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 Table of Contents  
ORIGINAL ARTICLES
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 301-304

A prospective study to evaluate the effects of sodium-glucose cotransporter 2 inhibitors in type 2 diabetic patients with chronic kidney disease


Institute of Renal Sciences, Global Hospital, Mumbai, Maharashtra, India

Date of Submission16-Jun-2022
Date of Decision26-Jul-2022
Date of Acceptance27-Jul-2022
Date of Web Publication26-Sep-2022

Correspondence Address:
Dr. Bharat V Shah
Institute of Renal Sciences, Global Hospital, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_66_22

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  Abstract 

Introduction: Recent studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective at slowing the progression of kidney disease and lowering the risk of kidney failure in people with kidney disease and type 2 diabetes. There is no such study from India. The present study was performed to evaluate the effects of SGLT2i in Indian patients with diabetes and chronic kidney disease (CKD). Materials and Methods: This prospective study included 86 patients with diabetes and chronic kidney disease and with an estimated creatinine clearance of >30 mL/minute. Forty-one patients received SGLT2i and 45 patients did not receive SGLT2i. Patients were followed up for at least 12 months. Body mass index (BMI), blood pressure, HbA1c, urine protein to creatinine ratio (UPCR), doubling of serum creatinine and rate of decline of the estimated creatinine clearance were compared between the two groups. Results: The two groups were comparable at baseline in terms of age, sex, blood pressure, BMI, HbA1c, and degree of renal impairment. Over 12 months the UPCR decreased by 0.03 in SGLT2i group and increased by 1.1 in non SGLT2i group (P < 0.05). Doubling of serum creatinine occurred in 4.8% of patients in the SGLT2i group as compared to 18% in the control group (P < 0.05). The rate of decline of the estimated creatinine clearance in the SGLT2i group was 4.9 ml/min/year as compared to 9.4 ml/min/year in the non SGLT2i group (P < 0.05). At 12 months the BMI in the SGLT2i group decreased by 1.49 as compared to 0.12 in the non SGLT2i group (P < 0.05). The blood pressure and HbA1c control were similar in both groups during the study period suggesting that the observed effect was due to SGLT2 inhibition itself and not due to blood pressure or blood glucose control. Conclusion: Our study showed that treatment with SGLT2i had significant renoprotective effects, as shown by a reduction in urinary protein excretion, less percentage of patients developing doubling of serum creatinine, and a slower rate of decline in creatinine clearance.

Keywords: Chronic kidney disease, diabetes mellitus, SGLT2i


How to cite this article:
Saldanha N, Shah M, Dalal MS, Virani ZA, Parekh I, Vora H, Rajput P, Tapiawala S, Shah BV. A prospective study to evaluate the effects of sodium-glucose cotransporter 2 inhibitors in type 2 diabetic patients with chronic kidney disease. J Diabetol 2022;13:301-4

How to cite this URL:
Saldanha N, Shah M, Dalal MS, Virani ZA, Parekh I, Vora H, Rajput P, Tapiawala S, Shah BV. A prospective study to evaluate the effects of sodium-glucose cotransporter 2 inhibitors in type 2 diabetic patients with chronic kidney disease. J Diabetol [serial online] 2022 [cited 2022 Nov 30];13:301-4. Available from: https://www.journalofdiabetology.org/text.asp?2022/13/3/301/357135




  Introduction Top


Diabetes (DM) is a worldwide public health problem with high risk of microvascular and macrovascular complications. Kidney disease is a major microvascular complication of diabetes with ~30% of patients developing this complication.[1] Further, DM and CKD are both associated with increased morbidity and mortality. Therefore, multiple interventional approaches are recommended to reduce the progression of albuminuria and kidney dysfunction. Such approaches include blood pressure control, the use of renin-angiotensin inhibiting agents as well as maintaining strict glycaemic control. Since the introduction of angiotensin converting enzyme inhibitors and angiotensin receptor blockers which were proven to slow the progression of diabetic kidney disease[2],[3] there has been no further progress in treatment. Emerging interest in the role of the kidney in glucose homeostasis led to the development of sodium-glucose cotransporter 2 inhibitors. Initially, SGLT2i were developed to lower plasma glucose in type 2 diabetes mellitus (T2DM) patients, but large randomized controlled trials have demonstrated renal protection in diabetic patients with chronic kidney disease.[4],[5]

There is no Indian data on the effects of SGLT2i in diabetics with CKD. This study was undertaken to assess the effects of SGLT2 inhibitors in Indian diabetic patients with chronic kidney disease


  Materials and Methods Top


Study design

The present study was an observational prospective study carried out between July 2018 and April 2020 in the Nephrology Department. The protocol of the study was approved by the Institutional Scientific and Ethics Committee. Inclusion criteria were adult patients with diabetes mellitus and CKD and an estimated creatinine clearance of ≥ 30 mL/minute /1.73 meter[2]

The study included 102 patients with type 2 diabetes mellitus and CKD. Fifty patients (study group) received SGLT2i in addition to standard care while 50 patients (control group) continued standard care.

