Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes.

AIMS/INTRODUCTION: This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state. MATERIALS AND METHODS: We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2 , F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively. CONCLUSIONS: Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination.

Dipeptidyl peptidase-4 inhibitor-related renal disease.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital. METHODS: Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B). RESULTS: Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of -11.2 (-17.6, -9.2) mL/min/1.73 m2 after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m2 and a yearly median (IQR) eGFR slope of -1.6 (-3.1, -0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B. CONCLUSION: DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function.

Continuous low serum levels of advanced glycation end products and low risk of cardiovascular disease in patients with poorly controlled type 2 diabetes.

BACKGROUND: Type 2 diabetes is associated with an increased risk of developing cardiovascular events. Previous studies have reported that advanced glycation end products (AGEs) were related to cardiovascular events in type 2 diabetes. However, data on associations between long-term AGEs and cardiovascular events in type 2 diabetes are lacking. This study aimed to determine whether a long-time shift in the levels of serum AGEs is associated with cardiovascular events in patients with poorly controlled type 2 diabetes. METHODS: Two-time serum methyl-glyoxal-hydroimidazoline (MG-H1) levels were measured in 138 patients with type 2 diabetes whose mean glycated hemoglobin level was 10.1%. We categorized patients whose serum MG-H1 levels were < 2.8 µg/mL at both times as the continuous low MG-H1 group. The primary endpoints of this study were combined cardiovascular events, which were defined as heart disease, peripheral arterial disease, stroke, and all-cause death. Hazard ratios (HRs) for combined cardiovascular events with 95% confidence intervals (CIs) were calculated using the Cox proportional hazard models to compare the outcomes between the continuous low MG-H1 group and others. RESULTS: The continuous low MG-H1 group was associated with a significantly lower risk than others in combined cardiovascular events after adjusting for possible confounders (HR: 0.50; 95% CI, 0.28-0.87; P = 0.02). Furthermore, the same relationship was observed in patients without a history of cardiovascular events. CONCLUSIONS: Continuous low serum MG-H1 levels are associated with a low frequency of diabetes-related complications in patients with poorly controlled type 2 diabetes.

Japanese Type 1 Diabetes Database Study (TIDE-J): rationale and study design.

Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients.

Left Hemiplegia Possibly Due to Glucose Reperfusion Injury after Recovery of Severe Hypoglycemia in a Woman with Type 2 Diabetes Mellitus.

A 79-year-old woman with type 2 diabetes receiving insulin was rushed to our hospital due to severe hypoglycemia. Glucose was administered, and the consciousness disturbance was promptly improved. A few hours later, conjugate deviation of the eyes to the right and left hemiplegia occurred at a normal glucose level. Cerebral magnetic resonance imaging (MRI) showed hyperintensities of the right posterior limb of the internal capsule and the medial thalamus on diffusion-weighted imaging sequences. However, the changes observed using MRI disappeared completely on the third day, and her symptoms subsequently improved. This may have been a case of glucose reperfusion injury.

Four-Year Screening Interval and Vision-Threatening Retinopathy in Type 2 Diabetes Patients With Good Glycemic Control.

OBJECTIVE: To assess whether vision-threatening retinopathy developed after 4 years in patients with type 2 diabetes with good glycemic control during follow-up. PATIENTS AND METHODS: Using data from the Action to Control Cardiovascular Risk in Diabetes and Action to Control Cardiovascular Risk in Diabetes Follow-on studies (conducted from January 1, 2001, to October 14, 2014), we investigated the incidence of vision-threatening retinopathy after 4 years in patients with type 2 diabetes with good or poor glycemic control. Patients with proliferative diabetic retinopathy at baseline were excluded. Vision-threatening retinopathy was defined as severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, laser photocoagulation, or vitrectomy. Good and poor glycemic control was defined as mean glycated hemoglobin level less than 7% and 7% or greater during follow-up, respectively. RESULTS: This study included 2285 patients. Among patients with no retinopathy at baseline, the 4-year incidence of vision-threatening retinopathy was 0% (0 of 386) and 0.8% (6 of 721) in those with good and poor glycemic control, respectively (P=.54). Similarly, severe retinopathy was not observed at 8 years in patients who did not have retinopathy at 4 years. Among patients with mild to moderate nonproliferative diabetic retinopathy at baseline, the 4-year incidence of vision-threatening retinopathy was significantly higher in those with poor glycemic control than in those with good glycemic control (9.7% [77 of 790] vs 4.4% [13 of 297]; P=.004). Additionally, the remission rate of diabetic retinopathy was low in patients with a long duration of diabetes. Four-year incidences of vision-threatening retinopathy were higher in patients with retinopathy at baseline who had poorer glycemic control and longer durations of diabetes. CONCLUSION: It may be safe to extend screening intervals for diabetic retinopathy to 4 years or longer in patients with type 2 diabetes with no retinopathy.

Urinary albumin-to-creatinine ratio within normal range and all-cause or cardiovascular mortality among U.S. adults enrolled in the NHANES during 1999-2015.

PURPOSE: Urinary albumin-to-creatinine ratio (UACR) is one of the important diagnostic markers of chronic kidney disease. We aimed to investigate the association between UACR within normal range and cardiovascular or all-cause mortality. METHODS: This study included a nationally representative sample of 31,413 U.S. adults aged greater than or equal to 20 years enrolled in the National Health and Nutrition Examination Survey 1999-2014. Mortality was ascertained through 2015. We used multivariable Cox proportional models to investigate the association of UACR with all-cause and cardiovascular mortality. Stratum-specific analyses were conducted by age, sex, race, education status, and comorbidities (e.g., hypertension, diabetes, cardiovascular disease, and chronic kidney disease). RESULTS: Over a median follow-up of 7.6 years, 2854 all-cause deaths and 454 cardiovascular deaths were identified. Higher UACR (per 10 mg/g) was associated with increased risk of all-cause mortality (adjusted hazard ratio = 1.29, 95% confidence interval = 1.22-1.37) and cardiovascular mortality (adjusted hazard ratio = 1.34, 95% confidence interval = 1.17-1.55). The association was larger among women for both all-cause and cardiovascular mortality, and among younger and highly educated participants only for all-cause mortality. The association did not differ by the presence of comorbidities. CONCLUSIONS: Elevated UACR within normal range was associated with higher all-cause and cardiovascular mortality risk across almost all subgroups including participants without comorbidities. Our findings suggest the importance of the early detection of albuminuria and careful evaluation of UACR even within normal range to reduce mortality risk.

Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension.

Background Resistant hypertension is a salt-retaining condition possibly attributable to inappropriate aldosterone secretion. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin-angiotensin system blocker (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53-0.91; P=0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83-1.20; P=0.97). There was a significant interaction between spironolactone use and resistant hypertension (P=0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only. Conclusions Spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.

Thiazide Use and Decreased Risk of Heart Failure in Nondiabetic Patients Receiving Intensive Blood Pressure Treatment.

The SPRINT (Systolic Blood Pressure Intervention Trial) study reported that intensive blood pressure (BP) treatment with a systolic BP target of <120 mm Hg decreased the risks of cardiovascular events. However, it remains unknown whether specific medications can further improve cardiovascular outcome in patients receiving intensive BP treatment. This study examined whether thiazide use improves cardiovascular outcome in patients receiving intensive BP treatment. We used data of nondiabetic patients receiving intensive BP treatment in the SPRINT study. The primary outcome was a composite end point of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. We analyzed hazard ratios for outcomes with 95% CIs in patients taking thiazides compared with those not taking thiazides using Cox proportional hazard models. This study included 2847 patients and the mean follow-up period was 3.3 years. The risk of primary outcome events was significantly lower in patients taking thiazides than in those not taking thiazides in both entire and propensity score-matched cohorts. Particularly, heart failure risk was significantly lower in those taking thiazides. These associations were also observed in various subgroups. In addition, thiazide use was associated with decreased risk of all-cause mortality. Hypokalemia occurred more frequently in patients taking thiazides than in those not taking thiazides. Thiazide use decreased risk of cardiovascular events, particularly heart failure, in nondiabetic high-risk patients receiving intensive BP treatment.

Thiazide Use and Cardiovascular Events in Type 2 Diabetic Patients With Well-Controlled Blood Pressure.

Evidence regarding the efficacy and safety of thiazides in patients with well-controlled and relatively low blood pressure (BP) is lacking. This study aimed to assess whether thiazide use is effective and safe in type 2 diabetic patients with well-controlled BP and whether intensive BP control leads to decreased risk of cardiovascular events depending on thiazide use. We performed an observational cohort study using data from the ACCORD study (Action to Control Cardiovascular Risk in Diabetes). The primary outcome was major adverse cardiovascular events (MACE), which was a composite end point including cardiovascular death, myocardial infarction, and stroke. Hazard ratios for primary and secondary outcomes with 95% CIs were calculated using Cox proportional hazards models. We included 10 011 type 2 diabetic patients. The overall mean follow-up period was 7.7 years, and 1776 patients experienced MACE. Mean systolic BP at baseline in patients taking and not taking thiazides was 137.2 and 135.7 mm Hg, respectively. Thiazide use was associated with increased risk of MACE, particularly stroke (hazard ratio, 1.49 [95% CI, 1.18-1.88]). In addition, thiazide use was significantly associated with higher risks of MACE and stroke in patients receiving intensive BP control but not in those receiving standard BP control. Similar associations were observed in analyses using propensity score matching. Intensive BP control reduced the risks of MACE and stroke in patients not taking thiazides but not in patients taking thiazides. Thiazide use may be harmful in type 2 diabetic patients with relatively low BP.

Effects of storage temperature, storage time, and Cary-Blair transport medium on the stability of the gut microbiota.

How long fecal samples can withstand a period of refrigeration or room temperature, and the appropriate preservative, are largely unknown. Cary-Blair transport medium has been used for many years because it is inexpensive and prevents bacterial overgrowth. However, its effectiveness for metagenomic analyses has never been tested. We found that the microbial compositions using a 16S rRNA sequence of samples left at 4°C for 3 or 7 days or at 25°C for 1, 3, or 7 days differed significantly from samples stored at -80°C in no-preservative method. Whereas samples stored in Cary-Blair medium remained unchanged for longer periods. The relative abundances of phylum Bacteroidetes and Actinobacteria, changed significantly at 25°C, whereas Cary-Blair medium inhibited the reduction in Bacteroidetes and the increase in Actinobacteria. The bacterial survival counts were significantly lower in the RNAlater samples than in the Cary-Blair samples under aerobic and anaerobic culture conditions. In conclusion, storage time and storage temperature significantly affect the gut microbial composition in fecal samples. Given the low cost, inhibitory effect on bacterial changes, and potential utility in bacterial isolation, Cary-Blair medium containers are suitable for large-scale or hospital-based microbiome studies, especially if direct freezing at -80°C is unavailable.

Use of Nitrates and Risk of Cardiovascular Events in Patients With Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: To assess the association of nitrate use with cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF). PATIENTS AND METHODS: Patient data were collected from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial, which had been conducted at 233 sites in 6 countries from August 10, 2006, through January 31, 2012. The primary outcome was the occurrence of a major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) or heart failure hospitalization. The association between nitrate use and cardiovascular risk was evaluated using Cox proportional hazards analysis. In addition, we verified the results using propensity score-matched patients. RESULTS: A total of 3417 patients with HFpEF were evaluated over a mean follow-up of 3.1 years, and 778 experienced a primary outcome event. The risk of primary outcome events was significantly higher in patients taking nitrates than in those not taking nitrates (hazard ratio [HR], 1.21; 95% CI, 1.01-1.46, P=.04). The risk of major adverse cardiovascular events was significantly higher in patients taking nitrates than in those not taking nitrates (HR, 1.32; 95% CI, 1.05-1.66, P=.01). Furthermore, the risk of hospitalization for heart failure was higher in patients taking nitrates (HR, 1.25; 95% CI, 0.99-1.60, P=.06), with propensity score-matched analyses revealing similar findings. In addition, a similar association was observed in various subgroups. CONCLUSION: This study reported that nitrate use in patients with HFpEF was associated with a significantly increased risk of cardiovascular events.

Poorly controlled type 2 diabetes with no progression of diabetes-related complications and low levels of advanced glycation end products: A Case report.

RATIONALE: Previous studies have suggested that increased levels of advanced glycation end products (AGEs) and soluble receptor for AGE (sRAGE) are associated with diabetes-related complications. However, there is little evidence on the association between long-term levels of AGEs and sRAGE and progression of diabetes-related complications. PATIENT CONCERNS: A 64-year-old man had poorly controlled type 2 diabetes, obesity, smoking, hypertension, and dyslipidemia. He had many risk factors for diabetes-related complications. DIAGNOSIS: Despite poor glycemic control over 15 years, the patient did not exhibit diabetes-related complications. INTERVENTIONS: We examined serum AGEs (CEL and MG-H1) and sRAGE levels in this patient over the past 10 years. OUTCOMES: The patient maintained low serum AGEs and sRAGE levels. LESSONS: AGEs and sRAGE levels may be associated with long-term development of diabetes-related complications.

