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Recent randomized trials demonstrating the beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in type 2 diabetes suggest that early reductions in eGFR upon initiation of SGLT2i therapy are associated with improved renal outcomes. Multiple concomitant medications, including antidiabetic and antihypertensive agents, are commonly used, however, which may modify the renal hemodynamic action of SGLT2is. Here we found that background treatment with metformin diminished the SGLT2i-induced reductions in eGFR after 3 months of SGLT2i therapy in patients with type 2 diabetes and hypertension (−2.29 ± 0.90 vs −5.85 ± 1.27 mL/min/1.73 m2 for metformin users (n = 126) and nonusers (n = 97), respectively). Other antidiabetic agents (DPP4 inhibitors, sulfonylureas and insulin) had no effect on the eGFR response to SGLT2is. Antihypertensive drugs, including calcium channel blockers (CCBs) and β blockers, did not affect the SGLT2i-induced changes in eGFR, whereas renin-angiotensin system inhibitors (RASis) tended to enhance this response (p = 0.059). Next, we evaluated the interaction between metformin and RASis in the eGFR responses to SGLT2is. Under no background treatment with RASis, metformin abrogated the eGFR response to SGLT2is, but this response was preserved when RASis had been given along with metformin (decreases of 0.75 ± 1.28 vs. 4.60 ± 1.15 mL/min/1.73 m2 in eGFR, p = 0.028). No interaction between metformin and insulin or between metformin and DPP4 inhibitors was observed. In conclusion, metformin blunts the SGLT2i-induced decrease in eGFR, but coadministration of RASis ameliorates this response. Furthermore, the inability of CCBs to modify the SGLT2i-induced reduction in eGFR suggests that the SGLT2i-induced renal microvascular action is mediated predominantly by postglomerular vasodilation rather than preglomerular vasoconstriction.

Background In the diagnosis of pulmonary embolism (PE), the d -dimer threshold is based on studies conducted in Western countries, where the incidence rate is 5 times higher than that in Asian countries, including Japan. If we could elevate the d -dimer threshold based on the low pre-test probability in the Japanese population, we could omit the computed tomography pulmonary angiography (CTPA) which might lead to radiation exposure and contrast-induced nephropathy. Therefore, we aimed to determine a new d -dimer threshold specific to Japanese individuals. Methods We conducted a retrospective cohort study at an emergency department in Japan, using medical charts collected from January 2013 to July 2017. We included patients whose d -dimer were measured for suspicion of PE with low or intermediate probability of PE and CTPA were performed. The primary outcome was failure rate of the new d -dimer threshold, defined as the rate of PE detected by CTPA among patients with d -dimer under the new threshold ranging from 1000 to 1500 μg/L by 100. The new d -dimer threshold was appropriate if the upper limit of 95% confidence interval of the failure rate of PE was approximately 3%. Results In 395 patients included, the number of patients with PE was 24 (the prevalence was 6.1%). If the d -dimer threshold was 1100 μg/L, the failure rate was 0% (0/119), the upper limit of the 95% confidence interval of the failure rate was 3.1%, and 30% (119/395) of the CTPA might be omitted. Conclusion The new d -dimer threshold could safely exclude PE. This result can be generalized to other Asian populations with a lower incidence of PE. Further prospective studies will be needed.

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