Therapeutic Effects of a Sodium Glucose Cotransporter 2 Inhibitor in Diabetic Patients with Chronic Kidney Disease

Multiple large-scale clinical trials have indicated that sodium glucose cotransporter 2（SGLT2）inhibitors reduce the incidence of cardiovascular events, deterioration of renal function and mortality. However, the therapeutic effects of SGLT2 inhibitors are supposed to be limited in patients with reduced renal function considering the mechanism of their action. In this study, a SGLT2 inhibitor, ipragliflozin was given to 30 type 2 diabetic patients with nephropathy whose estimated glomerular filtration rate（eGFR）was not lower than 30 mL/min/1.73 m2. After 12 to 16 weeks, hemoglobin A1c decreased by 0.6％（p＜0.001）, body weight was reduced by 1.8 kg（p＜0.01）and blood pressure was lowered by －10/－6 mmHg（p＜0.001/p ＜0.001）. This was accompanied by reductions in serum uric acid（－0.7 mg/dL, p＜0.001）, triglycerides （－25 mg/dL, p＝0.028）and g-glutamyl transferase（－8 U/L, p＝0.001）. On the other hand, plasma B-type natriuretic peptide also decreased by 12％（p＝0.020）and urinary albumin excretion was reduced by 23％ （p＝0.018）although the eGFR was not significantly changed. It is concluded that ipragliflozin is effective in lowering blood glucose even in patients with diabetic kidney disease and is beneficial in improving theaccompanying obesity and hypertension. In addition, ipragliflozin is thought to have favorable influences on the metabolisms of uric acid and lipids. These properties of ipragliflozin is expected to bring about protective effects against the progression of nephropathy and the development of cardiovascular disease resulting in the improvement of prognosis in diabetic patients with mild to moderate chronic kidney disease

Progression of Renal Dysfunction in Patients with Cardiovascular Disease

It has been established that patients with chronic kidney disease (CKD) suffer from frequent cardiovascular events. On the other hand, recent studies suggest that renal damage tends to worsen in patients with cardiovascular diseases (CVD). Although the mechanisms for the cardiorenal association are unclear, the presence of arteriosclerotic risk factors common to both CVD and CKD is important. In arteriosclerosis, vascular derangement progresses not only in the heart but also in the kidney. In addition, heart failure, cardiac catheterization and hesitation of medical treatments due to renal dysfunction may explain the progression of renal damage. Therefore, the goal of treatments is a total control of arteriosclerotic risk factors. Medication should be selected among agents with protective effects on both heart and kidney. It is important to always consider the presence of CKD for the treatment of the cardiovascular disease and strictly control the risk factors

Comparisons of Increasing Calcium Channel Blocker dose and Adding Thiazide Diuretic in Hypertensive Patients Given Medium-dose Angiotensin II Receptor Blocker and Amlodipine

We compared the efficacies of 2 prescriptions, one of a medium-dose angiotensin II receptor blocker （ARB） with high-dose of calcium channel blocker （CCB） and another of medium-dose of ARB with medium-dose of CCB and a thiazide diuretic in 22 hypertensive patients who did not achieve the target blood pressure level with the combination of medium-dose of ARB and medium-dose of CCB. A randomized crossover study was performed giving a fixed combination of 100 mg irbesartan with 10 mg amlodipine or a fixed-dose combination of 100 mg irbesartan with 5 mg amlodipine added by 1 mg trichlormethiazide for 12-16 weeks each. The blood pressure measured in hospital was comparable between the high-dose CCB period （130/77 mmHg） and the thiazide period （130/79 mmHg）. The morning and the evening blood pressures measured at home were also comparable in the high-dose of CCB and the thiazide periods, while the evening heart rate was higher in the thiazide period than in the high-dose CCB period. As for the laboratory data, hemoglobin A1c （＋0.2％, p＝0.013）, serum nonHDL cholesterol （＋12 mg/dL, p＝0.047） and serum uric acid （＋0.8 mg/dL, p＝0.001） were significantly higher in the thiazide period than in the high-dose CCB period. On the other hand, urinary albumin excretion （－28.8％，p＝0.026） and estimated glomerular filtration rate （－5.8％，p＝0.012） were significantly lower in the thiazide period than in the high-dose CCB period. In the combination drug therapy of hypertension, the increase of CCB dose is preferable in preserving renal function and in avoiding adverse effects on metabolisms of glucose, lipid and uric acid

