Metformin-associated Lactic Acidosis with Hypoglycemia during the COVID-19 Pandemic.

Metformin-associated lactic acidosis (MALA) is an extremely rare but life-threatening adverse effect of metformin treatment. The lifestyle changes associated with the coronavirus disease 2019 (COVID-19) pandemic may increase the potential risk of MALA development in patients with diabetes. We herein report a 64-year-old Japanese man taking a small dose of metformin who presented with MALA accompanied by hypoglycemia secondary to increased alcohol consumption triggered by lifestyle changes during the pandemic. Physicians should prescribe metformin judiciously to prevent MALA development and pay close attention to lifestyle changes in patients at risk for MALA during the COVID-19 pandemic.

Medium-term Influence of the Coronavirus Disease 2019 Pandemic on Patients with Diabetes: A Single-center Cross-sectional Study.

Objective This study evaluated the lifestyle changes in patients with diabetes and their independent associations with glycemic and body weight control. In addition, the correlation between changes in mental health and lifestyles was evaluated. Methods This single-center cross-sectional study included 340 patients with diabetes who periodically visited our department. Changes in dietary habits, activities of daily living, and mental health before and during approximately six months after the onset of the coronavirus disease 2019 (COVID-19) pandemic were evaluated using a questionnaire, including the International Physical Activity Questionnaire-Short Form. Results Approximately 20%, 30%, and over 50% of patients had worsened dietary habits, decreased activities of daily living, and deteriorated mental health, respectively. A multiple regression analysis showed that irregular meal timing was significantly associated with change in HbA1c (ß=0.328, p=0.001), and decreased walking time was significantly associated with changes in body weight (ß=-0.245, p=0.025). The change in fear and anxiety was positively associated with changes in meal timing regularity (r=0.129, p=0.019) and carbohydrate consumption (r=0.127, p=0.021). Subsequently, the change in depressed mood was positively associated with changes in carbohydrate (r=0.142, p=0.010) and alcohol (r=0.161, p=0.037) consumption, and the change in psychological stress was positively associated with changes in carbohydrates (r=0.183, p=0.001) and snack (r=0.151, p=0.008) consumption as well as sedentary time (r=0.158, p=0.004). Conclusion The COVID-19 pandemic has had a considerable medium-term impact on the lifestyle and mental health of patients with diabetes. Lifestyle changes were associated with glycemic and body weight control, and mental health changes were associated with lifestyle changes. These findings may provide important information on diabetes care during the pandemic.

A low serum IGF-1 is correlated with sarcopenia in subjects with type 1 diabetes mellitus: Findings from a post-hoc analysis of the iDIAMOND study.

AIM: Our previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM. METHODS: This cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study. RESULTS: The z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p < 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM. CONCLUSIONS: A low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

Clinical Utility of Carotid Ultrasonography in the Prediction of Cardiovascular Events in Patients with Diabetes: A Combined Analysis of Data Obtained in Five Longitudinal Studies.

AIM: It remains unclear whether measures used in carotid ultrasonography such as the intima-media thickness (IMT) and ultrasonic tissue characterization of the carotid using the gray-scale median (GSM) can add prognostic information beyond the conventional cardiovascular risk markers in patients with diabetes. METHODS: This study employed a combined analysis of data obtained in five longitudinal studies including a total of 3263 patients with diabetes but without apparent cardiovascular disease (CVD) at baseline. The associations between carotid ultrasonography measures and the first occurrence of CVD (488 cases), which were defined as cardiovascular death, coronary artery diseases, stroke, or peripheral artery disease, were analyzed. RESULTS: Common carotid artery (CCA)-mean-IMT, CCA-max-IMT, Max-IMT, plaque-GSM, and the presence of low-GSM echolucent plaques at baseline were prognostic factors for CVD even after adjustment for conventional risk factors. Time-dependent receiver-operating-characteristic (ROC) curve analysis indicated that the use of CCA-mean-IMT, CCA-max-IMT, and Max-IMT in addition to the conventional risk factors improved significantly the prediction of occurrence of CVD. Increments in the CCA-mean-IMT (hazard ratio [HR] 2.37 for every 0.1-mm/year increment [95% confidence interval [CI]: 1.63-3.47], p＜0.001), Max-IMT (HR 1.51 for every 0.1-mm/year increment [95% CI: 1.07-2.14], p=0.020), and Mean-GSM (HR 0.22 for every 10-U/year increment [95% CI: 0.06-0.76], p=0.016) during the observation period were also prognostic factors for CVD even after adjusting for the baseline value of the respective measure. CONCLUSIONS: Addition of carotid ultrasonography measures to conventional risk factors significantly improved the stratification of patients by cardiovascular risk. Changes over time in carotid ultrasonography measures may be used as therapeutic outcome measures.

