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Associate Professor of Medicine
Nephrologist and Hypertension Specialist
Division of Nephrology
Department of Medicine
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, California
Susanne B. Nicholas, MD, MPH, PhD, has disclosed that she has received funds for research support from Bayer, Goldfinch Bio, and Travere; consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, and Janssen; and fees for non-CME/CE services from AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, and Janssen.
Should we be concerned about calcium levels in patients taking sodium glucose cotransporter 2 (SGLT2) inhibitors? Is there a threshold for albumin reabsorption before tubular damage occurs? In this commentary, I answer these and other questions from learners who participated in the webinar, “Chronic Kidney Disease in Type 2 Diabetes: Contemporary Approaches to Renoprotection.”
SGLT2 increases reabsorption of phosphate with activation of the parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) with reduction of the level of vitamin D. How does this drug affect calcium metabolism?
That is a great question, but we do not have data examining that specifically. The question was addressed in part when canagliflozin first came out and there were reports of increased fractures. There was some data from small studies showing increased phosphate and calcium loss. However, subsequent studies have not demonstrated that fracture problem. Now, whether the fractures were due to calcium loss or due to people just falling with postural hypotension is unclear. It likely happened too soon for it to be a calcium‑related problem. You have to lose calcium for many years to have fractures. At the time of canagliflozin’s approval, the FDA concluded that this was not a significant issue. Also, post-hoc analysis of dapagliflozin vs placebo showed no correlation between changes in phosphate homeostasis markers and changes in eGFR or albumin excretion with no changes in calcium or vitamin D levels in early chronic kidney disease (CKD) patients.
In my patients, I have not seen specific issues around calcium, and we do check PTH with calcium, particularly ionized calcium, fairly frequently. I think it is an area that should be investigated further, because it becomes important in more advanced CKD stages, where we are concerned about vitamin D metabolism and PTH level.
When it comes to direct tubular damage, is there a threshold for reabsorption before damage occurs? What is that threshold level for albumin?
No, there is not. As part of the pathology, we know that when there is excess filtration of albumin and other proteins, it surpasses the resorptive threshold of the proteins within the proximal tubules. In terms of clinical threshold, I consider anything over 1000 mg/24h of albumin excretion too high; that will be very toxic to the kidney tubules. We know that if we look at UACR, the target is to get below 300 to 500 mg/24h as much as possible and that minimizes the damage.
This is another reason to be measuring albuminuria, because if you have the patient on an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) and the blood pressure is well controlled but albuminuria is increasing, that is an indicator of damage. The patient needs more aggressive therapy, including an SGLT2 inhibitor, finerenone, etc. Also, too many patients are on low doses of ACE inhibitors and ARBs. If they are tolerating them at low doses, they are not likely to get side effects at trial doses, and you could decrease their risk substantially. In the phase III CREDENCE trial, we saw that it is possible to extend kidney life by 15 years when using appropriate combination therapy (canagliflozin plus maximally tolerated ACE inhibitor or ARB). Why would we not use these medications in our patients?
To conclude, we are in a wonderful, exciting time for nephrologists with effective treatment options for our patients. I think a lot of primary care providers are hesitant to manage patients with kidney disease because they think we can only offer dialysis. But that is the past, and we have entered a new stage of management now.
What questions do you have on managing patients with chronic kidney disease and type 2 diabetes? Answer the polling question and post your comments in the discussion section.