The parameters monitored in the study were: body mass index, blood pressure, HbA1c, urine protein to creatinine ratio, doubling of serum creatinine, and rate of decline of the estimated creatinine clearance. All patients were followed periodically at intervals depending on their clinical condition. Both groups of patients received standard care such as dietary modification (for diabetes, high blood pressure and CKD), antidiabetic agents and blood pressure control including the use of ACEI/ARB.

HbA1c, serum creatinine, and Urine protein to creatinine ratio (UPCR) were measured using commercially available assay kits. Estimated creatinine clearance was calculated from the Cockcroft-Gault equation.

Statistical analysis

Statistical analysis was done using SPSS software version 22. Qualitative data were expressed using frequency and percentage. Quantitative data were expressed by using mean, median, and standard deviation. Chi-square test / Fisher’s exact test was used to compare the qualitative data variables in 2 independent groups. The independent-sample t test was used to compare the quantitative data variables in 2 independent groups. P-value <0.05 was considered as significant.


  Results Top


Of the 52 patients in the SGLT2i group, 6 cases were lost to follow-up. In 4 cases the drug was stopped due to urinary tract infection and in one patient drug was stopped due to volume depletion. Of the 50 patients in the non SGLT2i group, 5 were lost to follow-up. Thus, we had 41 patients in the study group and 45 patients in the control group for analysis.

There was no significant difference in various parameters in the two groups at baseline [Table 1].
Table 1: Baseline characteristics of patients in the study group and control group

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[Table 1] shows baseline characteristics of patients in 2 groups. There was no significant difference in various parameters between the two groups.

Effect on glycaemic control, blood pressure, and BMI

At 12 months the BMI in the SGLT2i group decreased by 1.49 as compared to 0.12 in the non SGLT2i group (P < 0.05). The BP and HbA1c control were similar in both groups [Table 2].
Table 2: BMI, Blood pressure, and HbA1c in the study group and control group

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Effect on renal parameters

The mean urine protein to creatinine ratio (UPCR) did not differ between the two groups (1.36 vs 1.68) at baseline. During the period of study, there was a significant increase in proteinuria in the control group (P < 0.05) as compared to the study group [Figure 1].
Figure 1: Mean urine protein to creatinine ratio (UPCR) in study group and control group

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Doubling of serum creatinine was observed in 4.8% of patients in the SGLT2i group as compared to 18% in the control group (P < 0.05).

The rate of decline in the eCrCl was 4.9 ml/min/year in the study group while it was 9.4 ml/min/ year in the control group (P < 0.05) [Figure 2].
Figure 2: Mean creatinine clearance in the study group and control group

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  Discussion Top


Many glucose-lowering medications are now available. Until recently, no class of glucose-lowering agent was considered as preferred treatment. Rather, the recommendation was to achieve a glycaemic target determined by HbA1c level.

When SGLT2i became available, they were mainly considered an addition to the existing antidiabetic agents working by a different mechanism (inhibiting reabsorption of glucose in proximal tubules promoting urinary glucose excretion). They were introduced mainly for better blood glucose control.

In recent studies, SGLT2i were found to not only reduce blood glucose but also protect the kidney.[4],[5] There are no Indian studies to date which have looked at the efficacy and safety of SGLT2i in diabetic patients with CKD.

This study looked at three major variables: the behaviour of proteinuria, percentage of patients with a doubling of creatinine and rate of decline in the renal function (estimated creatinine clearance). Both groups were receiving standard care such as dietary modifications for blood glucose and blood pressure control, anti-diabetic drugs and antihypertensive drugs including use of ACEI/ARB.

The degree of proteinuria is widely recognized as a marker of future decline in the glomerular filtration rate.[6] Patients in our study did have significant proteinuria. At baseline urine protein to creatinine ratio (UPCR) did not significantly differ between the two groups (1.36 in study group vs 1.68 in the control group). However, there was a stabilization of proteinuria in the SGLT2i group. At 12 months the UPCR in the SGLT2i group declined by an absolute value of 0.03 as compared to an increase in the control group by 1.1. The findings in our study are similar to findings in the other studies.[4],[7],[8]

Doubling of the serum creatinine was considered to be an important outcome in trials assessing the renoprotective efficacy of SGLT2 inhibitors. In our study, 4.8% of patients in the SGLT2i group had a doubling of their creatinine value as compared to 18% in the group on regular diabetes care. In the CREDENCE trial doubling of serum creatinine was observed in 5.35% in the SGLT2i group vs 8.53% in the non SGLT2i group.[4]

The group of patients receiving SGLT2 inhibitors had a significantly slower rate of eCrCl decline versus the group on regular diabetes care. The rate of decline in the eCrCl observed in the group receiving the SGLT2i was 4.9 ml/min/year versus a decline of 9.4 ml/min/ year in the control group. The findings of our study are similar to those of other studies assessing the renoprotective benefits of SGLT2i.[4],[5],[9]

There are several mechanisms by which SGLT2 inhibitors have renoprotective effect:

  1. SGLT2i block the reabsorption of sodium and glucose in the proximal tubules, regulate renal tubule-glomerular feedback and reduce glomerular capillary pressure.[10]


  2. SGLT2i inhibit the active reabsorption of sodium in proximal tubules, thus reducing renal energy consumption and protecting the kidney.[11]


  3. SGLT2i reduce renal inflammatory reactions.[11]


Could the reduction in proteinuria and slower decline in renal function observed in our patients be due to RAS blockade as has been described in studies of diabetic patients with CKD?.[12],[13] This is unlikely as 72% of patients in the SGLT2i group and 70% of patients in the control group were already on maximum tolerated ACEi/ARB therapy. Thus, similar to the DAPA CKD trial[5]the observed benefits in our study were obtained on a background of renin-angiotensin system blockade.

There was a significant reduction in weight loss and BMI in the SGLT2i group at 12 months as compared to the control group. This weight loss is likely to be due to glucose loss (calorie loss) in the urine.[14] Other probable mechanisms of weight loss include decreased serum insulin levels, promotion of lipid degradation and the increased oxidative metabolism of fat.[15] Weight loss could be one of the indirect mechanisms by which the use of SGLT2i could have offered renoprotection.

Could the observed renoprotective effects of SGLT2i be due to better glycaemic control or blood pressure reduction? This is unlikely as the BP and HbA1c control were similar in both groups.

The current study has limitations. First, this was a single-centre study. Second, this is an observational study and not randomised controlled study. Fortunately, characteristics of patients in both groups were similar. Third, the sample size is small, and duration of observation is short. However, there was clear difference in parameters monitored in the 2 groups at all time points.

In summary, the use of SGLT2i in our diabetic patients with CKD was associated with a reduction in weight, stabilization of proteinuria, and reduction in rate of decline in eCrCl. The fact that this happened despite similar blood glucose and blood pressure control suggests a beneficial effect of SGLT2i by intrarenal mechanisms.


  Conclusion Top


This is the first Indian study to show that the use of SGLT2i is associated with renoprotective benefits in diabetic patients with chronic kidney disease. Considering this and the fact that the cost of these drugs has considerably come down, SGLT2i should become the first line therapy for patients with diabetes and chronic kidney disease.

Acknowledgment

We thank all the patients who participated in this study.

Ethical approval

The study was approved by the Institutional Scientific and Ethics Committee.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016;39 Suppl 2:S165-71.  Back to cited text no. 1
    
2.
Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: A blood pressure-independent effect. Circulation 2002;106:672-8.  Back to cited text no. 2
    
3.
Persson F, Rossing P, Hovind P, Stehouwer CD, Schalkwijk C, Tarnow L, et al. Irbesartan treatment reduces biomarkers of inflammatory activity in patients with type 2 diabetes and microalbuminuria: An IRMA 2 substudy. Diabetes 2006;55:3550-5.  Back to cited text no. 3
    
4.
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.  Back to cited text no. 4
    
5.
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.  Back to cited text no. 5
    
6.
Cravedi P, Remuzzi G Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol 2013;76:516-23.  Back to cited text no. 6
    
7.
Takashima H, Yoshida Y, Nagura C, Furukawa T, Tei R, Maruyama T, et al. Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial. Diab Vasc Dis Res 2018;15:469-72.  Back to cited text no. 7
    
8.
Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: Cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752-72.  Back to cited text no. 8
    
9.
Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50.  Back to cited text no. 9
    
10.
Novikov A, Vallon V Sodium glucose cotransporter 2 inhibition in the diabetic kidney: An update. Curr Opin Nephrol Hypertens 2016;25:50-8.  Back to cited text no. 10
    
11.
Ni L, Yuan C, Chen G, Zhang C, Wu X SGLT2I: Beyond the glucose-lowering effect. Cardiovasc Diabetol 2020;19:98.  Back to cited text no. 11
    
12.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.  Back to cited text no. 12
    
13.
Investigators HOPES. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. The Lancet 2000;355:253-9.  Back to cited text no. 13
    
14.
Pereira MJ, Eriksson JW Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs 2019;79:219-30.  Back to cited text no. 14
    
15.
Ito M, Tanaka T The anticipated renoprotective effects of sodium-glucose cotransporter 2 inhibitors. Intern Med 2018;57:2105-14.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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