Obesity Primer for Nephrologists: An Interview

AJKDBlog Interviews Editor Timothy Yau (@Maximal_Change) talked with Alexander Chang (@alexchangmd) and Evan Zeitler (@LittleBigGloms) about their recently published AJKD Perspective, which recommends prescribing practices as a practical tool to engage nephrologists and patients with CKD in the treatment of obesity-related morbidity.


Dr Alexander Chang is a physician-scientist and Associate Professor in the Departments of Nephrology and Population Health Sciences at Geisinger. He has devoted his clinical and scientific career to preventing and decreasing the burden of CKD and related cardiometabolic complications.


Dr Evan Zeitler is a nephrologist at UNC-Chapel Hill. He is a physician scientist with an interest in obesity related kidney diseases.

AJKDBlogRates of obesity in the US and worldwide have risen recently to the point where it is commonly referred to as an epidemic.  Before we jump into the myriad of newer treatment options for obesity, can you describe the impact of obesity on kidney health and its importance to nephrologists and their patients?

Dr Chang: Obesity has a massive impact on kidney health. In addition to insulin resistance and diabetes, obesity can cause kidney damage through glomerular hyperfiltration and intraglomerular hypertension, stimulation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and dysregulated adipocytokines. While we may have a tendency to think of the most severe manifestation—obesity-related focal segmental glomerulosclerosis (FSGS), we really need to think about all our patients struggling with obesity. About ½ of patients with CKD in the U.S. now have obesity and more than ¼ have severe obesity (BMI ≥ 35 kg/m2). With new options to address obesity here and more on the horizon, it is very important for nephrologists to learn more about treating obesity as a disease rather than a moral failing.

AJKDBlogThere have been several conflicting reports on targeting weight loss in patients with chronic kidney disease or end-stage kidney disease.  The “obesity paradox” or “reverse epidemiology” theory describing better outcomes in obese patients are likely driven by selection bias and flawed metrics.  Where do we stand currently on the benefits of weight loss in patients with kidney disease?

Dr Chang: While observational research is very important, there are certain things that probably will not be addressable without randomized controlled trials in my opinion. So we are talking about many observational studies done showing that patients, particularly those on hemodialysis, with high BMI live longer and those with the greatest amount of weight loss have the highest mortality. When I think of patients losing substantial weight (without some kind of major intervention), I think there is usually some underlying illness going on, rather than the patient having a lot of success with weight loss. There is also a study showing the opposite. Among patients with severe obesity and end-stage kidney disease, those who have bariatric surgery have much lower risk of death and are more likely to get transplanted.

The only way that we will be able to know for sure about effects on mortality in patients with advanced CKD will be dedicated randomized trials targeting weight loss in this population. There will be some data with some CKD subgroups available coming up from large GLP1-RA cardiovascular and CKD progression outcome trials, but to my knowledge this is a definite need to resolve in more advanced CKD and ESKD.

AJKDBlogWeight loss drugs in the past were fraught with safety concerns with regards to cardiovascular health.  What is different about the newer classes of medications such as glucagon-like peptide (GLP-1) agonists and glucose-dependent insulinotropic polypeptides (GIP)?

Dr Chang: All the prior cardiovascular safety concerns in the past with various weight loss drugs also have made me cautious about weight loss medications. What’s different with these incretin medications? GLP1 agonists have been studied extensively for safety outcomes in a very large number of patients with type 2 diabetes, including many with stage 3 CKD. They have been shown to reduce risk of major atherosclerotic cardiovascular events. In terms of kidney outcomes, studies show that these agents reduce albuminuria and some studies have shown promising results on GFR slope, but a definitive trial is still needed. The FLOW trial will hopefully provide us with this data, and hopefully many more studies will show us the way in terms of GLP-1/GIP combination medications. There are some potential risks such as increased risk of cholelithiasis and biliary disorders, and they also need to be avoided in patients with personal or family history of medullary thyroid carcinoma.

<img fetchpriority="high" decoding="async" aria-describedby="caption-attachment-41147" data-attachment-id="41147" data-permalink="https://ajkdblog.org/2023/12/13/obesity-primer-for-nephrologists-an-interview/zeitler-fig-1/" data-orig-file="https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-2.jpg" data-orig-size="1573,1757" data-comments-opened="1" data-image-meta="{"aperture":"0","credit":"","camera":"","caption":"","created_timestamp":"0","copyright":"","focal_length":"0","iso":"0","shutter_speed":"0","title":"","orientation":"0"}" data-image-title="Zeitler Fig 1" data-image-description data-image-caption="

Prevalence of obesity, abdominal obesity, and severe obesity in chronic kidney disease. Prevalence of obesity (BMI ≥ 30 kg/m2), elevated waist circumference (>102 cm for men, >88 cm for women), and severe obesity (BMI ≥ 35 kg/m2) in patients with chronic kidney disease. Data from NHANES 2007-2018. Figure 1 from Zeitler et al, AJKD.

