Twenty-Four-Hour Blood Pressure-Lowering Effect of a Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Diabetes and Uncontrolled Nocturnal Hypertension: Results From the Randomized, Placebo-Controlled SACRA Study.

BACKGROUND: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. METHODS: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). RESULTS: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m2). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (-6.3 mm Hg; P=0.004); between-group difference in change from baseline was -4.3 mm Hg (P=0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (-9.5, -7.7, -7.5, and -8.6 mm Hg, respectively; all P≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (-1.3 kg and -0.33%; both P<0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (-12.1%; P=0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (-8.2% [P=0.008] and -9.7% [P=0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. CONCLUSIONS: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT03050229.

Drug-induced Liver injury Caused by Ipragliflozin Administration with Causality Established by a Positive Lymphocyte Transformation Test (LTT) and the Roussel Uclaf Causality Assessment Method (RUCAM): A Case Report.

A 75-year old male patient had been regularly visiting our hospital for the management of his type 2 diabetes mellitus since he was diagnosed at age 64 years. When he developed hypoglycemic episodes with sulfonylurea, ipragliflozin (50 mg/day) was started to replace the sulfonylurea therapy. However, 49 days after starting ipragliflozin, his AST increased from 13 to 622 U/L, ALT increased from 9 to 266 U/L, ALP increased from 239 to 752 U/L, and (Υ-GTP) increased from 19 to 176 U/L. ZTT was 3.5 U, TTT was 0.4 U, and total bilirubin was 0.7 mg/dL. IgM hepatitis A antibody, hepatitis B antigen, hepatitis C virus antibody, IgM CMV antibody, and IgM EB VCA antibody were negative, whereas a lymphocyte transformation test for ipragliflozin was positive. Abdominal CT scan showed mild fatty liver but no sign of nodular lesions. Following admission to our hospital, he received liver supportive therapy with the discontinuation of ipragliflozin therapy. He was discharged from the hospital 18 days later with AST and ALT levels reduced to 20 U/L and 13 U/L, respectively. Based on the clinical presentation of this patient, it is highly important to monitor liver function along with other possible clinical complications (e.g., dehydration, ketosis, and urinary tract infection) associated with SGLT2 inhibitortherapy.

Comparison of serum amylase level between dipeptidyl peptidase-4 inhibitor and GLP-1 analog administration in patients with type 2 diabetes mellitus.

We monitored serum amylase level in patients with type 2 diabetes mellitus (T2DM) prescribed either dipeptidyl peptidase-4 inhibitor or GLP-1 analog (GLP-1 group) as monotherapy. Patients were treated for a 36-month period. All subjects were non-smoker and did not take any alcoholic beverages. Forty-nine patients were prescribed DPP4is (DPP4i group), and 9 patients were prescribed GLP-1 analogs (GLP-1 group). The median of serum amylase levels in DPP4is group was 73 U/mL and the median of serum amylase levels in GLP-1 analog group was 76. Thus, there was no statistical significance between the two groups. However, the increased serum amylase levels in the three patients were observed only in the DPP4is group. One strength of the current study is that the serum amylase level was consistently measured in all subjects, and those subjects had been treated with either DPP4is or GLP-1 analogs as monotherapy. The incidence of elevated serum pancreatic amylase levels beyond normal range was calculated as 6.12% in the DPP4is group although the frequency was 0% in the GLP-1 analog group. Measurement of serum amylase consistently might have clinical meaning to catch the onset of pancreatitis and minimize the side effects due to DPP4is and GLP-1 analogs.

Lower Renal Threshold for Glucose Reabsorption in Type 1 Diabetes Mellitus (T1DM) May Explain the Smaller Contribution of SGLT2 Inhibitors to the Improvement of Plasma Glucose Control Compared with T2DM.

INTRODUCTION: Previously, we reported that the renal threshold for glucose reabsorption can be measured as the lowest plasma glucose level that correlates with the first detectable appearance of urine glucose. These data revealed significant variations among patients with type 2 diabetes mellitus (T2DM), and there was a significant negative correlation between the renal threshold for glucose reabsorption and HbA1c levels following treatment with the sodium-glucose co-transporter 2 (SGLT2) inhibitor ipragliflozin. Recently approved SGLT inhibitors may not show the same efficacy in patients with T1DM as in those with T2DM unless the renal threshold for glucose reabsorption shows similar levels between the two groups. SGLT2 inhibitors improve plasma glucose control in patients with T2DM by reducing glucose reabsorption via the epithelial cells of the proximal tubule. METHODS: The renal threshold for glucose reabsorption was defined as the minimum blood glucose concentration that results in the presence of measurable glycosuria in at least 12 measurements. RESULTS: The renal threshold for glucose reabsorption in patients with T2DM [n = 64; 201.8 ± 33.6 (range 121-268) mg/dL] was significantly higher than that in patients with T1DM [n = 33; 171.0 ± 33.0 (range 76-259) mg/dL; p = 0.00022]. CONCLUSION: The renal threshold for glucose reabsorption in patients with T1DM was near the normal range and significantly lower than that in patients with T2DM. The efficacy of the SGLT2 inhibitor was better in patients with a higher renal threshold for glucose reabsorption. Thus, these results indicate that it is advisable to estimate the renal threshold for glucose reabsorption prior to initiating SGLT2 inhibitor therapy in patients with T1DM.

