Long-term efficacy and safety of early alogliptin initiation in subjects with type 2 diabetes: an extension of the SPEAD-A study.

We previously reported in the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A) that alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the progression of carotid atherosclerosis in subjects with type 2 diabetes and no history of cardiovascular disease. This extension study of the SPEAD-A trial investigated whether early alogliptin initiation improved long-term cardiovascular outcomes. The SPEAD-A trial randomized 341 subjects with type 2 diabetes to either alogliptin or conventional treatment to investigate the effects of alogliptin on atherosclerosis. All subjects who completed that trial were eligible for this prospective, observational cohort study. The primary endpoint was the first occurrence of a major cardiovascular event, defined as death due to any cause, acute myocardial infarction, or stroke. During the 520-week follow-up period, composite primary outcome events occurred in only a few subjects in each group [8 (5.4%) in the alogliptin group and 9 in the conventional treatment group (5.9%)]. There were no significant differences in the incidence rate of the primary outcome between the two groups. Post hoc Poisson regression analysis showed no significant difference between the two groups in the incidence rate of composite recurrence events for the same outcomes as the primary endpoint. On the other hand, this incidence rate was significantly lower in subjects who received DPP-4 inhibitors before an initial cardiovascular event than in those who did not (5.8 vs. 13.3 per 1000 person-years, respectively, p = 0.04). Early initiation of alogliptin was not associated with a reduced risk of composite cardiovascular disease, which could be attributed to fewer events and/or the addition of DPP-4 inhibitors during the follow-up period.

Olfactory dysfunction predicts the development of dementia in older patients with type 2 diabetes.

AIMS: Olfactory dysfunction is associated with the transition from normal cognition to dementia in persons without type 2 diabetes. This study aimed to investigate whether olfactory dysfunction could be an early marker of future dementia in older patients with type 2 diabetes. METHODS: This exploratory study included 151 older Japanese outpatients with type 2 diabetes who did not have a diagnosis of probable dementia at baseline. A multivariate logistic regression model was used to determine whether Open Essence (OE) test score at baseline is associated with the development of probable dementia. RESULTS: Over 3 years, approximately 9% of the study subjects developed probable dementia. Subjects with olfactory dysfunction at baseline developed probable dementia more frequently than those without. Multivariate logistic regression showed that lower OE test score, higher age, lower Mini-Mental State Examination (MMSE) score, higher total protein concentration, and more frequent use of a sulfonylurea are significantly associated with the development of probable dementia. Stepwise multivariate regression analysis demonstrated that change in OE test score over 3 years is significantly associated with change in MMSE score. CONCLUSIONS: Our study suggested that olfactory dysfunction precedes the development of probable dementia in older patients with type 2 diabetes.

Determinants and impact of physical impairment in patient-reported outcomes among older patients with type 2 diabetes mellitus in Japan.

OBJECTIVE: To investigate the predictive factors associated with physical impairment among older patients with type 2 diabetes mellitus (T2DM) in Japan and to examine the potential impact of physical impairment on patient-reported health outcomes in this population. METHODS: A cross-sectional analysis was conducted using patient-reported data from the 2012-2014 Japan National Health and Wellness Survey. Physical impairment was measured using the Physical Component Summary (PCS) score of the Short-Form 36-Item Health Survey (SF-36) three-component model (using Japanese norms). Older T2DM patients (≥65 years old; n = 1511) were dichotomized into physically impaired (PCS ≤ 25th percentile; n = 378) and non-physically impaired (PCS > 25th percentile; n = 1133). Work productivity (absenteeism, presenteeism and overall work impairment), activity impairment and healthcare resource utilization were compared between these groups. RESULTS: Age, female sex, low and high body mass index (BMI), diabetes-related complications, cardiovascular events, unawareness of having hypoglycemic events in the past 3 months, and lack of regular exercise were significant factors associated with physical impairment in multivariable analysis. The physically impaired group reported significantly more regular outpatient visits (13.48 vs. 10.16, respectively, p < .001), 1% or greater absenteeism (16.7% vs. 4.1%, p = .005), greater presenteeism (27.8% vs. 12.2%, p = .001), overall work impairment (30.0% vs. 13.0%, p = .001) and overall activity impairment (39.5% vs. 17.2%, p < .001) than the non-physically-impaired group after adjusting for covariates. CONCLUSIONS: This study identified age, BMI, diabetes-related comorbidities, history of cardiovascular events and lack of exercise as key predictors associated with physical impairment in older patients with T2DM in Japan, which predicted low work productivity as well as activity impairment. This study provides support that physical impairment in patients with T2DM may lead to low work productivity and activity impairment.Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1846170.

Sitagliptin Attenuates the Progression of Carotid Intima-Media Thickening in Insulin-Treated Patients With Type 2 Diabetes: The Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE): A Randomized Controlled Trial.

OBJECTIVE: The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM. RESEARCH DESIGN AND METHODS: This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period. RESULTS: Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (-0.5 ± 1.0% vs. -0.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (-0.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; -0.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; -0.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline. CONCLUSIONS: Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.

Alogliptin, a Dipeptidyl Peptidase 4 Inhibitor, Prevents the Progression of Carotid Atherosclerosis in Patients With Type 2 Diabetes: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).

OBJECTIVE: Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTS: Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 ± 0.7% vs. -0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively). CONCLUSIONS: Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

Relationship between dietary pattern and cognitive function in elderly patients with type 2 diabetes mellitus.

OBJECTIVE: To analyse the relationships between dietary patterns and cognitive function in elderly patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM completed a 3-day dietary record and Mini-mental State Examination (MMSE). Dietary patterns were identified by factor analysis. RESULTS: The study included 73 patients and identified five dietary patterns, one of which was characterized by high loading for vegetables and fish. A higher consumption of vegetables and fish was significantly associated with improved MMSE score (unadjusted model, model adjusted for age and sex, and model adjusted for age, sex, education, diabetic nephropathy and alcohol consumption), and decreased prevalence of suspected mild dementia (unadjusted model, model adjusted for age and sex). CONCLUSIONS: A high score in the vegetables and fish dietary pattern was associated with high MMSE score and low prevalence of suspected mild dementia in elderly patients with T2DM.

Relationship between olfactory dysfunction and cognitive impairment in elderly patients with type 2 diabetes mellitus.

AIMS: Recent clinical studies identified the relation between olfactory dysfunction and cognitive impairment in the elderly without type 2 diabetes mellitus. The aim of the present study was to define the relation between olfactory function and cognition in elderly patients with type 2 diabetes mellitus. METHODS: The study participants comprised 250 elderly (age, 68-77, median 72) Japanese outpatient with type 2 diabetes mellitus free of clinically-evident cognitive impairment. Olfactory and cognitive functions were evaluated by the Open Essence (OE) test and Mini-mental State Examination (MMSE), respectively. RESULTS: Based on the MMSE score, 62.0%, 24.4%, and 13.6% of the participants were considered to have no impairment, possible cognitive impairment and probable dementia, respectively. The OE test score of the probable dementia group was significantly lower than other groups. Furthermore, age and serum uric acid were significantly higher in the probable dementia group than other groups. Simple correlation analysis showed positive correlation between the MMSE score and diastolic blood pressure, education, OE test score, total cholesterol, LDL cholesterol, folic acid, and negative correlation with age, HbA1c, aspartate aminotransferase, serum adiponectin and urinary albumin excretion. Multivariate regression analysis showed that OE test score correlated significantly and independently with MMSE score (standardized coefficients ß=0.542, R(2)=0.478, P<0.01), in addition to education level, HbA1c and serum adiponectin. CONCLUSIONS: The results suggested the association of olfactory dysfunction with cognitive impairment in elderly patients with type 2 diabetes mellitus.

Rationale, design, and baseline characteristics of a clinical trial for prevention of atherosclerosis in patients with insulin-treated type 2 diabetes mellitus using DPP-4 inhibitor: the Sitagliptin Preventive study of Intima-media thickness Evaluation (SPIKE).

BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to achieve glycemic targets in patients with type 2 diabetes mellitus (T2DM). The addition of DPP-4 inhibitors to ongoing insulin therapy is expected to reduce insulin dosage, leading to a reduction in the frequency of hypoglycaemia and/or weight gain. Recent studies have demonstrated potential anti-atherosclerotic effects for DPP-4 inhibitors. The aim of the present ongoing study is to assess the effects of sitagliptin on the progression of atherosclerosis in patients with insulin-treated T2DM using carotid intima-media thickness (IMT), an established marker of cardiovascular disease. METHODS AND DESIGN: The Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between February 2012 and September 2012, 282 participants who failed to achieve glycemic control despite insulin therapy were recruited at 12 clinics and randomly allocated to the sitagliptin group (n = 142) or the control group (n = 140). Primary outcomes are changes in maximum and mean IMT of the common carotid artery after 24-month treatment period measured by carotid arterial echography. Secondary outcomes include changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, occurrence of cardiovascular events and adverse events such as hypoglycaemia, and biochemical markers of vascular function. DISCUSSION: The present study is designed to assess the effects of sitagliptin on the progression of carotid IMT. Results will be available in the near future, and the findings are expected to provide new strategy to prevent atherosclerosis in patients with insulin-treated T2DM. CLINICAL TRIAL REGISTRATION: UMIN000007396.

Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study.

AIM: The present study evaluated the effects of pioglitazone treatment on the incidence of primary cardiovascular events in Japanese subjects with type 2 diabetes mellitus at high risk of stroke. METHODS: A prospective, multicenter, randomized, open label, comparative study was conducted among diabetic patients recruited from 50 medical institutions nationwide. A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n=254) or without pioglitazone (n=268) and observed for a medium of 672 days. The hypertension and dyslipidemia were concurrently treated according to the respective treatment guidelines. The primary outcome was the time to the first occurrence of a composite of all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction. RESULTS: Treatment with pioglitazone resulted in significant reductions in the levels of HbA1c, diastolic blood pressure and LDL-cholesterol and a significant increase in the levels of HDL-cholesterol. The pioglitazone non-users exhibited a significant reduction in the LDL-cholesterol levels alone. Primary events were registered during the study period in nine patients in the pioglitazone group and 10 patients in the non-pioglitazone group. The difference in the cumulative incidence of the primary outcome was not significant between the two groups(1.8% per year). CONCLUSIONS: Pioglitazone therapy produces immediate and effective improvements in glycemic control, diastolic blood pressure and lipid profiles. While this study was too underpowered to determine the effects of pioglitazone on the incidence of cardiovascular events, the results indicated that two years of pioglitazone treatment did not produce any statistically significant reductions in the rate of primary cardiovascular events.

Mean postprandial triglyceride concentration is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes.

BACKGROUND: Postprandial hypertriglyceridemia is a risk factor for atherosclerotic disease. However, the postprandial triglyceride (PTG) concentration fluctuates markedly and is poorly reproducible. The aim of this study was to determine whether the mean PTG (mean-PTG) concentration is a risk factor for carotid atherosclerosis in patients with type 2 diabetes. METHODS: We measured the fasting and postprandial lipid concentrations, and the maximum intima-media thickness (max IMT) of carotid arteries by ultrasound in 115 diabetic patients. A carotid plaque was defined as max IMT of >1.0mm. The mean-PTG concentration was calculated from several PTG concentrations measured on different days during a 1-year follow-up period. RESULTS: PTG concentrations showed marked intra-individual variability, and ranged from 0.29 to 6.03 mmol/l. Patients with carotid plaques had higher mean-PTG concentrations than those without carotid plaques (1.51 ± 0.57 vs. 1.29 ± 0.47 mmol/l, p=0.025). Neither fasting triglycerides nor one-point PTG concentrations differed between the two groups. Multivariate stepwise logistic regression analysis revealed that the mean-PTG concentration was significantly associated with carotid plaques [OR 1.20 (95% CI, 1.05-1.37), p=0.009], even after adjusting for traditional risk factors including HDL-cholesterol, LDL-cholesterol, age, hypertension, and duration of diabetes. CONCLUSIONS: The mean-PTG concentration is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes.

