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Continuous Glucose Monitoring: A Rapidly Evolving New Tool to Understand Pathophysiology and Enhance Clinical Care in CKD

2023; Lippincott Williams & Wilkins; Linguagem: Inglês

10.2215/cjn.0000000000000125

1555-905X

Ian H. de Boer, Irl B. Hirsch,

Hyperglycemia and glycemic control in critically ill and hospitalized patients

Glycemia management is a perilous task for people with CKD, especially those with kidney failure. For patients with diabetes, individualization of glycemic control is a fundamental component of care.1 Long-term benefits of intensive glycemic therapy to reduce the risks of retinopathy, neuropathy, cardiovascular diseases, and progression of kidney disease (if still relevant) must be balanced against short-term risks of hypoglycemia and financial costs. However, rigorous trial data quantifying these benefits and risks for people with established CKD are scant, and several substantial barriers currently limit intensive therapy.1,2 First, severe hypoglycemia, a condition with high morbidity and mortality, is known to occur substantially more frequently with lower eGFR and to occur in the absence of diabetes among people with kidney failure (for reasons that remain incompletely understood). Second, hemoglobin A1c, a basic tool for guiding glucose-lowering therapies, loses precision at low eGFR and becomes inaccurate in kidney failure because of abnormalities in red blood cell turnover. Third, some medications that safely and effectively lower blood glucose are contraindicated at low eGFR (such as metformin). As a result, for patients with diabetes and kidney failure, managing glycemia could be compared with driving a curvy mountain road at night, without a map or headlights, in an old Mack truck. Continuous glucose monitoring (CGM) is a rapidly evolving new technology that has revolutionized the treatment of diabetes, particularly for patients treated with insulin.2 CGM offers a new tool to quantify glycemia with unprecedented granularity, closely titrate therapy, and understand previously poorly characterized pathophysiology. Subcutaneous CGM sensors measure interstitial glucose concentrations that correlate well with blood glucose, with a fidelity that has progressively improved with each successive version. "Factory-calibrated" models allow patients to avoid finger sticks for self-monitored blood glucose measurements. Collection of data that is recorded but not immediately accessible to the CGM wearer (blinded mode, also called "professional CGM") is particularly useful for research and allows quantification of an internationally standardized set of glycemic metrics and an ambulatory glucose profile.3 Real-time visualization of CGM data additionally allows patients to actively titrate their activities, food intake, and medication use to optimize glycemia. Rigorous clinical trials have demonstrated that real-time CGM can improve glycemic control without increasing risk of hypoglycemia for patients with type 1 and 2 diabetes using multiple daily insulin injections.4,5 Combining real-time CGM with an insulin pump in a hybrid closed-loop system further improves glycemic control, and this has become a preferred treatment of type 1 diabetes. CGM may be particularly useful for patients with CKD, given the challenges of glycemia management in this population. Theoretical concerns about interfering substances and expanded extracellular fluid appear not to compromise modern CGM function. Among hemodialysis patients, the DexCom G6 was recently reported to have excellent performance compared with venous blood and capillary blood glucose.6 However, published studies using CGM to understand glycemic patterns and to assess the effect of CGM on clinical care in CKD have so far been limited to case series, small cohort studies, and pilot trials of relatively few participants. In this issue of CJASN, Ushiogi et al. present what may be the largest study of CGM among people with CKD to date.7 A total of 366 participants recruited from nephrology and endocrinology departments in a single center in Japan, including 131 with kidney failure treated with hemodialysis (with and without diabetes); 132 with eGFR <60 ml/min per 1.73 m2 (with and without diabetes); and 103 control participants with diabetes, eGFR ≥60 ml/min per 1.73 m2, and normal urine albumin excretion, were included. Each participant wore the Abbot Freestyle Libre for 10 days in blinded mode. The proportion of participants with at least one observed glucose <70 mg/dl (or <54 mg/dl) in 7 days was significantly higher with lower kidney function (with or without diabetes), as was a metric that combines the amount of time with glucose <70 mg/dl and its severity (area above the curve). Only two participants