Renal threshold for glucose reabsorption predicts diabetes improvement by sodium-glucose cotransporter 2 inhibitor therapy.

In the present study we examined the efficacy of sodium-glucose cotransporter 2 inhibitors on improvement of glycated hemoglobin (HbA1c) in comparison with the renal threshold for glucose reabsorption in patients with type 2 diabetes mellitus. Patients visited the hospital once a month for a regular follow-up examination with the determination of blood glucose and HbA1c levels, and urinary glucose concentration from spot urine samples. Patient samples were compared before and after ipragliflozin administration. We defined the renal threshold for glucose reabsorption as the lowest blood glucose level that correlated with the first detectable appearance of urine glucose. These data showed a significant negative correlation between improvement of HbA1c level and renal threshold for glucose reabsorption in patients treated with the sodium-glucose cotransporter 2 inhibitor. These findings show that patients who have a higher renal threshold for glucose reabsorption can be expected to more effectively respond to sodium-glucose cotransporter 2 inhibitor therapy in terms of lowering HbA1c levels.

Subcutaneous abdominal adipose tissue is associated with an index of insulin sensitivity/resistance.

To assess whether there is any clinical significance for determining the normal range of subcutaneous abdominal fat area, we compared fat area with insulin sensitivity. Visceral and subcutaneous abdominal fat area the L4-L5 thoracic level was determined by computed tomography (CT). Plasma glucose and insulin levels were determined after an overnight fast and calculated by the homeostatic model assessment of insulin resistance (HOMA-IR). We analyzed 350 (180 male and 170 female) subjects whose BMI was 18.5≤BMI<25. The subcutaneous abdominal fat area of the female subjects was 124.7 ± 46.13 cm2 and that of male subjects was 77.53 ± 37.53 cm2 (mean ± SD). We compared HOMA-IR between subjects whose visceral abdominal fat area was above 100 cm2 and subcutaneous abdominal fat area below the mean + 2SD (15 subjects, 6 male and 9 female) with subjects whose visceral abdominal fat area was also above 100 cm2 but whose subcutaneous abdominal fat area was above the mean + 2SD (20 subjects, 7 male and 13 female). The HOMA-IR of the former subjects group was 8.17+/-6.22 and that of the latter subjects group was 3.37+/-2.07 (p = 0.0486). Subjects with increased subcutaneous abdominal fat area displayed lower HOMA-IR values, demonstrating a protective effect of subcutaneous fat for individuals with visceral fat area above 1002 cm.

Effect of a novel calcium channel blocker on abnormal nocturnal blood pressure in hypertensive patients.

The authors examined the effect of cilnidipine, a unique L/N-type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N-Channel Blocker Cilnidipine (ACHIEVE-ONE), a large-scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24-hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12-week treatment with cilnidipine significantly reduced 24-hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were -17.9 mm Hg from 154.6 mm Hg in risers and -11.9 mm Hg from 142.1 mm Hg, -6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but -7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients (-0.2%±9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients.

Drug-induced Liver Injury Caused by Ipragliflozin Administration with Causality Established by a Positive Lymphocyte Transformation Test (LTT) and the Roussel Uclaf Causality Assessment Method (RUCAM): A Case Report

ABSTRACT A 75-year old male patient had been regularly visiting our hospital for the management of his type 2 diabetes mellitus since he was diagnosed at age 64 years. When he developed hypoglycemic episodes with sulfonylurea, ipragliflozin (50 mg/day) was started to replace the sulfonylurea therapy. However, 49 days after starting ipragliflozin, his AST increased from 13 to 622 U/L, ALT increased from 9 to 266 U/L, ALP increased from 239 to 752 U/L, and γ-GTP increased from 19 to 176 U/L. ZTT was 3.5 U, TTT was 0.4 U, and total bilirubin was 0.7 mg/dL. IgM hepatitis A antibody, hepatitis B antigen, hepatitis C virus antibody, IgM CMV antibody, and IgM EB VCA antibody were negative, whereas a lymphocyte transformation test for ipragliflozin was positive. Abdominal CT scan showed mild fatty liver but no sign of nodular lesions. Following admission to our hospital, he received liver supportive therapy with the discontinuation of ipragliflozin therapy. He was discharged from the hospital 18 days later with AST and ALT levels reduced to 20 U/L and 13 U/L, respectively. Based on the clinical presentation of this patient, it is highly important to monitor liver function along with other possible clinical complications (e.g., dehydration, ketosis, and urinary tract infection) associated with SGLT2 inhibitor therapy.