Effect of sitagliptin on tissue characteristics of the carotid wall in patients with type 2 diabetes: a post hoc sub-analysis of the sitagliptin preventive study of intima-media thickness evaluation (SPIKE).

BACKGROUND: Ultrasonic gray-scale median (GSM) of the carotid wall reflects its composition and low-GSM carotid plaque is considered to be vulnerable. This study aimed to evaluate the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes mellitus (T2DM). METHODS: This is a post hoc sub-analysis using data obtained from the SPIKE trial, a randomized controlled trial that demonstrated the beneficial effect of sitagliptin on the progression of carotid intima-media thickness in patients with T2DM. A total of 274 T2DM patients with no past history of apparent cardiovascular disease (137 in the sitagliptin treatment group and 137 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA during the 104-week treatment period. RESULTS: The mean GSM-CCA significantly increased in the sitagliptin treatment group (adjusted ΔGSM = 2.40 ± 1.19 [mean ± SE], p = 0.044) but not in the conventional treatment group (adjusted ΔGSM = 1.32 ± 1.19, p = 0.27). However, there was no significant difference in changes in mean GSM-CCA between the treatment groups. CONCLUSIONS: A post hoc sub-analysis suggests that the tissue characteristics of the carotid arterial wall were improved in the sitagliptin treatment group during the 104-week treatment period, but not in the conventional treatment group. However, there was no between-group difference in the changes of GSM values between the two treatment groups. Prespecified studies with large sample sizes would be necessary to confirm our findings. Trial registration UMIN000028664, Registered 15 August 2017 ("retrospectively registered").

Evaluation of the Effect of Alogliptin on Tissue Characteristics of the Carotid Wall: Subanalysis of the SPEAD-A Trial.

INTRODUCTION: Ultrasonic tissue characterization of the carotid wall using gray-scale median (GSM) reflects its composition and low-GSM plaque is considered to be unstable. The present study evaluated the effect of alogliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes (T2DM). METHODS: This is a post hoc subanalysis using data obtained from the SPEAD-A trial, a randomized controlled trial that demonstrated the beneficial effect of alogliptin treatment on the progression of carotid intima-media thickness in patients with T2DM with no past history of apparent cardiovascular disease. A total of 322 subjects (161 in the alogliptin treatment group and 161 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA (common carotid artery) during the 104-week observation period. RESULTS: Both alogliptin treatment and conventional treatment significantly increased the mean GSM-CCA (from 60.7 ± 12.3 to 65.9 ± 10.1, p < 0.001 and 58.8 ± 14.4-65.2 ± 12.2, p < 0.001, respectively) and there was no significant difference in changes in mean GSM-CCA between the treatment groups (p = 0.95). Additionally, there were no differences in the changes in the left and right GSM-CCA between the groups. CONCLUSIONS: A post hoc subanalysis revealed an improvement of tissue characteristics in the carotid arterial wall in both the alogliptin treatment group and the conventional treatment group during the 104-week treatment period and that there was no significant difference between the treatment groups. CLINICAL TRIAL REGISTRATION: UMIN000019951.

The usefulness of a cholesterol absorption inhibitor in Japanese type 2 diabetes patients with dyslipidemia.

AIM: Cholesterol absorption has been suggested to be an independent risk factor for cerebral and cardiovascular events. We studied the clinical efficacy of ezetimibe in Japanese patients with type 2 diabetes mellitus complicated by dyslipidemia, in whom increased cholesterol absorption had been reported. SUBJECTS AND METHODS: Ninety-six patients with type 2 diabetes complicated by dyslipidemia received ezetimibe at 10 mg/day for 12 weeks. The lipid profile, a cholesterol synthesis marker (lathosterol), and cholesterol absorption markers (cholestanol, sitosterol, and campesterol) were measured before and after the therapy to evaluate the clinical efficacy of ezetimibe. RESULTS: Serum low-density lipoprotein-cholesterol (LDL-C) levels were positively associated with cholesterol absorption markers but not associated with a cholesterol synthesis marker, suggesting that serum LDL-C levels are more strongly related to cholesterol absorption than synthesis. During the 12-week ezetimibe treatment period, cholesterol absorption markers significantly decreased, and serum lipid profiles, including LDL-C levels, significantly improved. The LDL-C-lowering rate was greater in those patients who had been receiving statin therapy and were newly started on ezetimibe additionally than in the ezetimibe monotherapy group (-31.4% vs. -18.4%; P<0.001). CONCLUSIONS: It is suggested that ezetimibe improves the lipid profile in Japanese type 2 diabetes patients with dyslipidemia through the substantial reduction of cholesterol absorption.

Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients.

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy.

The risk factors associated with ultrasonic tissue characterization of carotid plaque in type 2 diabetic patients.

AIMS: Little is known about the related factors of plaque echogenicity in diabetic subjects. METHODS: This was a single-center, retrospective, study investigating a subgroup of patients of a previously published trial. We enrolled 179 middle-aged and older Japanese type 2 diabetic patients with carotid plaque, and examined the parameters related with echogenicity of carotid plaque evaluated by gray-scale median (GSM). RESULTS: Proportion of males and body mass index (BMI) were significantly higher and HDL-cholesterol was significantly lower in the patients with low GSM (< 48) plaques (n = 89) as compared to those without it (n = 90). A multiple logistic regression analysis with gender, BMI, and HDL-cholesterol as independent variables and the presence of low GSM plaques as an objective variable showed that male (odds ratio (OR) 2.36, 95%CI 1.05-5.31, p = 0.037) and BMI (OR 1.12 [1.01-1.24], p = 0.029) were independently associated with low GSM plaques. Another multiple logistic regression analysis with gender, BMI, and low-HDL-cholesterolemia (HDL-C < 40 mg/dl) as independent variables showed that low-HDL-cholesterolemia (OR 2.30 [1.03-5.13], p = 0.042) and BMI (OR 1.11 [1.00-1.22], p = 0.046) were independently associated with low GSM plaques. CONCLUSIONS: Our study suggests that gender, BMI and low-HDL-cholesterol are important determinants of the content of the vascular wall in diabetic subjects.

The utility of ultrasonic tissue characterization of carotid plaque in the prediction of cardiovascular events in diabetic patients.

OBJECTIVE: The aim of this study was to evaluate whether non-invasive ultrasonic tissue characterization of carotid plaque using gray-scale median (GSM) can be a predictor of future cardiovascular disease (CVD) events in type 2 diabetic patients. METHODS: A total of 287 type 2 diabetic patients with carotid plaque but without CVD were enrolled (male 72%, mean age 65 ± 7 years). We prospectively evaluated the association between GSM, a quantitative parameter of the plaque echogenicity, and CVD. RESULTS: The median follow-up period was 55 months, and there were 34 new CVD events. The risk of CVD event was significantly higher in the patients with echolucent (GSM ≤ 37) plaque (n = 67) as compared to those without (n = 220) (HR = 6.99, 95% CI 3.46-14.14, p < 0.001). Cox proportional hazards regression analysis showed that the presence of echolucent plaque (HR = 4.55, 95% CI 2.10-19.84, p < 0.001) as well as plaque thickness (HR = 1.44, 95% CI 1.01-2.06, p = 0.005) were independent predictors of CVD, even after adjustment for other risk factors. Time-dependent receiver-operating-characteristic curve analysis revealed that the addition of plaque thickness to Framingham risk score (FRS) resulted in significant increase in area under the curve (AUC) [from 0.60 (95% CI; 0.49-0.70) to 0.73 (95% CI; 0.63-0.82), p < 0.05]. Notably, the addition of plaque echogenicity (presence/absence of echolucent plaque) to the FRS and plaque thickness resulted in further and significant increase in AUC [from 0.73 (95% CI; 0.63-0.82) to 0.82 (95% CI; 0.75-0.88), p < 0.05]. CONCLUSION: Ultrasonic tissue characterization of carotid plaque using the GSM can improve the risk prediction of cardiovascular event in asymptomatic type 2 diabetic patients with carotid plaque.

The utility of carotid ultrasonography in identifying severe coronary artery disease in asymptomatic type 2 diabetic patients without history of coronary artery disease.