Rationale, design, and baseline characteristics of a trial for the prevention of diabetic atherosclerosis using a DPP-4 inhibitor: the Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).

AIM: Alogliptin, an efficacious inhibitor of DPP-4 that improves glycemic control, as well as the pancreatic beta-cell function, is now increasingly used to accomplish glycemic targets in type 2 diabetic patients. Interestingly, recent experimental studies have shown that alogliptin exerts anti-atherosclerotic effects in GLP-1-dependent and -independent manners. The aim of the present ongoing study is to investigate the preventive effects of alogliptin on the progression of atherosclerosis in type 2 diabetic subjects using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease. METHODS AND RESULTS: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between March 2011 and March 2012, 341 participants were recruited at 11 clinical sites, and were randomly allocated either to an alogliptin treatment group (172 patients) or a conventional treatment group (169 patients). The primary outcomes are the changes in the maximum and mean IMT of the common carotid artery during a 24-month treatment period, as measured by carotid arterial echography. The secondary outcomes include the changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, the occurrence of cardiovascular events and adverse events and biochemical measurements reflecting vascular function. CONCLUSIONS: This is the first study to address the effects of DPP-4 inhibitors on the progression of changes in the carotid IMT, with the patients without DPP-4 inhibitor treatment serving as a control group. The results will be available soon, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent cardiovascular disease.

Comparison of effects of azelnidipine and trichlormethiazide in combination with olmesartan on blood pressure and metabolic parameters in hypertensive type 2 diabetic patients.

UNLABELLED: Aims/Introduction: Angiotensin II type 1 receptor blockers (ARB) are regarded as first-line treatment for type 2 diabetes with hypertension. However, lowering blood pressure to the target level often requires more than one antihypertensive agent as recommended by the guideline. In this open-label, prospective, crossover clinical trial, we compared the effects of combination treatment of ARB with a calcium channel blocker (CCB) or with a low-dose thiazide diuretic on blood pressure (BP) and various metabolic parameters in hypertensive patients with type 2 diabetes. MATERIALS AND METHODS: A total of 39 Japanese type 2 diabetics with hypertension treated with olmesartan (20 mg/day) for at least 8 weeks were recruited to this study. At study entry, treatment was switched to either olmesartan (20 mg/day)/azelnidipine (16 mg/day) or olmesartan (20 mg/day)/trichlormethiazide (1 mg/day) and continued for 12 weeks. Then, the drugs were switched and treatment was continued for another 12 weeks. We measured clinical blood pressure and various metabolic parameters before and at the end of each study arm. RESULTS: Compared with the olmesartan/trichlormethiazide treatment, treatment with olmesartan/azelnidipine achieved superior clinical blood pressure and pulse rate control. In contrast, the treatment with olmesartan/trichlormethiazide resulted in increased HbA1c, serum uric acid and worsening of estimated glomerular filtration rate, though there were no differences in other metabolic parameters including urine 8-hydroxy-2'-deoxyguanosine, C-reactive protein and adiponectin between the two treatments. CONCLUSIONS: Our results show that the combination of ARB with azelnidipine is more beneficial with regard to blood pressure control and metabolic outcome than the combination of olmesartan with low dose trichlormethiazide. This trial was registered with UMIN clinical trial registry (no. UMIN000005064). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00135.x, 2011).

Anti-oxidative effect of fluvastatin in hyperlipidemic type 2 diabetic patients.

An open-label prospective cross-over trial was performed to evaluate the antioxidative effect of fluvastatin in Japanese type 2 diabetics with hyperlipidemia. The study subjects were 10 patients who were on pravastatin (10 mg/day) or simvastatin (5 mg/day). After at least 12 weeks of continuous pravastatin or simvastatin therapy, the drugs were washed out for 12 weeks and replaced with fluvastatin (30 mg/day), then the treatment was continued for another 12 weeks. Total cholesterol and LDL cholesterol were efficiently and comparably reduced by all three statin agents. There were no differences in serum parameters of oxidative stress such as malondialdehyde-modified low-density lipoprotein, thiobarbituric acid-reactive substances, and 8-iso-prostaglandin F2alpha between pravastatin/simvastatin and fluvastatin. However, fluvastatin, but not pravastatin/simvastatin, significantly reduced 3,5,7-cholestatriene in erythrocyte membrane, representing the extent of membrane cholesterol peroxidation. Our data demonstrated that fluvastatin has a unique anti-oxidative effect in patients with type 2 diabetes and hyperlipidemia, compared with other statins.

