Summary | Understanding CKD and SGLT2-inhibition: what are the key mechanisms?
Prof. Groop set out to explain the mechanisms and outcomes of SGLT2 inhibition. First, he started with a few words on the consequences of CKD. Prof. Groop: ‘The consequences of CKD are grim. Data from many trials and observational studies show a many-fold increased risk of premature mortality in T2DM patients with albuminuria and/or impaired eGFR, which is due to CVD . Every T2DM patient with CKD has a doubled risk of myocardial infarction, stroke, peripheral vascular disease and premature death  due to risk factors that come with CKD, such as hypertension, oxidative stress, insulin resistance, arterial calcification, inflammation, left ventricle hypertrophy, endothelial dysfunction, activation of the reno-angiotensin-aldosterone system, activation of the sympathetic nervous system, anemia etc. Without doubt, CKD and CVD go hand in hand’.
Next, Prof. Groop shared renal outcome findings from the EMPA-REG OUTCOME trial and the CANVAS Program . The CANVAS program evaluated another SGLT2 inhibitor, canagliflozin. As prof. Wanner had already mentioned, the EMPA-REG OUTCOME trial demonstrated a 39% reduction in new onset or worsening of CKD in patients who were exposed to either 10 or 25 mg empagliflozin compared to placebo on top of standard care. Also, the composite endpoint of doubling of serum creatinine level, initiation of renal replacement therapy or death due to renal disease was reduced with 46% and a 55% decrease in the likelihood of ending on dialysis was observed after treatment with empagliflozin. Besides, empagliflozin-treated patients showed an initial drop in the eGFR followed by preservation of kidney function, which was not observed in the placebo group .
The CANVAS Program, which included low renal risk patients, showed a very similar effect of 40% reduction in the composite endpoint of eGFR, end stage renal disease or renal death. Again, an initial drop in eGFR was found, followed by normalization and preservation of kidney function. Summarized, these two big outcome trials demonstrated renal benefits in patients with T2DM after treatment with SGLT2 inhibitors .
The next question was: ‘Why do SGLT2 inhibitors work so well?’. Although SGLT2 inhibitors are not indicated for use in patient with type 1 diabetes (T1DM), we can learn a lot about SGLT2 inhibitors from a T1DM study. One study showed a reduction of the eGFR by 33 ml/min/1.73m2 in hyperfiltering T1DM patients after treatment with empagliflozin . Hyperfiltering T1DM patients have glomerular hypertension and increased intra-glomerular pressure. T1DM patients with normal filtering did not show any effect on renal function measures after treatment with 25 mg empagliflozin. This drug did, however, reduce both the intra-glomerular pressure and the eGFR in hyperfiltering T1DM patients . This was accompanied by a decrease in renal blood flow and an increase in renal vascular resistance, which is consistent with an increased tone in the afferent arteriole .
The renal effects of the SGLT2 inhibitors can be explained by the tubular hypothesis. Normally, the SGLT2 transporter in the proximal tubule absorbs glucose and sodium, which is a balanced process. Residual sodium reaches the macula densa next to the glomerulosa, where it is absorbed again by another counter-transporter that transports sodium, potassium and chloride. Absorption of sodium requires energy, which is generated from ATP. During ATP hydrolysis, adenosine is generated, which is a basal constrictor of the afferent arteriole.
Hyperfiltering T2DM and T1DM patients with established CKD show an exaggerated reabsorption of glucose and sodium in the proximal tubule, into the blood. In this case sodium does not reach the macula densa and consequently there is no vasoconstriction in the afferent arteriole, but instead vasodilation. SGLT2 inhibitors block the sodium reabsorption, and consequently sodium reaches the macula densa again. This allows adenosine to be generated, causing vasoconstriction . Prof. Groop emphasized the effect of empagliflozin on glomerular hyperfiltration by displaying a diagram that shows a similar effect of ACE inhibitors (decrease of 35 mL/min versus 33 mL/min respectively) .
Hypoxia also seems to play a role, which he illustrated with observations in experimental studies. In diabetic mice, renal hypoxia, increased eGFR and a slight increase in proteinuria were observed within three days after diabetes induction . Moreover, hypoxia was not only seen in the cortex, but also in the medulla of the kidneys. After administration of dinitrophenol, a mitochondrial uncoupler, increased proteinuria, kidney vimentin expression and infiltration of inflammatory cells were observed, which is similar to the phenotype of diabetes, obesity and hypertension .
According to the tubular hypothesis and results in diabetic mice, prof. Groop hypothesized: ‘Due to administration of a SGLT2 inhibitor there is less sodium handling, leading to reduced oxygen consumption and hypoxia, which in the end results in renal benefit’.
In summary, CKD is a common complication with grim consequences. SGLT2 inhibitors have been shown to result in CV protection and renal protective effects, beyond their effects on glucose control. However, the renal protective effects have to be studied in dedicated renal trials in the future.
This is a summary of the presentation given by prof. Groop, during the PACE symposium entitled 'Diabetic Kidney Disease: Exploring mechanisms and outcomes of SGLT2 inhibition', held during ERA-EDTA in Copenhagen, Denmark, on May 25, 2018