Mechanistic insights from sequential combination therapy with a sodium glucose co-transporter-2 inhibitor and a dipeptidyl peptidase-4 inhibitor: Results from the CANARIS Trial using canagliflozin and teneligliptin.

AIM: To elucidate the mechanisms involved in the sequential use of SGLT2 and DPP4 inhibitors (SGLT2i and DPP-4i). METHODS: Twenty-six type-2 diabetes mellitus patients were recruited into a stepped regimen of 100 mg of canagliflozin daily from day 1, supplemented with 20 mg of teneligliptin daily from day 4. Glucose (Glu), insulin and glucagon were measured at fasting and after ingesting a mixed meal on days 1, 4 and 6. RESULTS: Canagliflozin decreased fasting plasma glucose to an extent inversely proportional to the change in the glucagon-to-insulin (G/I) ratio. This correlation at fasting was maintained when adding teneligliptin, while the change in the area under the curve of Glu (GluAUC) correlated closely with that in the G/I ratio at fasting and 60 min with canagliflozin. Moreover, these correlations persisted at 60 and 120 min postprandially, but not at fasting on day 6 when teneligliptin was added. CONCLUSION: The result suggested that the dominant mechanism responsible for the glucose metabolism reflected in the G/I ratio was attributable to SGLT2i and that its active mechanism persisted, despite adding a DPP-4i.

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody-insight into the pathogenesis of autoimmune endocrinopathy.

Therapeutic blocking antibodies against programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are applied for advanced cancer therapy, but induce a wide range of immune-related adverse events. In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.

Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects.

BACKGROUND: Lowering cholesterol levels decreases the risk of atherosclerotic diseases. Effective ways to stably reduce LDL-C level are warranted in type 2 diabetic patients, a high-risk population for CVD, with various anti-diabetic therapeutic background. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles. We evaluated long-term ezetimibe add-on therapy in T2DM patients with hypercholesterolemia. METHODS: In a randomized, multicenter, open-label, prospective study, a total of 109 T2DM patients not attaining LDL-C target value despite first-line dose statin (10 mg of atorvastatin or 1 mg of pitavastatin) therapy in Japan were recruited. We investigated the difference in cholesterol lowering effect between ezetimibe (10 mg) add-on statin (EAT) group and double-dose statin (DST) group. Changes of parameters related to atherosclerotic event risks were assessed. RESULTS: The reduction of LDL-C was larger in the EAT group (28.3%) than in the DST group (9.2%) at 52 weeks as well as the primary endpoint of 12 weeks. EAT achieved significant lower levels of TC and apo B, respectively. Both treatments attained significant reduction in sd-LDL-C or hsCRP on this long-term basis. Notably, sd-LDL-C in EAT reduced as low as 36.1 ± 14.9 mg/dl to reach near the threshold (35.0 mg/dl) for atherosclerosis with significantly higher achievement rate (55.6%) than DST treatment. Simultaneously, hsCRP reduction by EAT attained as low value as 0.52 ± 0.43 mg/l. CONCLUSIONS: In the present 52-week long-term period, ezetimibe add-on therapy showed a robust advantage in lowering LDL-C and in attaining target LDL-C values compared with the doubling of statin dose. Moreover, it's meaningful that sd-LDL, powerfully atherogenic lipoprotein, exhibited prominent decrease consistently prominently by ezetimibe add-on therapy. DM patients with hypercholesterolemia are at high risk for CAD, and adding ezetimibe onto usual-dose statin treatment in Japan has been suggested as the first-line therapy for those DM patients who failed to attain the target LDL-C value (UMIN000002593).

[Mechanisms and efficacy of SGLT2 inhibitors].

SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

RESEARCH (Recognized effect of Statin and ezetimibe therapy for achieving LDL-C Goal), a randomized, doctor-oriented, multicenter trial to compare the effects of higher-dose statin versus ezetimibe-plus-statin on the serum LDL-C concentration of Japanese type-2 diabetes patients design and rationale.

AIMS: Hypercholesterolemia coexisting with diabetes still requires clinical intervention to manage the high risk of cardiovascular disease it poses. No second-step strategy is established, however, for cases where strong statins fail to bring cholesterol down to target levels. In this study we seek to demonstrate the superior effect of ezetimibe in combination with strong statins to reduce LDL-C in Japanese patients suffering from both T2DM and hyper LDL-cholesterolemia. METHODS: T2DM outpatients (109 patients from 16 institutes) who failed to achieve the target LDL-C value were recruited and randomly assigned to two groups, a double-dose-statin group and ezetimibe-plus-statin group. Follow-ups were scheduled at 0, 12, 26, and 52 weeks. The primary endpoint was the percentage change in the level of LDL-C from baseline to 12 weeks. INTERIM RESULTS: We could successfully create randomized (gender, age, LDL-C, HbA1c, etc.) two groups except for slight differences in apolipoprotein-B and sd-LDL. CONCLUSIONS: RESEARCH is the first prospective, parallel-group, multicenter study comparing a double dose of strong statin with ezetimibe plus strong statin for T2DM patients. The RESEARCH study will provide reliable evidence with which to establish a clinical strategy for diabetics who fail to achieve the target LDL-C value.

Chronic cold agglutinin disease after a third COVID-19 mRNA vaccination.

COVID-19 mRNA vaccines manufactured by Pfizer-BioNTech and Moderna have been approved in many countries, and have been administered since 2020. Recent reports of mRNA vaccination exacerbating autoimmune hematologic disorders, such as immune thrombocytopenia or autoimmune hemolytic anemia, have caught the attention of the general public, resulting in alarm over the risks of serious consequences. Meanwhile, in very rare cases, vaccination was reported to trigger new onset of hemolytic anemia. However, it remains unknown whether this was a transient reaction or a persistent event, because all cases reported to date were immediately treated with corticosteroids or rituximab. Here, we present a case of newly diagnosed cold agglutinin disease after a third COVID-19 mRNA vaccination. The patient was followed for 4 months without treatment and continued to exhibit high levels of cold agglutinin and aggregation of red blood cells. The present case indicates that the disease can become chronic, and provides insights into the pathogenesis and treatment strategies.

Outcome of pitavastatin versus atorvastatin therapy in patients with hypercholesterolemia at high risk for atherosclerotic cardiovascular disease.

BACKGROUND: There has been no report about outcome of pitavastatin versus atorvastatin therapy in high-risk patients with hypercholesterolemia. METHODS: Hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases (n = 664, age = 65, male = 54%, diabetes = 76%, primary prevention = 74%) were randomized to receive pitavastatin 2 mg/day (n = 332) or atorvastatin 10 mg/day (n = 332). Follow-up period was 240 weeks. The primary end point was a composite of cardiovascular death, sudden death of unknown origin, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, or heart failure requiring hospitalization. The secondary end point was a composite of the primary end point plus clinically indicated coronary revascularization for stable angina. RESULTS: The mean low-density lipoprotein cholesterol (LDL-C) level at baseline was 149 mg/dL. The mean LDL-C levels at 1 year were 95 mg/dL in the pitavastatin group and 94 mg/dL in the atorvastatin group. There were no differences in LDL-C levels between both groups, however, pitavastatin significantly reduced the risk of the primary end point, compared to atorvastatin (pitavastatin = 2.9% and atorvastatin = 8.1%, HR, 0.366; 95% CI 0.170-0.787; P = 0.01 by multivariate Cox regression) as well as the risk of the secondary end point (pitavastatin = 4.5% and atorvastatin = 12.9%, HR = 0.350; 95%CI = 0.189-0.645, P = 0.001). The results for the primary and secondary end points were consistent across several prespecified subgroups. There were no differences in incidence of adverse events between the statins. CONCLUSION: Pitavastatin therapy compared with atorvastatin more may prevent cardiovascular events in hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases despite similar effects on LDL-C levels.

Efficacy and safety of empagliflozin in Japanese patients with type 2 diabetes mellitus: A sub-analysis by body mass index and age of pooled data from three clinical trials.

AIMS: To investigate the efficacy and safety of empagliflozin in subgroups based on body mass index (BMI) and age, using a pooled data set from Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Pooled data from 1403 patients treated with empagliflozin at 10mg/day or 25mg/day in three clinical studies (≥52week treatment) were stratified by baseline BMI (<22, 22 to <25 and ≥25kg/m2) and baseline age (<50, 50 to <65 and ≥65years). RESULTS: Empagliflozin at 10mg/day and 25mg/day reduced mean glycated hemoglobin (HbA1c) (-0.77 to -0.87% and -0.76 to -0.97%, respectively), mean fasting plasma glucose (FPG) (-20.79 to -27.06mg/dL and -26.08 to -29.60mg/dL) and mean body weight (-3.4 to -4.7% and -3.7 to -4.7%) in all subgroups of baseline BMI and age, regardless of age and degree of obesity. Adverse events were observed in approximately 70-80% patients in BMI and age subgroups of both empagliflozin groups. No hypoglycemia requiring assistance was observed. Neither UTI nor genital infection rates differed markedly among the BMI and age subgroups. Volume depletion was increased in patients ≥65years of age as compared to younger patients. CONCLUSIONS: Empagliflozin was well tolerated and improved HbA1c, FPG and body weight in all BMI and age subgroups of Japanese patients with T2DM, regardless of age and degree of obesity. Empagliflozin is considered to be effective and well tolerated for treating a wide range of Japanese patients with T2DM. TRIAL REGISTRATION: Study 1 (NCT01193218), Study 2 (NCT01289990) and Study 3 (NCT01368081).

