Role of the Kidney in Type 2 Diabetes and Mechanism of Action of Sodium Glucose Cotransporter-2 Inhibitors

Abstract

The kidney has an important role in glucose homeostasis. It produces glucose via gluconeogenesis, it filters glucose from the blood, and reabsorbs the filtered glucose in the proximal tubule, mainly via the sodium-glucose cotransporter-2 (SGLT-2). SGLT-2 is paradoxically upregulated in individuals with type 2 diabetes (T2D), which results in increased glucose reabsorption and hyperglycemia. This core defect in the pathophysiology of T2D provides the rationale for the use of SGLT-2 inhibitors to increase urinary glucose excretion and reduce hyperglycemia in an insulin-independent manner. Benefits of SGLT-2 inhibitor use in patients with T2D, in addition to improved glycemic control, include modest weight loss, decreased systolic blood pressure, reduced serum uric acid, and reduced risk of cardiovascular events. Common adverse events are urinary tract infection and genital mycotic infections. The risk of hypoglycemia is low with SGLT-2 inhibitors, particularly when they are given as monotherapy.

Type 2 diabetes (T2D) is a complex, chronic disease resulting from the interaction of genetic and environmental factors and is the consequence of multiple pathophysiological defects in various organs and tissues, including the pancreas, liver, muscle, fat, intestine, brain, and kidney.^1,2 Although the role of the kidney in glucose homeostasis in healthy individuals has been well characterized, until recently the contribution of the kidney to the pathophysiology of T2D has been less well appreciated. With the development and approval of sodium glucose cotransporter-2 (SGLT-2) inhibitors, the newest class of antidiabetes medications, the importance of the kidney in the maintenance of hyperglycemia and as a target for pharmacologic intervention in T2D has received renewed interest. The objective of this brief report is to discuss the role of the kidney in glucose homeostasis and, more importantly, its role in the pathophysiology of T2D.

The Kidney and Glucose Homeostasis
Glucose Reabsorption

The kidneys are responsible for regulating fluid and electrolyte balance as well as for excreting metabolic waste products. The kidneys accomplish this by the processes of filtration of the blood by the glomeruli, tubular reabsorption of vital electrolytes and nutrients, and tubular secretion of waste products. With respect to glucose, in healthy individuals under normal physiological conditions, the kidneys reabsorb virtually all (>99%) of the glucose that is filtered (~180 g/d)³ and return it to the circulation. Most of the filtered glucose (~90%) is reabsorbed by SGLT-2, which is located in the early proximal tubule⁴ (Figure 1).^5,6Another sodium-glucose cotransporter, SGLT-1, which is located in the late proximal tubule, is responsible for reabsorbing the remaining glucose.

Figure 1. Mechanism of action of SGLT-2 inhibitors^5,6

(A) Renal glucose reabsorption under normal conditions in healthy individuals.
(B) SGLT-2 inhibitors reduce renal glucose reabsorption.

Abbreviations: SGLT-1, sodium-glucose cotransporter-1; SGLT-2, sodium-glucose cotransporter-2.

Modified with permission from: Freeman JS. Review of insulin-dependent and insulin-independent agents for treating patients with type 2 diabetes mellitus and potential role for sodium-glucose co-transporter 2 inhibitors. Postgrad Med 2013;125:214-226, publisher Taylor & Fancis Ltd, and Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335-1380.

Although the kidneys are extremely effective at reabsorbing glucose, they have a finite capacity, referred to as the transport maximum for glucose (Tm_G). At a constant glomerular filtration rate (GFR), the amount of glucose filtered by the kidneys increases linearly with increasing plasma-glucose concentrations. If the filtered load of glucose, which is the product GFR and plasma glucose concentration, exceeds the Tm_G (variable, but averages ~375 mg/min in normal individuals),⁴ excess glucose is excreted in the urine (Figure 2).^7,8,9 The plasma concentration of glucose at which the TmG is exceeded and glucose appears in the urine is called the threshold (variable in healthy individuals, but averages 170‒180 mg/dL).^9,10 In healthy individuals, the Tm_G is not exceeded, and virtually all filtered glucose is reabsorbed (Figure 2).

Figure 2. Increased glucose excretion threshold and glucose reabsorption capacity (Tm_G) in patients with diabetes^7,8,9

Renal Gluconeogenesis and Glucose Utilization

An often overlooked fact is that the kidneys are the only organs besides the liver that have the necessary enzymes for the production of glucose via gluconeogenesis.¹¹ The intake of glucose in a typical Western diet is approximately 180 g/day and the body stores ~450 g of glucose. The turnover of glucose is ~250 g/day, with the brain consuming ~125 g/day.¹² The difference between the amount of glucose the body uses per day and daily dietary intake of glucose is made up by release of stored glucose and by gluconeogenesis by the liver and kidney. Based on a number of studies in healthy individuals, the kidneys contribute 20% to 25% of glucose released into the circulation in the fasting state, whereas the remainder comes from the liver through a combination of gluconeogenesis and glycogenolysis.¹¹ Like other organs and tissues, the kidneys also require glucose for energy production. In fasting healthy individuals, the kidneys consume 5% to 10% of all glucose used by the body for energy requirements, compared with, for example, the brain, which utilizes 40% to 45%.¹¹ Thus, the kidneys contribute to overall glucose homeostasis by reabsorbing filtered glucose, by producing glucose for circulation via gluconeogenesis, and by uptake and utilization of glucose for energy needs.