No beneficial effects of aspirin on secondary cardiovascular prevention in patients with type 2 diabetes using non-steroidal anti-inflammatory drugs.

There is little evidence on whether non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin interact in secondary cardiovascular prevention in type 2 diabetic patients. This is an observational study using data from the Action to Control Cardiovascular Risk in Diabetes and Follow-on studies. Hazard ratios (HRs) for mortality with 95% confidence intervals (95% CIs) were calculated using Cox proportional hazard models to compare time to death in patients using and not using aspirin who were simultaneously using or not using NSAIDs. A total of 3600 type 2 diabetic patients with cardiovascular disease were included. During a mean follow-up period of 8.8 years, 948 patients died. After adjustments, the risk of all-cause mortality in patients not using NSAIDs was significantly lower in those using aspirin than in those not using aspirin (HR, 0.81; 95% CI, 0.70-0.93; P = 0.004). The risk in patients using NSAIDs did not differ significantly between the two groups. There was a significant interaction between aspirin use and NSAIDs use. In type 2 diabetic patients with cardiovascular disease, aspirin use was not beneficial for those using NSAIDs.

Optimal cardiac strategy based on the history of myocardial infarction in type 2 diabetic patients with coronary artery disease.

The aim of this study was to evaluate the association between the cardiac treatment strategy and cardiac event risk in type 2 diabetic patients with coronary artery disease (CAD) based on the history of myocardial infarction. Using Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial data, a Cox proportional hazard model was used for calculating hazard ratios (HRs) for major cardiac events in patients receiving early revascularization or intensive medical therapy. Patients without (n = 1,557) and with myocardial infarction (n = 736) were separately analyzed. In patients without myocardial infarction, risk of major cardiac events was similar for percutaneous coronary intervention and intensive medical therapy groups, whereas it was significantly lower in the coronary artery bypass grafting group than in the intensive medical therapy group (HR: 0.48, 95% confidence interval [95%CI]: 0.30-0.76, P = 0.002). Conversely, in patients with myocardial infarction, risk of major cardiac events was significantly higher in the early revascularization group than in the intensive medical therapy group (HR: 1.47, 95%CI: 1.03-2.11, P = 0.03). In type 2 diabetic patients with CAD, benefits of early revascularization were observed only in those without previous myocardial infarction. For patients with previous myocardial infarction, intensive medical therapy exerted superior benefits.

Effects of bowel preparation on the human gut microbiome and metabolome.

Large bowel preparation may cause a substantial change in the gut microbiota and metabolites. Here, we included a bowel prep group and a no-procedure control group and evaluated the effects of bowel prep on the stability of the gut microbiome and metabolome as well as on recovery. Gut microbiota and metabolome compositions were analyzed by 16S rRNA sequencing and capillary electrophoresis time-of-flight mass spectrometry, respectively. Analysis of coefficients at the genus and species level and weighted UniFrac distance showed that, compared with controls, microbiota composition was significantly reduced immediately after the prep but not at 14 days after it. For the gut metabolome profiles, correlation coefficients between before and immediately after the prep were significantly lower than those between before and 14 days after prep and were not significantly different compared with those for between-subject differences. Thirty-two metabolites were significantly changed before and immediately after the prep, but these metabolites recovered within 14 days. In conclusion, bowel preparation has a profound effect on the gut microbiome and metabolome, but the overall composition recovers to baseline within 14 days. To properly conduct studies of the human gut microbiome and metabolome, fecal sampling should be avoided immediately after bowel prep.

Strategies for glycemic control in nonobese and obese type 2 diabetic patients with coronary artery disease.