Association between LDL particle size and postprandial increase of remnant-like particles in Japanese type 2 diabetic patients.

Small, dense LDL, as well as chylomicron- and VLDL-remnant lipoproteins, are known to be important risk factors for coronary heart disease in patients with type 2 diabetes mellitus. The aim of this study was to clarify the relationship between LDL particle size and postprandial remnant lipoprotein levels in Japanese type 2 diabetic patients. Forty-six patients with type 2 diabetes mellitus were divided into tertiles according to LDL particle size. The peak LDL particle diameter was <26.30 nm in tertile 1, 26.30-26.85 nm in tertile 2, and >26.85 nm in tertile 3. After a test meal, tertile 1 had a significantly greater increment of triglycerides (TG), remnant-like particle (RLP)-TG, and RLP-cholesterol (RLP-C) than tertiles 2 and 3. There was a negative correlation between LDL particle size and the postprandial increases of TG, RLP-TG, and RLP-C. These results indicate that smaller sized LDL particles may be a marker of fasting state for an exaggerated postprandial increase of remnant lipoproteins as well as an increase of TG-rich lipoproteins.

Ankle brachial pressure index and carotid intima-media thickness as atherosclerosis markers in Japanese diabetics.

The aim of this study was to assess the clinical significance of ankle brachial pressure index (ABI) and carotid intima-media thickness (IMT) in Japanese patients with type 2 diabetes. ABI and ultrasonographic carotid IMT measurements were made in 1311 patients and the relationships between ABI, IMT, and cardiovascular diseases were examined. Patients were assigned to one of three groups depending on their ABI index: (i) ABI > or = 1.0; (ii) ABI from > or = 0.9 to < 1.0; and (iii) ABI < 0.9. The odds ratios (ORs) for groups (ii) and (iii) compared with (i) for the prevalence of coronary heart disease (CHD), cerebrovascular disorder (CVD), and carotid atherosclerosis (mean carotid IMT > or = 1.1mm) demonstrated that these conditions were inversely related to ABI. As the combined ABI/carotid IMT score increased, each OR for the prevalence of CHD and CVD increased significantly. This suggests that a lower ABI is associated with generalized atherosclerosis. Measurements of the ABI and carotid IMT might provide a good prognostic indicator, and both should be assessed during screening for atherosclerosis in Japanese patients with type 2 diabetes.

Different effects of two alpha-glucosidase inhibitors, acarbose and voglibose, on serum 1,5-anhydroglucitol (1,5AG) level.

Serum 1,5-anhydroglucitol (1,5AG) is a useful glycemic marker in the control of diabetes; however, treated with alpha-glucosidase inhibitors (alpha-GIs), acarbose (Aca) and voglibose (Vog), it tends to show the discrepancy between serum 1,5AG and related glucose levels. Twenty patients were randomly assigned to adding Aca or Vog to the current treatment. We measured serum 1,5AG levels and other parameters of diabetic control before, 2 and 4 weeks after the alpha-GI treatment. We also measured urinary 1,5AG levels using gas chromatography/mass spectrometry (GC/MS). Glycated albumin, Hb(A1c), and fasting plasma glucose (FPG) levels were significantly decreased after 2 and 4 weeks of treatment, and the changes were similar in the two groups. Despite the similar urinary excretion of 1,5AG and other glycemic parameters, serum 1,5AG level was significantly lower in the Aca group than in the Vog group (3.4+/-0.5 vs. 7.9+/-1.2 microg/ml, P<.005; mean+/-S.E.) at the period of 4 weeks. Even in the same glycemic level, the less increase of serum 1,5AG after treatment with Aca might be due to a reduction of intestinal 1,5AG absorption via inhibition of alpha-amylase that features Aca.