Comparison between High-dose Telmisartan and Fixed dose Combination of Telmisartan and Hydrochlorothiazide in Patients with Hypertension

We compared treatment with a high-dose angiotensin II receptor blocker(ARB)and combination of ARB with a thiazide diuretic in 17 patients with hypertension. A randomized crossover study was performed giving 80 mg telmisartan or fixed-dose combination of 40 mg telmisartan and 12.5 mg hydrochlorothiazide for 16 weeks each. Although the clinic blood pressure was comparable between the high-dose ARB period(134/81 mmHg)and the combination period(134/82 mmHg), the morning home blood pressure was lower in the combination period than in the high-dose ARB period(138/82 vs. 151/88 mmHg, p=0.026/0.013). No significant difference was observed in urinary albumin excretion, but estimated glomerular filtration rate was lower in the combination than in the high-dose ARB period(58.9 vs. 62.1 mL/min/1.73 m^2, p=0.039). Serum uric acid was higher in the combination than in the high-dose ARB period(6.7 vs. 5.9 mg/dL p=0.022). The indices of glucose metabolism, serum lipids, oxidative stress, inflammation and adipocytokine did not significantly differ between the two periods. There was no significant difference in the measurement of endothelium-dependent vasodilation between the two periods. It is suggested that the addition of thiazide diuretic to medium-dose ARB is more effective in lengthening the hypotensive effect than high-dose ARB, however, care should be taken for the elevation of serum uric acid and the decrease in renal function

Protective Effects of Olmesartan and Azelnidipine against Cardiovascular Organ Injuries in Spontaneously Hypertensive Rats

In the treatment of hypertension, care should be taken for preventing of hypertensive organ injuries as well as lowering blood pressure to the adequate level in order to reduce the risk of cardiovascular diseases. The purpose of this study is to examine the effects of angiotensin II receptor blockers (ARB), calcium channel blockers (CCB) and their combination on the development of cardiovascular organ injuries in spontaneously hypertensive rats (SHR). Four groups of male 8-week-old SHR (n=9 each) were given vehicle(control), 10 mg/kg azelnidipine (AZL), 10 mg/kg olmesartan (OLM, n=9), or the combination of AZL and OLM(5 mg/kg each)for 12 weeks, and their effects on cardiovascular organ injuries were evaluated. Tail-cuff blood at 12 weeks was similarly lowered by AML, OLM and the combination therapy(148, 143 and 143 mmHg, respectively)as compared with the control SHR (198 mmHg). Pulse rate was significantly less in the AZL group but not in the OLM group or the combination therapy group than in the untreated control group (-27, -12, +6 bpm, respectively). The cardiac ventricular weight (AZL -12%, OLM -15%, combination -18% vs. control) and aortic thickness (AZL -17%, OLM -16%, combination -19% vs. control) were reduced by similar extents in the three groups given antihypertensive treatments. Regarding the myocardial fibrosis, left ventricular hydroxyproline content was reduced in the OLM and the combination groups but the change was not significant in the AZL group (AZL -14%,OLM -30%, combination -27% vs. control). In the echocardiographic evaluation of cardiac function, the index of left ventricular diastolic function is significantly improved in the OLM and the combination groups but not in the AZL group, while the index of systolic function was not different between the four groups. It is suggested that the antihypertensive therapy including ARB is superior to the monotherapy by CCB in preventing the myocardial fibrosis and preserving the left ventricular diastolic function

神経筋疾患専門病院におけるPEG 施行患者の予後予測栄養因子の検討

This study aimed to extract prognostic nutritional factors in patients undergoing percutaneous endoscopic gastrostomy in a hospital specializing in neuromuscular diseases. One-year survival analysis was conducted using the Cox proportional-hazards model analysis and the log-rank test. The results of the 1-year survival analysis revealed that patients with a preoperative tracheotomy, patients who required nutritional support through the digestive tract and high levels of serum albumin（Alb） and hemoglobin（Hb） were more likely to survival. Analysis of long-term survival using the log-rank test identified Alb more than 3.5g/dl, PNI more than 40, Hb more than 12g/dl and requiring a preoperative tracheotomy or nutritional support through the digestive tract as significant variables. According to the Cox proportionalhazards model, the presence or absence of tracheotomy and Alb were identified as preoperative prognostic nutritional factors

Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing