Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data

May combine two claims.

In the diabetic state with moderate renal function, GFR was in the normal range (87 ml/min) but SNGFR increased further to 73 nl/min.

“In the diabetic state with moderate renal function, GFR was in the normal range (87 ml/min) but SNGFR increased further to 73 nl/min.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

A model with only direct SGLT2 inhibition was completely unable to explain the data and predicted small decreases in serum creatinine, opposite of those observed.

“This model case was completely unable to explain the data and in fact predicted small decreases in serum creatinine, opposite of those observed.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

In the diabetic state with renal impairment, GFR was reduced to 40 ml/min but SNGFR increased even further, to 81 nl/min.

“In the diabetic state with renal impairment, GFR was reduced to 40 ml/min but SNGFR increased even further, to 81 nl/min.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

At baseline, nearly all glucose reabsorption occurs through SGLT2, and reabsorption through SGLT1 is minimal.

“At baseline, nearly all glucose reabsorption occurs through SGLT2, and reabsorption through SGLT1 is minimal.”

May combine two claims.

Multiple mechanisms are required to explain the observed clinical response to dapagliflozin in healthy subjects: direct SGLT2 inhibition, SGLT2-driven NHE3 inhibition, and osmotic diuresis coupled with peripheral sodium storage.

“Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of Na ϩ /H ϩ exchanger 3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

Case 2 (direct SGLT2 inhibition plus osmotic diuresis) improved prediction of water excretion and serum creatinine dynamics but still poorly fit the data, with serum creatinine decreasing overall.

“As shown in Fig. 3, prediction of water excretion improved and the dynamics of serum creatinine were more similar to the observed data, but serum creatinine still decreased overall and the model still poorly fit the data.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

Dapagliflozin inhibition of SGLT2 allows additional glucose and Na to reach SGLT1, so that while SGLT2 reabsorption decreases, SGLT1 reabsorption increases, and the total decrease in glucose reabsorption is much less than the decrease in SGLT2.

“Dapagliflozin inhibition of SGLT2 allows additional glucose (and Na ϩ ) to reach SGLT1, so that while SGLT2 reabsorption decreases, reabsorption through SGLT1 increases, and the total decrease in glucose reabsorption is much less than the decrease in SGLT2 (Fig. 4A).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Reducing nephron number to 60% of normal reduced baseline GFR to 87 ml/min.

“To simulate this, we reduced the number of nephrons to 60% of normal, which reduced baseline GFR to 87 ml/min.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

NHE3 accounts for the bulk of proximal tubule Na reabsorption, and inhibiting NHE3 by 7% resulted in a similar reduction in total PT Na reabsorption, with the direct effect of dapagliflozin on Na reabsorption through SGLT2 having a negligible effect.

“As shown in Fig. 4, E and F, reabsorption through NHE3 accounts for the bulk of PT Na ϩ reabsorption, and inhibiting NHE3 by just 7% resulted in a similar reduction in total PT Na ϩ reabsorption, with the direct effect of dapagliflozin on Na ϩ reabsorption through SGLT2 having a negligible effect.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

Both GFR and SNGFR were increased in the hyperfiltering diabetic state.

“Both GFR and SNGFR were increased in the hyperfiltering diabetic state (Fig. 5A).”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

Mean arterial pressure was reduced by 3.5 mmHg in both diabetic virtual patients, in agreement with clinical observations of a mild antihypertensive effect of SGLT2 inhibitors.

“MAP was reduced by 3.5 mmHg in both diabetic virtual patients, in agreement with clinical observations of a mild antihypertensive effect of SGLT2i (21).”

• cites [21] sourceNot checked yet

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May combine two claims.

Interstitial fluid volume reduction was larger in the diabetic virtual patient with preserved renal function compared with the healthy state, but renal impairment limited the interstitial volume reduction.

“Interstitial fluid volume reduction was larger in the diabetic virtual patient with preserved renal function compared with the healthy state, but renal impairment limited the interstitial volume reduction.”

May combine two claims.

Na reabsorption through SGLT was doubled in the diabetic hyperfiltering virtual patient compared with normal, mostly due to increased SGLT1 reabsorption.

“Na ϩ reabsorption through SGLT was doubled in the diabetic hyperfiltering virtual patient compared with normal (Fig. 5C).Most of this increase was due to increased SGLT1 reabsorption.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

The model predicts that the natriuretic and diuretic effect of SGLT2 inhibition is weaker but sustained in normoglycemia compared with diabetes and with renal impairment compared with normal renal function.

“In agreement with recent simulations by Layton and Vallon, our model predicts that the natriuretic and diuretic effect of SGLT2 inhibition is weaker but sustained in normoglycemia compared with diabetes and with renal impairment compared with normal renal function (22).”

