SGLT 2 inhibitors in kidney disease

R. Balasubramaniyam*, Balaji Kirushnan

Department of Nephrology, Kauvery Hospital, Chennai

*Correspondence: rbskidneydr@gmail.com

Introduction

It is interesting to note that kidneys play an important role in contributing to blood glucose pool. In the fasting and in post absorptive state kidneys add 10–50 g of glucose (20–25% of the glucose released into the circulation). In the post prandial state (4 to 5 h after meal) kidneys are responsible for 60% of the endogenous glucose release (70 g). This quantum increases in diabetes by 30 %.

With 125 ml GFR per min, the kidneys filter about 180 g of glucose and of this only 500 mg is excreted. This means that almost 99% of the filtered glucose is reabsorbed. This happens due to the presence of sodium glucose transporters (SGLT). There are two important transporters – SGLT1 that is predominantly located in the intestines that are responsible for glucose absorption and also in the S3 segment of the proximal tubule that reabsorbs 10% of the filtered glucose. SGLT2 is located in the S1 and S2 segments of the proximal tubule that reabsorbs 90% of the filtered glucose. The glucose, once it enters the proximal tubular cells, exits by the GLUT transporters that are located on the basolateral membrane [1].

Fig. 1 Glucose transport across the proximal tubular cells

This makes inhibition of SGLT2 an important target for controlling blood glucose levels (Fig.1).

Search of A New Renoprotective Drug

It has been a continuous search towards finding out new drugs that help in retarding the progression of CKD. The introduction of ACE inhibitors and ARB was a big boon, but beyond this no therapeutic strategies succeeded, until SGLT2 inhibitors were used. By blocking the glucose reabsorption in the proximal tubule, these drugs

  1. Cause osmotic diuresis thereby helps in removal of excess water (beneficial in patients with concomitant heart failure).
  2. Increase in distal sodium delivery.
  3. They cause afferent arteriolar vasoconstriction, thereby decreasing proteinuria.
  4. Though there is initial decline in GFR, this stabilizes over a period of time and in the long run the GFR is better maintained.
  5. It increases erythropoietin secretion by causing afferent arteriolar constriction and producing glomerular ischemia.
  6. Blood pressure is better controlled, as it causes sodium loss.
  7. These agents do not cause hypoglycemia, as they do not interfere with insulin release. It has made inroads into being used in non-diabetic individuals also.
  8. Since glucose is excreted, the body has to mobilize the endogenous sources of energy that leads to weight loss.
  9. It is also supposed to decrease arterial stiffness and inflammation.

Some of the adverse effects due to these drugs are – increase in genital and urinary tract infections due to excessive urinary glucose, volume depletion, euglycemic ketoacidosis.

EMPA – REG trial

Compared empagliflozin10 and 25 mg with placebo. Patients with DM and eGFR > 30ml m-1 were included. The primary outcomes were – death from CVD, non-fatal MI and non- fatal stroke. Empagliflozin proved to be superior to placebo [2] (Fig. 2).

Fig 2. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.

The secondary endpoints of this study also looked into the renal outcomes. The conclusions are

  1. Incident or worsening nephropathy for empagliflozin vs placebo: 12.7% vs 18.8%, HR 0.61, 95% CI 0.53–0.70; p < 0.001.
  2. Doubling of serum creatinine: 1.5% vs 2.6%, p < 0.001.
  3. Progression to macroalbuminuria: 11.2% vs 16.2%, p < 0.001.
  4. Initiation of renal replacement therapy: 0.3% vs 0.6%, p = 0.04.

This is one of the initial studies that proved that empagliflozin is beneficial in patients with heart and kidney diseases. Also, the beneficial effects of empagliflozin are seen regardless of the usage of ACEI/ARB, CCB, diuretics and NSAIDs.

CANVAS/CANVAS-R trial (canagliflozin and cardiovascular and renal events in type II diabetes).