” data-medium-file=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-5.jpg” data-large-file=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-6.jpg” class=” wp-image-41147″ src=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-2.jpg” alt width=”508″ height=”568″ srcset=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-2.jpg 1573w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-5.jpg 269w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-6.jpg 917w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-7.jpg 134w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-8.jpg 768w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-9.jpg 1375w, https://ajkdblog.org/wp-content/uploads/2023/12/Zeitler-Fig-1-1200×1340.jpg 1200w” sizes=”(max-width: 508px) 100vw, 508px”>

Prevalence of obesity, abdominal obesity, and severe obesity in chronic kidney disease. Prevalence of obesity (BMI ≥ 30 kg/m2), elevated waist circumference (>102 cm for men, >88 cm for women), and severe obesity (BMI ≥ 35 kg/m2) in patients with chronic kidney disease. Data from NHANES 2007-2018. Figure 1 from Zeitler et al, AJKD.

AJKDBlogCan you walk us through a bit of the history and physiology of the incretin hormones GIP and GLP-1?  The boom in this field is reminiscent of SGLT2-inhibitors, which were not initially known to have kidney/cardiac protective effects, but now are first-line agents in kidney disease and goal-directed medical therapy.  Was weight loss a secondary side effect after glycemic control for these agents? 

Dr Zeitler: The analogy with SGLT2 inhibitors is definitely an interesting one, in the sense that they were both identified based on long-known physiological effects (benign glucosuria in the case of SGLT2i and the “incretin” effect in the case of GLP1/GIP), and neither was suspected to have effects outside of glycemic control.

Weight loss was never the intended primary effect of these agents. The incretins in particular are powerful for improving glycemic control in patients with diabetes, but induce weight loss via a variety of mechanisms which are both central and peripheral. Increased satiety and decreased appetite drive this in part, but so does decreased gastric emptying, and this is only at the most basic level.

AJKDBlogWhat agents are currently approved for weight loss based on study data?  And what studies demonstrated that these could be used for obesity in the absence of diabetes?

Dr Zeitler: The only two incretins currently approved for treatment of obesity and overweight in patients without type 2 diabetes are liraglutide (based on the SCALE trial, in which patients without DM lost 5.6 kg more than those on placebo) and semaglutide (based on results of the STEP 1 trial, in which patients without DM lost 12.7 kg more than those on placebo). But as we discuss late in the article, many more treatments are in the pipeline, and quite far along.

AJKDBlogHow about combining these two agents together (GLP-1 agonists and GIP)?  And what about combining these agents with SGLT2-inhibitors as well, which have also been shown to cause mild weight loss?

Dr Zeitler: Combination therapy with GLP1 agonists and GIP agonists is very promising and actively being explored, with medicines like tirzepatide already approved for management of diabetes and demonstrating truly impressive weight loss results. Why this works better than GLP1 agonism alone remains the topic of significant debate.

The combination of incretin therapies with SGLT2 inhibitors is likely to become standard of care for patients with CKD and obesity, as it largely is for patients with diabetes at this point. Whether or not these new therapies demonstrate benefits for hard kidney outcomes, the important reductions in cardiovascular disease and proteinuria already suggest that they provide benefit for the most common patients we see in nephrology clinic, who tend to be at high risk of adverse cardiovascular outcomes. Hopefully, within 5 years a standard regimen for a patient with obesity or diabetes and CKD is going to be: ARB, SGLT2 inhibitor, mineralocorticoid receptor antagonist, GLP1 agonist (or other incretin therapy).

AJKDBlogWhat are the main adverse effects of these agents that nephrologists need to be aware of?

Dr Zeitler: The most commonly encountered adverse effects of these agents are GI symptoms, including nausea and changes in bowel habits. I hesitate to call decreased appetite an adverse effect of these medicines, but it certainly can be disturbing to some patients. When used in combination with insulin for patients with diabetes, providers should be aware to lower the insulin dose by 10-20%; while the incretin therapies don’t cause hypoglycemia on their own, they can potentiate the effects of insulin and oral hypoglycemic like sulfonylureas.

It is also important for nephrologists to understand that these medicines should be prescribed on the backbone of healthy diet and exercise. Exercise in particular is important for two reasons: 1) maintenance of weight loss and 2) maintenance of lean body mass during weight loss.