reported symptoms of hypoglycemia, suggesting that these episodes of biochemical hypoglycemia were largely subclinical. This study provides new data suggesting that the incidence of hypoglycemia, defined biochemically, increases with lower kidney function. These results parallel population-based studies that have reported higher incidence rates of severe hypoglycemia with lower eGFR, particularly among patients treated with dialysis.8,9 Like the population-based studies, the new study highlights the occurrence of hypoglycemia among dialysis patients without diabetes. In fact, among participants treated with dialysis, the proportion with any biochemical hypoglycemia was just as high for those without diabetes as for those with diabetes,7 which has not been observed for severe hypoglycemia in population-based studies.8,9 Overall, these data provide a compelling case to expedite evaluation of the application of CGM to patients with CKD to understand underlying pathophysiology and identify opportunities to improve care. The precise estimates of prevalence, time, and severity of hypoglycemia reported in the new study should be viewed with some skepticism. First, the study used an early CGM system (Abbott FreeStyle Libre Pro) that lacks the precision of more recent models, especially in the lower range of blood glucose (a common limitation for CGM devices that is improving over time). CGM precision is routinely measured as the mean absolute relative difference (MARD) comparing CGM with capillary or plasma blood glucose, with a modern-day target of <10%. While one study of the Abbott FreeStyle Libre Pro reported a MARD of 13%,10 another reported a MARD of 18%, with a MARD of 36% for glucose values <70 mg/dl.11 Second, only a single CGM reading <70 mg/dl (or <54 mg/dl) during 7 days was used to define the presence of hypoglycemia. Together, these limitations likely led to an overestimation of the proportions of people with hypoglycemia, although trends across kidney function are likely correct. There is much more to learn using CGM about glycemia and its management in CKD. A key first step is fully understanding the glycemic topography in this population, including unique subsets of patients such as those treated with hemodialysis or peritoneal dialysis, with or without diabetes. In addition to hypoglycemia, understanding the extent of uncontrolled hyperglycemia is also important because this may be substantially underestimated by hemoglobin A1c among patients with kidney failure and may still relate to short- and long-term complications (even if kidney protection is no longer a goal). Such studies would ideally use the most modern, accurate, and precise CGM sensors; quantify glycemia using the full range of established international standards3; explore unique glycemic patterns and their relationships to potentially modifiable clinical characteristics (including nutrition, diabetes medications, and dialysis procedures); and relate glycemia findings to relevant clinical outcomes. Large observational studies may also be useful to help establish which patients with CKD could derive clinically useful information from CGM, used either in blinded mode (to assess risks of hyperglycemia and hypoglycemia or establish an unbiased measure of average glycemic control) or in real time (to guide application of therapy). Moreover, trials are needed to test the effect of CGM on clinical care in CKD, potentially including a trial comparing the effect of different CGM targets on clinical outcomes. Notably, CGM metrics, such as glucose time in range, are now established and have been used as end points in clinical trials with acceptance by regulatory agencies,3 also facilitating the evaluation of new therapies to manage glycemia in CKD. Clinically, we recommend that patients with diabetes and CKD who have established indications strongly consider using CGM. In the United States, Medicare and many state Medicaids currently provide reimbursement for CGM for patients with type 1 or 2 diabetes who use three or more daily insulin injections or an insulin pump. Given limitations to accuracy in the hypoglycemic range, finger-stick glucose testing should be considered to verify hypoglycemia noted with CGM. We recommend that nephrologists advocate for patients to use CGM when indicated and partner with endocrinologists who are knowledgeable about the latest technologies and trained in the interpretation and application of CGM data. Technology and data are evolving rapidly in this field. Hopefully high-quality studies of this exciting technology will lead to a better understanding of glycemia in CKD, new opportunities to shine light on the curvy road of glycemic management, and ultimately a map that guides patients and clinicians to improved clinical outcomes.