• cites [22] sourceNot checked yet

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May combine two claims.

In the diabetic virtual patient with moderate renal function, GFR decreased by 12 ml/min, in agreement with reductions observed by iohexol measurements by Lambers Heerspink et al.

“In the diabetic virtual patient with moderate renal function, GFR decreased by 12 ml/min, in agreement with reductions observed by iohexol measurements by Lambers Heerspink et al. (21).”

• cites [21] sourceNot checked yet

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May combine two claims.

In diabetic virtual patients with moderate or impaired renal function, total glucose reabsorption decreased relative to the hyperfiltering case, but single-nephron total glucose reabsorption rose further as renal function fell.

“In the diabetic virtual patients with moderate or impaired renal function, total glucose reabsorption decreased relative to the hyperfiltering case, because of the reduced filtered load with fewer nephrons.However, single-nephron total glucose reabsorption rose further as renal function fell.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

Increasing blood glucose from the healthy to the diabetic state (normal renal function) caused a small increase in glucose reabsorption through SGLT2 (from 0.54 to 0.75 mEq/min) but a 10-fold increase in glucose reabsorption through SGLT1 (from 0.03 to 0.3 mEq/min).

“Increasing blood glucose from the healthy to the diabetic state (normal renal function) caused a small increase in glucose reabsorption through SGLT2 (from 0.54 to 0.75 mEq/min) but a 10-fold increase in glucose reabsorption through SGLT1 (from 0.03 to 0.3 mEq/min) (Fig. 5B)”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

As renal function declined, total proximal tubule Na+ reabsorption declined, but single-nephron proximal tubule Na+ reabsorption increased further.

“Again, total PT Na ϩ reabsorption declined as renal function declined, but single-nephron PT Na ϩ reabsorption increased further.”

May combine two claims.

In diabetic virtual patients with moderate and impaired renal function, Na reabsorption through SGLT decreased overall compared with the hyperfiltering case but increased at the single-nephron level.

“In the diabetic virtual patients with moderate and impaired renal function, Na ϩ reabsorption through SGLT followed trends similar to glucose, decreasing overall compared with the hyperfiltering case but increasing at the singlenephron level.”

• AssumptionThe authors state this as an assumption: SGLT2i produces three proximal effects and any additional effects are the consequence of these mechanisms: direct inhibition of glucose and Na by SGLT2; indirect reductions in water reabsorption due to glucose-driven osmotic diuresis; and reductions in Na reabsorption through NHE3.

May combine two claims.

Blood volume was reduced similarly in both diabetic cases and larger than in the normoglycemic case.

“Blood volume was reduced similarly in both diabetic cases and larger than in the normoglycemic case.”

May combine two claims.

In the healthy state, SGLT1/2 accounted for 5.8% of total proximal tubule Na+ reabsorption, but in all three diabetic states the contribution of SGLT was increased to 11%.

“In the healthy state SGLT (1, 2) accounted for 5.8% of total PT Na ϩ reabsorption, but in all three diabetic states the contribution of SGLT was increased to 11% (Fig. 5D).”

May combine two claims.

With renal impairment, urinary glucose excretion was lower and was similar to the normoglycemic case.

“With renal impairment, UGE was lower and was similar to the normoglycemic case.”

May combine two claims.

Reductions in glomerular pressure and single-nephron GFR were larger in diabetes than in normoglycemia and nearly independent of renal function.

“We further predicted that reductions in glomerular pressure and SNGFR were larger in diabetes than in normoglycemia and nearly independent of renal function.”

May combine two claims.

The glomerular pressure reduction was larger in both diabetic virtual patients than in the normoglycemic case, and renal impairment did not ameliorate the reduction.

“Still, importantly, the glomerular pressure reduction was larger in both diabetic virtual patients than in the normoglycemic case, and renal impairment did not ameliorate the reduction.”

May combine two claims.

Increases in proximal tubule Na reabsorption cause GFR to increase and serum creatinine to decrease.

“As we have previously modeled, increases in PT Na ϩ reabsorption cause GFR to increase (13) and serum creatinine to decrease, as predicted here.”

• cites [13] sourceNot checked yet

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May combine two claims.

SGLT2 in the S1 and S2 segments of the proximal tubule reabsorbs 90-97% of filtered glucose, whereas SGLT1 in the S3 segment reabsorbs the remaining 3-10%.

“SGLT2 in the S1 and S2 segments of the PT reabsorbs 90 -97% of filtered glucose, whereas SGLT1 in the S3 segment reabsorbs the remaining 3-10% (10,24,27,36,37).”

• cites [10] sourceNot checked yet

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• cites [24] sourceNot checked yet

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• cites [27] sourceNot checked yet

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• cites [36] sourceNot checked yet

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• cites [37] sourceNot checked yet

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May combine two claims.

SGLT2 inhibitors indirectly reduce blood pressure and blood volume.

“SGLT2i also indirectly reduces blood pressure and blood volume (21).”

• cites [21] sourceNot checked yet

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May combine two claims.

Recent cardiovascular outcomes trials demonstrate that SGLT2 inhibitors may reduce heart failure morbidity and mortality and slow decline in renal function.

“Recent cardiovascular outcomes trials demonstrate that therapies that inhibit sodium glucose cotransporter (SGLT)2 may reduce heart failure morbidity and mortality and slow decline in renal function (7,8,23,42,43).”

• cites [7] sourceNot checked yet

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• cites [8] sourceNot checked yet

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• cites [23] sourceNot checked yet

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• cites [42] sourceNot checked yet

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• cites [43] sourceNot checked yet

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May combine two claims.

Multiple mechanisms are required to quantitatively explain the renal hemodynamic effects of SGLT2 inhibitor inhibition: direct blocking of Na+ and glucose reabsorption through SGLT2, SGLT2-driven inhibition of NHE3 Na+ reabsorption, and osmotic diuresis coupled with peripheral Na+ storage.

“We demonstrated mathematically that multiple mechanisms are required to quantitatively explain the renal hemodynamic effects of SGLT2i inhibition: 1) direct blocking of Na ϩ and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of NHE3 Na ϩ reabsorption, and 3) osmotic diuresis coupled with peripheral Na ϩ storage.”

Classified as probably not a substantial claim.

Reductions of interstitial fluid volume with SGLT2 inhibitors may provide an explanation for the observed protective effects in heart failure.

“However, given that excessive congestion is a primary cause of heart failure hospitalization and mortality, reductions of interstitial fluid volume with SGLT2i may provide an explanation for the observed protective effects in heart failure and should be investigated further.”

• AssumptionRests on an assumption: Excessive congestion is a primary cause of heart failure hospitalization and mortality.

May combine two claims.

Decreased proximal tubule Na+ reabsorption is the primary mechanism responsible for the acute decrease in GFR, and this drop results from a decrease in glomerular pressure.

“This analysis supports decreased PT Na ϩ reabsorption as the primary mechanism responsible for the acute decrease in GFR and shows that this drop results from a decrease in glomerular pressure.”

May combine two claims.

Increased Na+ excretion following initiation of treatment produces a Na+ imbalance that must be restored, and a reduction in glomerular pressure and GFR helps achieve this, ultimately returning Na+ excretion to baseline but at a lower glomerular pressure.

“Increased Na ϩ excretion following initiation of treatment produces a Na ϩ imbalance that must be restored, and a reduction in glomerular pressure and GFR helps achieve this, ultimately returning Na ϩ excretion to baseline but at a lower glomerular pressure.”

• AssumptionRests on an assumption: Increased Na+ reabsorption induces a Na+ imbalance that must be corrected to return homeostasis, through increased filtration rate, decreased distal reabsorption rate, or both.

Probably not a substantial claim: may not pass S3 (load-bearing).

The model provides prospective predictions that require validation as additional data on these end points and populations are collected going forward.

“Thus the model provides prospective predictions that require validation as additional data on these end points and populations are collected going forward.”

May combine two claims.

In the diabetic state nephrons are hyperfiltering, and as nephrons are lost the degree of hyperfiltration in the remaining nephrons increases further.

“This is because in the diabetic state nephrons are hyperfiltering, and as nephrons are lost the degree of hyperfiltration in the remaining nephrons increases further.”

May combine two claims.

Empagliflozin increases NHE3 phosphorylation in mice, suggesting reduced NHE3 activity.

“empagliflozin increases NHE3 phosphorylation in mice, suggesting reduced NHE3 activity (9).”

• cites [9] Fu Y, 2014, Diabetes sourceNot checked yet

  Not checked in the free run.

May combine two claims.

If the renoprotective effects of SGLT2 inhibitors observed in patients with preserved renal function are indeed due to lowered glomerular pressure, these protective effects will extend to patients with CKD.

“If the renoprotective effects of SGLT2i observed in patients with preserved renal function are indeed due to lowered glomerular pressure (and associated reductions in proteinuria), these findings suggest that these protective effects will extend to patients with CKD.”

May combine two claims.

SGLT2 is reabsorbing at or near capacity, and SGLT1 is already contributing more to reabsorption.

“SGLT2 is reabsorbing at or near capacity, and SGLT1 is already contributing more to reabsorption.”

May combine two claims.

When SGLT2 is inhibited, there is a greater reduction in Na+ and glucose reabsorption and SGLT1 is less able to compensate, resulting in an overall increase in Na+ and glucose excretion at the single-nephron level.

“So when SGLT2 is inhibited there is a greater reduction in Na ϩ and glucose reabsorption and SGLT1 is less able to compensate, resulting in an overall increase in Na ϩ and glucose excretion at the single-nephron level.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

Nephropathy is complicated and other factors (strength of TGF, the myogenic response, neurohumoral activation) may change.

“We recognize that nephropathy is complicated and that other factors (strength of TGF, the myogenic response, neurohumoral activation) may change.”

May combine two claims.

Predicted changes in urinary glucose excretion, GFR, and blood volume in diabetes with normal renal function were consistent with clinical observations, but data could not be collected for validating predicted changes in interstitial fluid volume.

“While predicted changes in UGE, GFR, and blood volume in diabetes with normal renal function were consistent with clinical observations, data could not be collected for validating predicted changes in interstitial fluid volume.”

Classified as probably not a substantial claim.

The model utilized a simplified representation of the renal vasculature and other components.

“The model utilized a simplified representation of the renal vasculature and other components.”

May combine two claims.

A recent clinical trial showed a modest decrease in skin Na (5.8%) and no change in muscle Na+ in diabetic patients treated with dapagliflozin for 6 wk.

“A recent clinical trial showed a modest decrease in skin Na (5.8%) and no change in muscle Na ϩ in diabetic patients treated with dapagliflozin for 6 wk (18).”

• cites [18] sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

The simplifications may have some effect on specific numerical results, but they are not expected to impact the overall trends and conclusions.

“It is possible that these simplifications may have some effect on specific numerical results, but we do not expect that they impact the overall trends and conclusions.”

May combine two claims.

TGF provides a partial correction by increasing GFR, but if the pressure-natriuresis mechanism does not sufficiently adjust distal Na+ reabsorption, any remaining Na+ imbalance will cause additional fluid retention, increases in renal perfusion pressure, and increasing glomerular pressure and GFR until Na+ excretion again equals intake.

“TGF provides a partial correction by increasing GFR (although hyperfiltration will occur even in the absence of TGF) (38), but if the pressure-natriuresis mechanism does not sufficiently adjust distal Na ϩ reabsorption, any remaining Na ϩ imbalance will cause additional fluid retention, increases in renal perfusion pressure, and increasing glomerular pressure and GFR until Na ϩ excretion again equ”

• cites [38] sourceNot checked yet

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May combine two claims.

In diabetes with renal impairment, remaining nephrons are filtering more Na+ and more glucose because of both hyperfiltration and hyperglycemia.

“Thus in diabetes with renal impairment, remaining nephrons are filtering more Na ϩ and more glucose (because of both hyperfiltration and hyperglycemia).”

May combine two claims.

Treatment-induced reductions in proximal tubule Na+ reabsorption explained observed increases in serum creatinine and decreases in GFR, but the diuresis associated with this natriuretic response was not sufficient to explain observed increases in water excretion with dapagliflozin.

“Although treatment-induced reductions in PT Na ϩ reabsorption explained observed increases in serum creatinine and decreases in GFR, the diuresis associated with this natriuretic response was not sufficient to explain observed increases in water excretion with dapagliflozin.”

May combine two claims.

The consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and a mild reduction in blood pressure.

“The analysis further indicates that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and a mild reduction in blood pressure (in agreement with clinical observations).”

May combine two claims.

The primary data used to inform the effects of SGLT2 inhibitors were obtained in healthy subjects, and the analysis was conducted post hoc.

“The primary data used to inform the effects of SGLT2i were obtained in healthy subjects, and the analysis was conducted post hoc.”

Probably not a substantial claim: may not pass S2 (checkable).

The present analysis provides important and valid insights on the effect of reduced nephron number and Kf on the response to SGLT2 inhibitors.

“but we believe that the present analysis provides important and valid insights on the effect of reduced nephron number and K f on the response to SGLT2i.”

May combine two claims.

The consequences of SGLT2 inhibitor inhibition involve multiple mechanisms, including NHE3 suppression and osmotic diuresis, which subsequently lead to reduced glomerular hydrostatic pressure, reduced blood volume, and clearance of interstitial fluid.

“In conclusion, although the pharmacological action of SGLT2i in the PT at first appears straightforward, the consequences of this inhibition involve multiple mechanisms, including NHE3 suppression and osmotic diuresis, which subsequently lead to reduced glomerular hydrostatic pressure, reduced blood volume, and clearance of interstitial fluid.”