<img loading="lazy" decoding="async" aria-describedby="caption-attachment-41149" data-attachment-id="41149" data-permalink="https://ajkdblog.org/2023/12/13/obesity-primer-for-nephrologists-an-interview/zeitler-fig-2/" data-orig-file="https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-3.jpg" data-orig-size="2244,1982" data-comments-opened="1" data-image-meta="{"aperture":"0","credit":"","camera":"","caption":"","created_timestamp":"0","copyright":"","focal_length":"0","iso":"0","shutter_speed":"0","title":"","orientation":"0"}" data-image-title="Zeitler Fig 2" data-image-description data-image-caption="

Incretin production and end-organ effects. The incretin hormones, GIP and GLP-1, are produced in the enteroendocrine cells of the gastrointestinal tract in response to food ingestion. They act via both direct and indirect mechanisms to reduce appetite and food intake, and have a variety of end-organ effects leading to both weight loss and cardiometabolic benefits (blue boxes in figure). Created with BioRender.com. Figure 2 from Zeitler et al, AJKD.

” data-medium-file=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-10.jpg” data-large-file=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-11.jpg” class=”size-full wp-image-41149″ src=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-3.jpg” alt width=”2244″ height=”1982″ srcset=”https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-3.jpg 2244w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-10.jpg 300w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-11.jpg 1024w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-12.jpg 150w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-13.jpg 768w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-14.jpg 1536w, https://renal.platohealth.ai/wp-content/uploads/2024/01/obesity-primer-for-nephrologists-an-interview-15.jpg 2048w, https://ajkdblog.org/wp-content/uploads/2023/12/Zeitler-Fig-2-1200×1060.jpg 1200w” sizes=”(max-width: 2244px) 100vw, 2244px”>

Incretin production and end-organ effects. The incretin hormones, GIP and GLP-1, are produced in the enteroendocrine cells of the gastrointestinal tract in response to food ingestion. They act via both direct and indirect mechanisms to reduce appetite and food intake, and have a variety of end-organ effects leading to both weight loss and cardiometabolic benefits (blue boxes in figure). Created with BioRender.com. Figure 2 from Zeitler et al, AJKD.

AJKDBlogHave you encountered issues with insurance coverage for these agents, and what resources have you found to be useful in clinical practice?

Dr Zeitler: The insurance issues with these agents can be frustrating, but it is important to remember that liraglutide and semaglutide both have FDA approvals for weight loss in patients with obesity or overweight with complications, as discussed above. Tirzepatide is not yet approved for this without comorbid diabetes, but is on the fast-track to receive such designation. Insurance coverage is increasing because of the increasing acceptance of the importance of treating obesity for overall health. Other resources that can be helpful can be working with a clinical pharmacist, if available, or referring patients directly to the manufacturers’ websites, which often have reasonable medication assistance programs.

Dr Chang: I agree the insurance issues are very frustrating, especially for those without diabetes. If the patient has diabetes, it is much easier to get coverage for GLP1-RA for the diabetes indication. Sometimes insurance companies require the use of metformin before GLP1-RA and may require communication back to the insurance company that patients with eGFR <30 should not be on metformin.

AJKDBlogThis is really an exciting time for this field.  What lies ahead for the next decade of these agents, and what questions remain unanswered that ongoing studies are looking at?

Dr Zeitler: The currently approved medications represent only the beginning of medical obesity treatment. The combined GLP1/GIP agonists such as tirzepatide currently lead the pack of the next generation of therapies, but new treatments including triple agonists (with glucagon agonism) and amylin agonists combined with GLP1 agonism are extremely promising. Effective oral GLP1 agonists, such as high dose oral semaglutide and orforglipron will also make these treatments accessible to more people (this was summarized in a recent Kidney News Online article).  I think we are going to find that these medicines are effective at reducing additional obesity-related complications, as was found in the STEP-HFpEF Trial recently published in NEJM, and that is going to drive implementation and use of these medicines into broader populations.

To view Zeitler et alplease visit AJKD.org:
Title: Blockbuster Medications for Obesity: A Primer for Nephrologists
Authors: Evan M. Zeitler, Kulveer Dabb, Danial Nadeem, Christopher D. Still, and Alexander R. Chang
DOI: 10.1053/j.ajkd.2023.04.009


CALL FOR SUBMISSIONS:

We would like to invite blog post submissions related to next year’s World Kidney Day (WKD) campaign theme: “Kidney Health for All: Advancing equitable access to care and optimal medication practice”. Submissions should be between 800-1,200 words and sent to AJKD@pennmedicine.upenn.edu by February 14th, 2024.