Currently, the only indication for the use of these drugs is as third-line therapy for diabetes mellitus (see Chapter 41). SGLT2 inhibitors will reduce the hemoglobin A1c by 0.5–1.0%, similar to other oral hypoglycemic agents. Even though SGLT2 inhibitors are not indicated for other diagnoses, they do have other minor effects. SGLT2 inhibitors will result in an average weight loss of 3.2 kg versus a weight gain of 1.2 kg with glipizide. It is not clearly established how much of this is due to the diuretic effect, but it is notable that SGLT2 inhibitors also induce a drop in systolic blood pressure by an average of 5.1 mm Hg, compared with an increase in systolic blood pressure of approximately 1 mm Hg after starting sitagliptin. In one study, ipragliflozin resulted in an increase in urine volume from day 1 to day 3. There was a 0.7-kg decrease in body weight by day 3 compared to day 1. Both urine sodium and urine potassium excretion increased with the use of ipragliflozin, but the serum concentrations of both electrolytes remained stable. Thus, it is likely that at least part of the weight loss is due to the diuretic effect of the drugs. Recently there have also been reports of acute kidney injury (AKI) with these drugs. At this point, it is unclear how much the diuretic and blood pressure-lowering effects of these drugs contribute to the reported AKI.
SGLT2 inhibitor therapy is associated with a low incidence of hypoglycemia (3.5% versus 40.8% with glipizide). There is a sixfold increased incidence of genital fungal infection in women and a slightly higher risk of urinary tract infections (8.8% versus 6.1%). All of these agents have been shown to have no or minimal effects on serum electrolyte concentrations.
Loop diuretics selectively inhibit NaCl reabsorption in the TAL. Because of the large NaCl absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available.
The two prototypical drugs of this group are furosemide and ethacrynic acid (Table 15–4). The structures of these diuretics are shown in Figure 15–7. In addition to furosemide, bumetanide and torsemide are sulfonamide-based loop diuretics.
Ethacrynic acid—not a sulfonamide derivative—is a phenoxyacetic acid derivative containing adjacent ketone and methylene groups (Figure 15–7). The methylene group (shaded in figure) forms an adduct with the free sulfhydryl group of cysteine. The cysteine adduct appears to be the active form of the drug.
Organic mercurial diuretics also inhibit salt transport in the TAL but are no longer used because of their toxicity.
The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption
TABLE 15–4 Typical dosages of loop diuretics.
Bumetanide 0.5–2 mg 1As single dose or in two divided doses.
FIGURE 15–7 Two loop diuretics. The shaded methylene group on ethacrynic acid is reactive and may combine with free sulfhydryl groups.