This trial involved integration of two programs that used canagliflozin with placebo in patients with diabetes and with increased cardiovascular risk. Apart from the cardio vascular benefits, renal benefits in the form of reduction in proteinuria, the sustained reduction in GFR, the need for renal replacement therapy or death from renal causes occurred less frequently in Canagliflozin group, compared to placebo (Fig. 3).

Fig. 3. Canagliflozin and cardiovascular and renal events in type 2 diabetes.

EMPA-REG trial: here too it is proven that canagliflozin is superior to placebo, not in cardio vascular protection, but also in renal protection [3].

Credence trial: Patients with type II DM, with eGFR 30–90 and with proteinuria more than 300–5000 mg per day, who were already on maximum dose of ARB/ACEI were randomized to receive canagliflozin vs placebo, primary endpoints were ESRD, doubling of serum creatinine, death from renal or cardio vascular causes. Like other trials, credence also proved the beneficial effects of canagliflozin.

The reduction in risk of primary endpoints reduced by 30%, canagliflozin also reduced the rate of decline of GFR by 2.7 ml per min per year. These effects are seen across different ranges of GFR.

The importance of this trial, is that the beneficial effects are seen beyond the maximum dose of ACEI/ARB. This is a clear proof of benefit of canagliflozin in patients with diabetic kidney disease. Also, the patients chosen here are with macroproteinuria including nephrotic range proteinuria [4] (Fig. 4).

Fig. 4. Credence trial – outcomes

DAPA – CKD trial: Dapagliflozin and prevention of adverse outcomes in chronic kidney disease.

This is the first trial to use Gliflozins in non-diabetic individuals, as these drugs don’t cause hypoglycemia. Also patients with lower GFR (25–70 ml per min) were included with macroproteinuria (200–5000 mg). it is a multicentric trial and patients were randomized to receive dapagliflozin 10 mg to placebo. 67.5% were diabetic and 32.5% were non-diabetics.



Fig 5. DAPA – CKD trial outcomes.

Table 1. Primary and secondary outcomes and adverse events of speed interest.

During a median follow-up of 2.4 years, there were 197 primary endpoint events with dapagliflozin and 312 with placebo. The hazard ratio (HR) for the primary endpoint was 0.61 (95% confidence interval [CI] 0.51–0.72; p = 0.000000028). The benefit of dapagliflozin on the primary endpoint was consistent in patients with and without type 2 diabetes [5] (Fig.5, Table 1).

Dapagliflozin reduced all three secondary endpoints compared to placebo. The HRs were

  1. Worsening renal function or death from kidney failure 0.56 (95% CI 0.45–0.68; p < 0.0001).
  2. Hospitalisation for heart failure or cardiovascular death 0.71 (95% CI 0.55–0.92; p = 0.0089).
  3. All-cause mortality 0.69 (95% CI 0.53–0.88; p = 0.0035).

Recently there had been a systematic review and network meta-analysis of randomized controlled trials on SGLT2 inhibitors and GLP1 (glucagon like peptide 1) in patients with diabetes with variable renal and cardio vascular risks. Total of 726 trials were reviewed and concluded that both these classes of drugs lowered all-cause mortality, cardio vascular mortality, non-fatal myocardial infarction and kidney failure [6].

Conclusions

It is interesting to note that SGLT2 inhibitors beyond diabetic control has emerged as the major treatment with cardio vascular and renal benefits. Every trial has proven their role in reducing their superiority over placebo in reducing the morbidity and mortality associated with cardio vascular and renal diseases. These drugs would get positioned as high as ACEI/ARB and will form an essential part of patients with chronic kidney disease – both in diabetic as well as nondiabetic patients.

References:

  1. John P, Wilding H. Metabolism. 2014;63(10):1228–1237.
  2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
  3. Neal B, Perkovic V. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657.
  4. Perkovic V, Jardine MJ. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306.
  5. Heerspink HJL. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–1446.
  6. Palmer SC, Tendal B. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomized controlled trials. BMJ. 2021.

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