OBJECTIVE: Although many studies have shown that carotid intima-media thickness (IMT) is associated with coronary artery disease (CAD), it remains inconclusive whether assessment of carotid IMT is useful as a screening test for asymptomatic but severe CAD in diabetic patients. RESEARCH DESIGN AND METHODS: A total of 333 asymptomatic type 2 diabetic patients without history of CAD underwent exercise electrocardiogram or myocardial perfusion scintigraphy for detection of silent myocardial ischemia, and those whose test results were positive were subjected to coronary computed tomography angiography or coronary angiography. The ability of carotid IMT to identify severe CAD corresponding to treatment with revascularization was examined by receiver-operating characteristic (ROC) curve analyses. RESULTS: Among the 333 subjects, 17 were treated with revascularization. A multiple logistic regression analysis showed that maximum IMT was an independent predictor of severe CAD even after adjustment for conventional risk factors. ROC curve analyses revealed that the addition of maximum IMT to conventional risk factors significantly improved the prediction ability for severe CAD (from area under the curve, 0.67 to 0.79; P = 0.039). The greatest sensitivity and specificity were obtained when the cut-off value of maximum IMT was set at 2.45 mm (pretest probability, 5%; posttest probability, 11%; sensitivity, 71%). When we applied age-specific cut-off values, the sensitivity of screening further increased in both the nonelderly (pretest probability, 6%; posttest probability, 10%; sensitivity, 100%) and the elderly subjects (pretest probability, 5%; posttest probability, 15%; sensitivity, 100%). CONCLUSIONS: Our study suggests that carotid maximum IMT is useful for screening asymptomatic type 2 diabetic patients with severe CAD equivalent to revascularization.

Circulating soluble RAGE as a predictive biomarker of cardiovascular event risk in patients with type 2 diabetes.

It is still controversial whether circulating soluble form of receptor for AGE (sRAGE) is associated with atherosclerosis in diabetic patients. In this study, we enrolled 276 Japanese type 2 diabetic subjects without history of cardiovascular disease (CVD), assessed their baseline clinical and biochemical data including serum sRAGE levels, and prospectively evaluated the association between these parameters and CVD events. The median follow-up period was 5.6 years and there were 25 new CVD events. The tertile analysis showed that the risk for CVD events was higher as serum sRAGE levels were increased (p for trend = 0.046). A multivariate Cox proportional hazards regression analysis revealed that serum sRAGE levels were independently associated with CVD (HR per 1SD = 1.59, 95% CI 1.04-2.45, p = 0.034), even after adjusting for conventional coronary risk factors. In summary, elevated sRAGE levels were associated with the increased risk of CVD in Japanese type 2 diabetic subjects.

Plasma pentraxin 3 levels are associated with carotid IMT in type 1 diabetic patients.

AIMS: Pentraxin3 (PTX3), a recently discovered inflammatory mediator, is produced abundantly in various cells in atherosclerotic lesions, and therefore, its plasma level could reflect local inflammation at the site of atherosclerotic lesion. The present study evaluated whether plasma PTX3 levels are associated with subclinical atherosclerosis in young subjects with type 1 diabetes. METHODS: Plasma PTX3 levels, urinary albumin excretion, diabetic retinopathy, and carotid intima-media thickness (IMT) were examined in 78 Japanese type 1 diabetic patients (30 men and 48 women, aged 28.5 ± 5.3 years (±SD), duration of diabetes 19.7 ± 6.5 years). RESULTS: There was statistically significant association between plasma PTX3 levels and Max-IMT (r=0.363, p=0.001). A stepwise multivariate regression analysis including conventional coronary risk factors as independent variables revealed that plasma PTX3 levels (ß=0.389, p<0.001), duration of diabetes (ß=0.256, p=0.035), and serum triglyceride levels (ß=0.371, p<0.001) were independent determinants of Max-IMT. In addition, plasma PTX3 levels was an independent determinant of urinary albumin excretion, an indicator of diabetic nephropathy (ß=0.258, p=0.018). However, there was no significant association between plasma PTX3 levels and diabetic retinopathy. CONCLUSIONS: Increased levels of plasma PTX3 are associated with accelerated atherosclerotic change and increased albuminuria in young patients with type 1 diabetes.

Ultrasonic tissue characterization of carotid plaque improves the prediction of cardiovascular events in diabetic patients: a pilot study.

OBJECTIVE: The aim of this study is to evaluate whether noninvasive ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future cardiovascular events (CVE) in asymptomatic type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We prospectively evaluated the association between Calibrated-IBS value, an ultrasonic marker for tissue characteristics of carotid plaque, and CVE in 85 asymptomatic type 2 diabetic patients with carotid plaque. RESULTS: The median follow-up period was 7.9 years, and there were 20 new CVE. The risk of CVE was significantly higher in the subjects with low Calibrated-IBS values (<-17.1 dB; n = 42) as compared with those with high values (≥-17.1 dB; n = 43) (P = 0.004, log-rank test). Cox proportional hazards regression analysis revealed that both Calibrated-IBS value (hazard ratio [HR] 0.802 [95% CI 0.710-0.906]; P < 0.0001) and plaque thickness (1.938 [1.170-3.213]; P = 0.010) were independently associated with CVE, even after adjustment for the 10-year risk for a general cardiovascular disease estimated by Framingham risk scoring (FRS). Time-dependent receiver operating characteristic curve analysis for CVE at 10 years after the baseline examinations revealed that area under the curve for Calibrated-IBS was 0.76 (0.60-0.90) and substantially higher than those for plaque thickness (0.60 [0.45-0.79]) and FRS (0.60 [0.40-0.78]). These analyses also revealed that the addition of both plaque thickness and Calibrated-IBS value to conventional risk factors significantly improved the event prediction. CONCLUSIONS: Calibrated-IBS value could improve the risk prediction of CVE in asymptomatic type 2 diabetic patients with carotid plaque.

Maximum carotid intima-media thickness improves the prediction ability of coronary artery stenosis in type 2 diabetic patients without history of coronary artery disease.

OBJECTIVE: Carotid intima-media thickness (CIMT), a marker of early atherosclerosis and vascular remodelling, is one of the independent predictors of coronary artery disease (CAD). However, it is unknown whether ultrasonic assessment of carotid atherosclerosis, including CIMT, improves the prediction ability for CAD over and above conventional coronary risk factors in the diabetic patients. METHODS: Ultrasonic scanning of the common carotid artery (CCA), the carotid bulb (Bul), and the internal carotid artery (ICA) was performed. The site with the greatest IMT, including plaque lesions, was sought along the arterial walls and max-IMT (the greatest IMT in the observation-possible areas of the CCA, Bul and ICA) was measured. The association of max-IMT with coronary artery stenosis assessed by coronary computed tomography angiography and the incremental effect of adding max-IMT to the conventional risk factors for predicting coronary artery stenosis were evaluated in 241 asymptomatic type 2 diabetic patients. RESULTS: Multiple logistic regression analyses showed that max-IMT was significantly associated with coronary artery stenosis even after adjustment for conventional risk factors. ROC curve analysis revealed that the AUC significantly increased after addition of max-IMT to conventional coronary risk factors [from 0.64 (95% CI; 0.57-0.71) to 0.74 (95% CI; 0.67-0.80), p = 0.020]. The addition of max-IMT to conventional coronary risk factors increased the AUC in obese patients (from 0.58 to 0.76, p = 0.012) but not in non-obese patients (from 0.68 to 0.72, NS). CONCLUSIONS: In type 2 diabetic patients without apparent cardiovascular disease, the addition of max-IMT to conventional risk factors substantially improves the risk stratification for CAD.

Association of coronary artery stenosis with carotid atherosclerosis in asymptomatic type 2 diabetic patients.

AIMS: Carotid atherosclerosis assessed by ultrasound is an established surrogate marker for systemic atherosclerosis. This study aimed to evaluate the association between coronary artery stenosis assessed by coronary computed tomography angiography (CCTA) and intima-media thickness (IMT) in asymptomatic type 2 diabetic patients. METHODS: In a cross-sectional study, carotid IMT was measured by ultrasound and CCTA in 169 asymptomatic type 2 diabetic patients. RESULTS: Among 169 patients, 77 (46%) had coronary artery stenosis on CCTA. Multivariate logistic regression analysis revealed four independent predictors of coronary artery stenosis: diabetes duration (OR 4.07, 95%CI 2.34-7.12; p< 0.001), gender (OR 1.66, 95% CI 1.05-2.61; p=0.029), dyslipidemia (OR 2.07, 95%CI 1.34-3.18; p=0.001), and max-IMT (OR 2.71, 95%CI 1.70-4.33; p< 0.001). By ROC curve analyses, the area under the curve (AUC) for max-IMT was 0.73 (95%CI 0.66-0.81; p< 0.001) and mean-IMT was 0.64 (95%CI 0.56-0.73; p=0.001). The cut-off level for the greatest sensitivity and specificity for max-IMT was 1.55 mm (sensitivity 0.90, specificity 0.46), and mean-IMT was 1.05 mm (sensitivity 0.55, specificity 0.72). CONCLUSION: Carotid IMT was associated with coronary artery stenosis assessed by CCTA in asymptomatic type 2 diabetic patients. Measurement of both mean- and max-carotid IMT is useful for selecting asymptomatic type 2 diabetic patients who should undergo CCTA screening.