The Kidney in T2D
Glucose Reabsorption

In T2D, a number of maladaptive changes occur in the handling of glucose by the kidneys that contribute to hyperglycemia. Most important among these is the paradoxical increase in glucose reabsorption by the kidneys that occurs in T2D. This is akin to the increased gluconeogenesis by the liver that also occurs in T2D.¹ In a study in which renal glucose kinetics were measured, the Tm_G was significantly increased by 32% in individuals with T2D compared with healthy controls (420 vs 317 mg/min). In addition, the renal threshold was slightly, but not significantly, increased in individuals with T2D compared with controls (196 vs 171 mg/dL)⁹ (Figure 2). Thus, in patients with T2D and elevated Tm_G, excess glucose, which would normally be excreted in the urine in healthy individuals, is filtered by the kidneys and reabsorbed, which further exacerbates the existing hyperglycemia. The increased renal reabsorption of glucose in T2D may be the result of increased expression and/or activity of
SGLT-2.^4,13 Thus, increased renal glucose reabsorption represents a core defect in the pathophysiology of T2D.

Renal Glucose Production and Utilization in T2D

As mentioned above, gluconeogenesis is increased in the liver in T2D. In addition to increased glucose reabsorption, both fasting¹⁴ and postprandial¹⁵ renal gluconeogenesis is paradoxically increased in patients with T2D compared with healthy individuals. However, the uptake and consumption of glucose by the kidney for energy demands are also increased in T2D and appear to exceed renal glucose production, so that the enhanced renal gluconeogenesis appears unlikely to contribute to hyperglycemia to any great extent.^14,15

SGLT-2 Inhibitors
Mechanism of Action

Because SGLT-2 is responsible for the majority of glucose reabsorption by the kidney, inhibition of SGLT-2 represents an appealing, insulin-independent mechanism to increase renal excretion of glucose and reduce hyperglycemia. Glucosuria has typically been considered “bad” and associated with untreated diabetes or generalized disorders of proximal tubule function.¹⁶ However, almost 30 years ago, experiments in animal models of diabetes demonstrated that pharmacologically induced glucosuria with phlorizin, a relatively non-specific inhibitor of SGLTs, reduced plasma glucose concentrations, increased insulin sensitivity, and corrected defects in insulin secretion.^17,18 These experiments suggested that decreasing plasma glucose concentrations by inhibiting SGLT-2 could be a viable therapeutic approach for the treatment of T2D.

Insights into the potential consequences of SGLT-2 inhibition may be drawn from patients with familial renal glucosuria (FRG). Individuals with FRG have mutations in the gene encoding SGLT-2 that result in decreased renal glucose reabsorption, leading to glucosuria in the presence of normal plasma glucose concentrations.¹⁹ In severe cases, glucosuria can be ≥10 g/1.73 m²/day.¹⁶ Although rare and not extensively evaluated, no long-term severe clinical consequences of FRG have been reported.¹⁶ Polyuria and moderate volume depletion have been reported in individuals with FRG.²⁰

Effects of SGLT-2 Inhibition on Renal Glucose Handling

A mechanistic study in patients with T2D demonstrated that SGLT-2 inhibition resulted in a substantial decrease in the Tm_G by ~55% and a marked decrease in the threshold for glucose excretion (196 vs 21 mg/dL) (Figure 2).⁹ Thus, SGLT–2 inhibition resulted in a decrease in the capacity of the kidney to reabsorb glucose and a lowering of the plasma glucose concentration at which glucose starts to appear in the urine (threshold). The maximum percent inhibition of renal glucose reabsorption was approximately 80% at a plasma glucose concentration of 300 mg/dL.

Benefits of SGLT-2 Inhibition in Patients with T2D
Blood glucose

As a result of inhibition of renal glucose reabsorption and an increase in renal glucose excretion, SGLT-2 inhibitors, as monotherapy or as add-on therapy with other antidiabetes drugs, produce substantial and durable reductions in hyperglycemia, as reflected by reductions in glycated hemoglobin (A1C) ranging from ‒0.54% to ‒0.78% compared with placebo.^21-23 Importantly, because of their insulin-independent mechanism of action, SGLT-2 inhibitors are effective in a wide range of patients,²⁴ including those newly diagnosed with T2D, as well as patients with more severe disease and poor β-cell function, in whom insulin secretagogues, such as sulfonylureas, may be less effective. In addition, their insulin-independent mechanism of action confers a low risk of hypoglycemia, particularly when they are used as monotherapy (frequency, 0%–3.6%; no severe hypoglycemia reported).^25-27 The incidence of hypoglycemia increases in combination therapy with insulin or sulfonylureas; however, rates of severe hypoglycemia were low (0%–4%).^25-27

