Physiological Effects of SGLT-2 inhibition in Type II Diabetes

"Recently, episodes of ketoacidosis have been reported in some patients receiving SGLT-2 inhibitors, especially on the background of insulin treatment. Though infrequent, this serious complication of SGLT-2 inhibition has led both the US FDA and European Medicines Agency to include a warning on the product label.

In summary, we found that the physiological response to SGLT-2 inhibition in patients with type 2 diabetes and preserved renal function, as well as in subjects without diabetes includes an increase in the absolute and fractional excretion of β-HB, lactate, and sodium, which quantitatively track with glycosuria. .

These findings, and the increase in EPO production, indicate that substantial glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism that, taken together, may be beneficial for kidney function in the long term."

Diabetes Care


Diabetes Care

Original Study

June 2017

Objective: Drug-induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including DECREMENTS in plasma glucose and insulin levels, INCREMENTS in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes.

Research Design and Methods: We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (eGFR≥60) and in control subjects without diabetes at baseline and following empagliflozin treatment.

Results: 

With chronic, 4 weeks, SGLT-2 inhibition, baseline fractional glucose excretion (<2%) rose to 38% fasting and 46% postmeal (respectively; P < 0.0001) over a range of BMIs (23–41) and creatinine clearance (65–168).

Excretion of β-HB (median 0.08 to 0.31 µmol/min), lactate (0.06 to 0.28 µmol/min), and sodium (0.27 to 0.36 mEq/min) all increased (P ≤ 0.001 for all) and were each positively related to glycosuria (P ≤ 0.001).

These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal BNP were unaltered, plasma EPO concentrations increased by 31%.

Conclusion: 

We conclude that the SGLT-2 inhibitor–induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.


More from the publication:

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the proximal tubule reabsorption of filtered glucose, thereby causing glycosuria and decreases in plasma glucose concentrations. When large quantities of glucose are pharmacologically forced into urinary excretion, whole-body metabolism undergoes adaptive changes, involving glucose fluxes, hormonal responses, fuel selection, and energy expenditure. In previous work, we used empagliflozin (jardiance) to investigate the physiological response to forced glycosuria in patients with type 2 diabetes (T2D).

By combining a mixed meal with the double-tracer technique and indirect calorimetry, we found that following acute or chronic empagliflozin administration, endogenous glucose production rose, tissue glucose disposal decreased, and lipid use increased. Subsequently, we showed that the SGLT2-induced increase in lipid mobilization and oxidative use was associated with increased plasma ketone (β-hydroxybutyrate [β-HB]) levels and reduced plasma lactate concentrations. Recently, episodes of ketoacidosis have been reported in some patients receiving SGLT2 inhibitors (SGLT2i), especially on the background of insulin treatment. Though infrequent, this serious complication of SGLT2 inhibition has led both the US FDA and European Medicines Agency to include a warning on the product label.

The QUESTION, what is the role of renal clearance in the rise in ketonemia associated with SGLT2 inhibition, has not been addressed. With prolonged fasting for 24 days, circulating ketone concentrations rise progressively, whereas ketonuria initially increases then falls. This prompted us to measure urinary excretion of the main ketone body, β-HB, along with lactate and sodium, in a group of well-characterized patients with T2D and in subjects without diabetes under short-term fasting and postprandial conditions at baseline and then following acute and chronic SGLT2 inhibition.

Baseline urinary β-HB excretion was low, amounting to <1% of the filtered load both in the fasting state and postmeal. This confirms the great efficiency of the tubular kidney to reabsorb β-HB, similar to those of glucose and sodium, possibly through the joint action of multiple transporters. With empagliflozin administration, especially chronic, β-HB excretion, clearance rate, and fractional excretion all increased both in the fasting and postprandial state. Therefore, the observed rise in plasma β-HB concentrations was not because of reduced renal elimination, although a decrease in muscle ketone use cannot be ruled out.

At baseline, lactate excretion was similar to β-HB excretion in absolute terms, but fractional excretion was 10 times lower because of the higher lactate than β-HB levels in the plasma. As in the case of β-HB excretion, empagliflozin dosing was associated with progressive increments in lactate excretion, clearance rate, and fractional excretion, similarly under fasting and postprandial conditions.

Sodium excretion was consistently lower postmeal than at baseline, an expected consequence of oral glucose. Sodium excretion was acutely increased by single-drug administration both in the fasting and postprandial state. Importantly, postprandial natriuresis remained 35% higher than at baseline during chronic treatment, confirming that glycosuria imposes an added natriuretic pressure (as also predicted by a recent detailed mathematical model). In a recent study using 25-mg empagliflozin in patients with T2D on a controlled diet with standardized sodium, food, and fluid intake, 24-h natriuresis increased acutely and returned to baseline after 5 days.

