Introduction
Weight control is an important issue for patients with diabetic nephropathy, especially for those who are obese. In a secondary analysis of a multicenter randomized clinical trial, the effects of intensive lifestyle modification suggested that weight loss could delay the onset of chronic kidney disease (CKD) in obese diabetic patients [
1]. Several small studies have also reported that weight reduction can improve proteinuria, glomerular filtration, and hypertension [
2,
3]. In addition, sodium-glucose co-transporter-2 (SGLT2) inhibitors are particularly helpful in obese diabetic patients. SGLT2 is present in the proximal tubules of nephrons and primarily functions to re-absorb glucose; accordingly, inhibition of SGLT2 causes urinary glucose excretion and natriuresis and results in serum glucose control, weight reduction, and diuresis [
4].
The effectiveness of SGLT2 inhibitors in patients with stage 3 or higher CKD has not been demonstrated. Although SGLT2 inhibitors can induce a renoprotective effect in CKD patients with improvement of proteinuria, they have a reduced glucosuric effect and pose a renal risk through aggravation of the glomerular filtration rate (GFR) [
5–
7]. The GFR aggravation can be explained by glucosuria and natriuresis, leading to blood volume depletion through osmotic diuresis. Furthermore, proximal tubular natriuresis induces tubuloglomerular feedback, resulting in reduced intraglomerular pressure [
6,
7]. Based on this mechanism, we aimed to offset the impact of tubuloglomerular feedback by providing adequate hydration. Hydration might increase renal blood flow and maintain both GFR and the glucosuric effect. We suggest that SGLT2 inhibitors can be used safely in adequately hydrated CKD patients. In the following cases, the use of SLGT2 inhibitors was necessary because either the maximum dose of other hypoglycemic agents resulted in no improvement, the patients were too resistant to insulin, or management of volume overload failed because diuretics were contraindicated for fear that they would aggravate azotemia. We report five cases in which the SLGT2 inhibitor dapagliflozin induced significant weight reduction and edema control in patients with advanced CKD.
Discussion
Although these five patients had type 2 diabetes with moderate to severe renal impairment, they all showed a dramatic improvement in renal function, weight reduction, and glucose control.
According to Dr. Bernstein’s Diabetes Solution endocrinology textbook [
8], body fluid and serum glucose levels are closely related. High glucose levels can promote dehydration through glucosuria, and dehydration leads to contraction of peripheral blood vessels resulting in insulin resistance and markedly low glucose utilization. As a result of this vicious cycle, hyperglycemia and volume depletion are inseparable. If natriuresis and glucosuria are maintained by use of a SGLT2 inhibitor, the patient will develop insulin resistance from volume depletion, in addition to worsened GFR.
In previous studies, SGLT2 inhibitors were shown to be less effective at glycemic control and unsafe to continue when the GFR indicates advanced CKD compared with normal or mildly impaired renal function [
5–
7]. In almost all of the previous studies evaluating SGLT2 inhibitors, the researchers did not address the volume status of individual patients and did not consider the role of adequate hydration. Without volume status assessment and supplementation it might be impossible to achieve positive clinical results from SGLT2 inhibitor therapy in CKD patients. These experiences highlight the importance of knowing how to use a medication properly.
The renal proximal tubule contains two glucose reabsorption transporters: sodium-glucose co-transporter-1 (SGLT1) and SGLT2. More than 90% of the filtered glucose is reabsorbed by SGLT2 in a 1:1 ratio with sodium [
4]. When SGLT2 is inhibited, SGLT1 is upregulated and functions to decrease glucosuria in a euglycemic state [
9]. Correspondingly, serum glucose levels greater than the normal range would be required to maximize the glucosuric effect over the treatment period. We proposed that hydration matched to individual needs and decreased doses of oral hypoglycemic agents or insulin would help maintain excretion of large amounts of urine glucose. Although the use of isotonic or hypertonic fluids for hydration would be more effective for increasing renal blood flow, older patients do not tolerate this salt loading and must consume sufficient salt from their diet. Accordingly, we administered half-normal saline for intravenous hydration.
There is another benefit of SGLT2 inhibitors. Many patients complain of weight gain after the initiation of insulin. According to Henry et al [
10], who investigated this issue in 1993 through statistics, insulin causes a dose-related weight gain. SGLT2 inhibitors can overcome the problem of weight gain by increasing excretion of glucose and reducing the required insulin dose. As a result, the patients might experience further weight loss compared with the average reduction of 2 kg with SGLT2 inhibitors alone [
11]. A dramatic weight reduction can improve a patient’s quality of life, in addition to achieving glucose control. Also, a recent study reported that even a short-term intensive weight reduction intervention resulted in improvements of GFR, glucose control, and physical activity [
2].
Our cases were all negative or 1+ for urine glucose before using dapagliflozin. After administering dapagliflozin urine glucose increased to 3+, and with adequate hydration the daily urine output was greater than 2 L. In our experience, urine glucose positivity can be a useful predictor of the effect of dapagliflozin therapy. Certain patients who initially had 3+ glucosuria experienced difficulty with hyperglycemic episodes and thirst after using dapaliglifozin. We suggest that chronic glucosuria can induce non-symptomatic volume depletion and insulin resistance, and a SGLT2 inhibitor would not be tolerated in this situation. Glucose positivity indicated by urine analysis can be easily overlooked, but might be helpful in predicting the efficacy and effect of SGLT2 inhibitors.
Improvement of proteinuria was observed in only cases 4 and 5 among our described patients, and these patients were given dapagliflozin over a relatively long treatment period. If hydration decreases tubuloglumerular feedback, improvement of proteinuria is influenced by weight reduction rather than a reduction of intraglomerular pressure. These two patients also experienced a decrease in serum uric acid with the expanded uricosuric effect of dapagliflozin. However, the patients did not undergo 24-hour urine test or measurement of urinary uric acid level.
Lastly, there are concerns regarding genitourinary tract infection, but our patients did not have complications from infection. However, in case 3 the patient had voiding difficulty due to benign prostate hypertrophy and a Foley catheter was inserted only during hospitalization. We made every effort to avoid urinary tract obstruction in order to make the patients comfortable with the increased urine output.
All of the patients were able to either reduce or stop other oral hypoglycemic agents or insulin. Overall, our cases showed improved physical activity and arthralgia and back pain improved after the dramatic weight loss. We suggest that these changes are class effects of SGLT2 inhibitors, rather than specific to dapagliflozin.
SGLT2 inhibitors can be multipotent drugs that offer increased benefit when they are managed appropriately. For nephrologists who are skilled and experienced in volume control, these agents can safely provide various beneficial stable effects in patients with CKD. However, these benefits may not be applicable to all patients, especially in the context of CKD. Further research of volume states with close monitoring of CKD patients is required.