Body weight and blood pressure

Hypertension and obesity are common comorbidities in patients with T2D²⁸ and are risk factors for cardiovascular (CV) disease.²⁹ The increased renal excretion of glucose produced by SGLT-2 inhibitors represents the excretion of calories and results in a modest weight loss of ‒0.6 to 2.0 kg compared with placebo.^21-23 For example, a daily urinary glucose excretion of 70 g, as seen with SGLT-2 inhibition, represents the excretion of approximately 280 calories.³⁰ This contrasts with some other antidiabetes drugs, such as sulfonylureas and thiazolidinediones, which are associated with weight gain.³¹ Approximately two-thirds of the total weight loss associated with SGLT-2 inhibitors is the result of a reduction in body fat mass.^32,33

In clinical trials, decreases in systolic blood pressure of 3 to 7 mm Hg, compared with controls, are commonly observed with SGLT-2 inhibitors.^21-23,34,35 Blood pressure reductions are likely, at least in part, secondary to mild diuresis as a result of SGLT-2 inhibitor–induced glucosuria.³⁶

Uric acid

Hyperuricemia is associated with the development of gout and renal calculi,³⁷ may be associated with an increased risk of CV and renal disease,³⁸ and is an independent risk factor for the development of T2D.³⁹ SGLT-2 inhibition has been shown to reduce serum uric acid levels by ~40 μmol/L, compared with placebo, in patients with T2D,^40,41 especially in those with hyperuricemia (approximately 12% reduction vs placebo).⁴² However, whether these SGLT-2 inhibitor–induced reductions in serum uric acid have beneficial effects on renal or CV disease complications of T2D remains to be determined.

CV Outcomes in Patients With T2D

CV disease is the major cause of morbidity and mortality in individuals with diabetes.⁴³ Over the past decade, 3 major CV outcome trials in older patients with T2D and established CV disease or at high risk for CV disease failed to show a reduction in all-cause or CV mortality with intensive glucose control using antidiabetes agents such as metformin, sulfonylureas, thiazolidinediones, and insulin.^44-46 More recently, CV outcome trials with the dipeptidyl peptidase-4 inhibitors saxagliptin,⁴⁷ alogliptin,⁴⁸ and sitagliptin⁴⁹ in patients with T2D and established CV disease or at high risk for CV disease found that these agents neither increased nor decreased major adverse CV events compared with placebo.

In contrast to the aforementioned trials, the recently published CV outcome trial with the SGLT-2 inhibitor empagliflozin (EMPA-REG OUTCOME)⁵⁰ reported a significant 14% reduction in the occurrence of the primary composite end point of CV death, nonfatal myocardial infarction, or nonfatal stroke in patients with T2D and established CV disease treated with empagliflozin compared with placebo when added to standard care. Empagliflozin, compared with placebo, also significantly reduced CV death by 38%, all-cause death by 32%, and hospitalization for heart failure by 35%. Empagliflozin also significantly reduced prespecified renal outcomes compared with placebo: incident or worsening nephropathy by 39%, progression to macroalbuminuria by 38%, doubling of serum creatinine concentration by 44%, and initiation of renal replacement therapy by 55%.⁵¹ The possible mechanism(s) involved in the CV risk reduction afforded by empagliflozin is unknown but may include hemodynamic, renal, and cardiometabolic effects.^50,52-54 Furthermore, whether these beneficial CV effects are specific to empagliflozin or represent a class effect await the results of ongoing CV outcome trials with other
SGLT-2 inhibitors.^55,56

Adverse Events Associated With SGLT-2 Inhibition
The most common adverse events reported with SGLT-2 inhibitors in pooled placebo-controlled clinical trials include female genital mycotic infections (5.9%–11.6%) and urinary tract infection (5.4%–9.3%); genital mycotic infections led to study discontinuation in <1% of patients.^25-27 Postmarketing experience has identified additional adverse reactions that may or may not be related to drug exposure and inculde ketoacidosis, acute kidney injury and impairment in renal function, urosepsis, pyelonephritis, and anaphylaxis and angioedema (canagliflozin only).^25-27

Conclusions

With the renewed appreciation that increased glucose reabsorption by the kidney contributes to hyperglycemia and represents a core defect in the pathophysiology of T2D, SGLT-2 inhibitors have been developed that increase renal glucose excretion and improve glycemic control in patients with T2D, with the added benefits of modest weight loss and decreases in blood pressure. SGLT-2 inhibitors have a unique insulin-independent mechanism of action that is complementary to other classes of antidiabetes medications. Because T2D is a complex, multifactorial disease, individualized combination pharmacotherapy that targets the multi-organ defects of T2D may help patients achieve desired glycemic goals and produce favorable effects on CV risk factors.

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