Acute blockade of proximal sodium absorption delivers an excess of sodium (and chloride) to the macula densa, thereby triggering the release of vasoconstrictive molecules (adenosine, prostaglandin H2, and thromboxane A2) and vasoconstriction of the afferent glomerular arterioles. It has been argued that this resetting of the tubuloglomerular feedback is the likely mechanism underlying the acute decrement in GFR observed in patients with type 1 diabetes.

In contrast, under everyday life conditions, even mild natriuresis induced by the glycosuric effect of each daily SGLT2 dose should gradually reduce the body pool of exchangeable sodium (∼2.6 mol), which is characteristically expanded (by ∼10%) in patients with hyperglycemia regardless of whether they are hypertensive or normotensive. In this regard, it is of note that excretion of all three measured solutes—β-HB, lactate, and sodium—correlated with glucose excretion, which is further evidence for the central role of glycosuria in the changes in renal solute handling following SGLT2 inhibition.

The present analysis of SGLT2i-induced glycosuria yielded some unanticipated findings. Firstly, whereas CrCl was 35% lower in lean (mean BMI 23.8) than in obese participants (mean BMI 34.7), renal glucose clearance in response to chronic empagliflozin administration was only 23% lower in the former than the latter in the fasting state and 16% lower during the meal. This quantitative difference between GFR and SGLT2i-induced renal glucose clearance would translate into a difference of only 18% in 24-h glycosuria between the lean and the obese (e.g., 96 vs. 117 g using the mean fasting and postmeal glucose levels measured in our patients with T2D). However, an obese 60-year-old man has an estimated calorie consumption of 2,375 kcal/day, whereas a lean 60-year-old woman consumes 1,715 kcal/day; assuming 50% carbohydrate in both of their diets, those urinary glucose losses would amount to 34% of carbohydrate intake in the obese man and 45% of carbohydrate intake in the lean woman.

This calculation highlights the fact that SGLT2 inhibition induces a degree of glycosuria, relative to the filtered glucose load, that is essentially independent of body size, thereby exposing the lean person to a substantially higher degree of carbohydrate deficit than the obese individual. This may represent an additional circumstance predisposing less obese patients with T2D on SGLT2i treatment on a low- carbohydrate diet to an augmented reliance on fat use for energy production, hyperketonemia, and, occasionally, ketoacidosis.

Finally, CrCl was consistently higher during the mixed meal than in the fasting state, a well-known consequence of protein stimulation of glucagon release (along with vasopressin and urea). However, both acute and chronic empagliflozin dosing were associated with a significant ∼10% decrease in both fasting and postmeal CrCl, similarly in subjects with T2D and without diabetes. This finding directly confirms the drop in estimated GFR that has been consistently observed in the early stages of SGLT2i development and in subsequent clinical studies. This change in CrCl has been related to blood-volume depletion. However, in our subjects, volume contraction, as judged from the plasma albumin concentrations, was very small over the few hours following single-drug administration. As mentioned above, proximal tubular natriuresis could lead to vasoconstriction of the afferent glomerular arteriole by activating tubuloglomerular feedback at the macula densa. Additionally, the observed prompt rise in plasma glucagon and glucagon-like peptide 1 levels following single empagliflozin dosing might have had a role of its own given the presence of both glucagon and glucagon-like peptide 1 receptors in the distal tubular nephron.

Finally, the finding of an increase in serum EPO after 4 weeks of empagliflozin treatment raises the possibility that part of the increase in hematocrit, which sets in rapidly and is sustained for as long as treatment continues, may be the result of enhanced erythropoiesis. In a previous study using dapagliflozin in 10 patients with T2D, a 6% increase in red blood cell mass, as measured by the direct 51Cr-labeled erythrocyte technique, was detected in concomitance with a transient rise in serum EPO levels. Regulation of EPO production by interstitial renal fibroblasts involves multiple factors (oxygen sensing through hypoxia-inducible factor, adenosine, and renin among others). In our data, the correlation between hemoglobin and EPO levels does suggest that the release of the hormone responds to relative hypoxemia in the renal medulla. Thus, with SGLT2 inhibition, sodium escaping proximal reabsorption may impose a work overload on the distal tubule, resulting in a transient increase in oxygen consumption and reduction in oxygen tension in the medulla. Enhanced erythropoiesis could then follow and raise the oxygen-carrying capacity of perfusing blood, thereby re-establishing appropriate, if not better, kidney oxygenation. However, the precise sequence of events starting from enhanced glycosuria to oxygen availability and stimulation of EPO production needs to be elucidated.

In summary, we found that the physiological response to SGLT2 inhibition in patients with T2D and preserved renal function as well as in subjects without diabetes includes an increase in the absolute and fractional excretion of β-HB, lactate, and sodium, which quantitatively track with glycosuria. These findings, and the increase in EPO production, indicate that substantial glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism that, taken together, may be beneficial for kidney function in the long term.