BACKGROUND: This study aimed to assess strategies of insulin-providing (IP) or insulin-sensitizing (IS) therapy for glycemic control in nonobese diabetic patients with coronary artery disease (CAD) with possibly higher cardiovascular risk and lower insulin secretion than obese diabetic patients with CAD. METHODS: We used data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial to calculate hazard ratio (HR) with 95% confidence interval (95%CI) for outcome events in patients with type 2 diabetes and CAD using Cox proportional hazard models. The comparison between the IP and IS groups was performed using the randomized design of the BARI 2D trial separately for nonobese (n = 1021) and obese (n = 1319) patients. The primary outcome was a composite endpoint including all-cause death, myocardial infarction, and stroke. RESULTS: During the follow-up, 231 nonobese and 295 obese patients had one confirmed primary outcome event. In nonobese patients, the risk of primary outcome events was significantly higher in the IP group than the IS group (HR: 1.30, 95%CI: 1.00-1.68, P = 0.04), whereas that in obese patients did not differ significantly between the two groups. Moreover, in nonobese patients, the risk of primary outcome events in those without abdominal obesity was significantly higher in the IP group than that in the IS group (HR: 1.51, 95%CI: 1.05-2.19, P = 0.02). There were no significant interactions between the strategy for glycemic control and various subgroups of nonobese patients. CONCLUSIONS: In nonobese patients with type 2 diabetes and CAD, the IS treatment strategy may be more beneficial than the IP treatment strategy.

Correction: Low-Carbohydrate Diets and All-Cause Mortality: A Systematic Review and Meta-Analysis of Observational Studies.

[This corrects the article DOI: 10.1371/journal.pone.0055030.].

Thrombotic/Thrombolytic Balance as a Cardiac Treatment Determinant in Patients With Diabetes Mellitus and Coronary Artery Disease.

Background This study aimed to assess whether the plasminogen activator inhibitor-1/tissue plasminogen activator ( PAI -1/ tPA ) ratio as a prothrombotic state is useful for optimizing cardiac treatment strategy. Methods and Results Using BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial data, we used a Cox proportional hazard model to calculate hazard ratios with 95% CI s for cardiac events in patients receiving early revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or medical therapy, separately in patients with low (n=1276) and high (n=894) PAI -1/ tPA ratios. The primary outcome was major cardiac events, which was a composite end point including cardiac death and nonfatal myocardial infarction. The mean± SD follow-up period was 4.1±1.7 years. The risk of major cardiac events in patients with high PAI -1/ tPA ratio was significantly higher when receiving percutaneous coronary intervention (hazard ratio, 1.84; 95% CI , 1.16-2.93; P=0.01) than when receiving medical therapy, whereas that in patients with low PAI -1/ tPA ratio did not differ significantly between the groups (hazard ratio, 0.95; 95% CI , 0.66-1.36; P=0.77); the interaction between the cardiac treatment strategy and PAI -1/ tPA ratio was significant ( P=0.02). However, regardless of the PAI -1/ tPA ratio, major cardiac event risk seemed to be lower in patients receiving coronary artery bypass grafting than in those receiving medical therapy. Conclusions In patients with type 2 diabetes mellitus and coronary artery disease, this study demonstrated that those with high PAI -1/ tPA ratio were at higher risks of major cardiac events when treated with percutaneous coronary intervention than when treated with intensive medical therapy.

Intensive Blood Pressure Treatment for Resistant Hypertension.

Evidence about the target blood pressure (BP) in patients with resistant hypertension is limited. The present study aimed to assess the efficacy of intensive BP treatment (systolic BP target, <120 mm Hg) versus standard BP treatment (systolic BP target, <140 mm Hg) in patients with resistant hypertension. This is a secondary analysis using data from SPRINT (Systolic Blood Pressure Intervention Trial). This study included 1397 patients with resistant hypertension and 7698 without resistant hypertension. Using the Cox proportional hazards model, we compared time to first occurrence of a major adverse cardiovascular event (cardiovascular death, myocardial infarction, and stroke) between the intensive and standard BP treatment groups. Mean follow-up was 3.1 years; major adverse cardiovascular events was confirmed in 381 patients. Risk of major adverse cardiovascular events was significantly lower in the intensive treatment group than in the standard treatment group (hazard ratio, 0.62; 95% CI, 0.40-0.96; P=0.03). Risks of all-cause and cardiovascular death in patients with resistant hypertension were also significantly lower in the intensive treatment group than in the standard treatment group (hazard ratio for all-cause death: 0.60; 95% CI, 0.38-0.97; P=0.03; hazard ratio for cardiovascular death: 0.34; 95% CI, 0.15-0.81; P=0.01). Similar associations were observed in various subgroups. Intensive BP treatment was significantly associated with a decreased risk of major adverse cardiovascular events in patients with resistant hypertension.