cycling haven’t been systematically studied in the GLP-1A era, and it may be the cycle of weight loss-regain with GLP-1A discontinuation is different. Maybe the resting metabolic rate reset remains a regular problem after GLP-1A discontinuation, or maybe it won’t. But, until we do know, it is worth being aware of the possibility that the real-world use of GLP-1A may not result in unqualified public health benefits.
Maybe the hope is that more “upstream” fully scaled interventions in patients with obesity will attenuate the rate of type 2 diabetes and its downstream complications, including chronic kidney disease. Maybe. A recent study using tirzepatide to attenuate new-onset insulin resistant diabetes exhibited impressive short-term results even after the medication was discontinued for 4-5 months.
But we also know that the fastest growing cohorts of patients with a high body mass index (BMI) are patients characterized as “obese” (BMI 30-35 kg/m2) and “severely obese” (BMI > 35 kg/m2). A substantial weight loss may make more severely obese patients merely “obese,” and obese people overweight. This attenuates downstream morbidity and mortality but doesn’t eliminate it. The DiRECT trial in the UK, which prescribed a diet-driven weight loss program in patients with type 2 diabetes, showed that losing more than 35 pounds in a year yielded 86 percent of patients were diabetes medication free. But, only 70 percent of them were medication free at two years, even if they kept all the weight off. For some, prior insulin resistance is not simply “switched off” with sustained weight loss. As with the “competing endpoints” of death and kidney failure, we may instead be faced with a population of patients who would have died from obesity related complications now living longer to encounter and experience other diseases, including kidney failure.
In short, these new GLP-1A drugs offer the promise of avoiding premature morbidity and death to millions of people, but as is often the case, we may exchange one positive public health benefit (reduced cardiovascular mortality, reduced CKD progression) for other unintended public health challenges (insufficient policy attention to drivers of “risky” obesity, complications of weight cycling, more patients surviving long enough to develop CKD or ESRD). At Fresenius Medical Care, our hope is that the attention to these new medications will galvanize the need for earlier kidney disease screening, underscore the importance of prescribing and not stopping cheap and effective RAAS inhibitors, and underscore to policy makers, regulators, and society that the fight against kidney disease must be a multi-pronged, long-term public health commitment.
Publication date: December 2024