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

BACKGROUND: There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks. METHODS: Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM. RESULTS: The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups. CONCLUSION: Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response. TRIAL REGISTRATION: The UMIN Clinical Trials Registry UMIN000002593.

Increased electronegative charge of serum low-density lipoprotein in patients with diabetes mellitus.

BACKGROUND: Patients with diabetes mellitus have been reported to show increased serum levels of modified low-density lipoprotein (LDL), including glycosylated, oxidized and small, dense LDL. This change has been suggested to represent an important risk factor for diabetic macroangiopathy. A common characteristic shared by these modified LDL species is the increase in electronegative charge on particle surfaces, which can be detected by agarose gel electrophoresis as "LDL charge modified frequency" (LDL-CMF) determined from the relative mobility of LDL fraction. METHODS: LDL-CMF was measured in the sera from 129 outpatients with type 2 diabetes mellitus and compared with the data from 34 normal subjects. RESULTS: The LDL fraction from diabetics migrates more closely to the anode side as compared with that from normal subjects. The LDL-CMF measured in diabetics, 5.5+/-8.1%, was significantly (p<0.0001) higher than 0.6+/-3.4% in normal subjects. Serum LDL-CMF showed significant positive correlations with triglyceride at r=0.552 (p<0.0001) and malondialdehyde modified LDL at r=0.390 (p<0.0001), as well as systolic blood pressure, body mass index, fasting plasma glucose, hemoglobin A(1c), total cholesterol, free fatty acid (FFA) and homeostasis model assessment ratio. It showed negative correlations with high-density lipoprotein and total superoxide dismutase activity. CONCLUSION: The results indicate that LDL-CMF reflects the degree of serum LDL modification in diabetics and can be regarded as an important risk factor for diabetic macroangiopathy.

Improvement of insulin resistance by a new insulin secretagogue, nateglinide--analysis based on the homeostasis model.

Type 2 diabetes is a heterogeneous disorder characterized by defects in the early phase of insulin secretion after meals and in insulin resistance at its early stage. A new insulin secretagogue, nateglinide, has been shown to elicit an acute insulin release and to reduce postprandial hyperglycemia. We have treated 30 patients with type 2 diabetes using nateglinide and performed a standard meal test at breakfast, both before and after the treatment. Insulin resistance and beta-cell function was assessed by the HOMA model. Nateglinide, at 1 and 2 h after the test meal, significantly stimulated postprandial insulin secretion by 62.0 and 41.0% and improved blood glucose values by 17.3 and 21.9%, respectively, after the treatment. Fasting blood glucose (FBG) and glycohemoglobin was significantly reduced by 9.8 and 10.3%, respectively. The reduction was significantly larger in postprandial glucose than in FBG (P<0.0005). A significant correlation was found in the HOMA-insulin resistant (IR) index and in the changes of fasting IRI. When the patients were divided into three groups, forming a markedly insulin resistant (MIR) group, an IR group and a non-insulin resistant (NIR) group, HOMA-IR levels improved significantly, from 7.0 +/- 4.3 to 4.5 +/- 2.8 (P=0.026) in the MIR group and showed a tendency toward improvement in the IR group, from 2.9 +/- 0.7 to 2.3 +/- 1.1 (P=0.062), but failed to exhibit such a positive response in the NIR group, changing from 1.2 +/- 0.2 to 1.9 +/- 0.9 (P=0.21). HOMA-beta, on the other hand, improved significantly in the NIR group only, from 16.4 +/- 7.8 to 26.9 +/- 9.9 (P=0.017), but not in the IR nor MIR groups (M +/- S.D.). In conclusion, nateglinide improved the excessive excursion of postprandial glucose by the augmentation of early insulin secretion after a meal and differentially affected fasting insulin levels and HOMA-IR indexes, depending on the degree of insulin resistance.

Screening and follow-up of diabetic retinopathy using a new mosaic 9-field fundus photography system.

AIM: To evaluate the clinical usefulness of a newly developed fundus photographing system and assess its applicability to telemedicine. METHODS: Nine overlapping 45 degrees fundus photographs were taken by a new camera equipped with nine internal fixation targets to provide standardized 9-field photographs. The digitally stored images were either edited in 3x3 form or reconstructed as collage (9F) and compared to the ophthalmological examination (OP) and single-field non-mydriatic photography (SC). In telemedicine, 9-field images derived from 61 adolescent diabetics were sent to ophthalmologists over an analog phone line. RESULTS: The sensitivities of the examinations by 9F without and with mydriasis (78 and 82%) were equivalent to OP (84%) and superior to SC (64%). The diagnosis of severity by 9F was also comparable to those by OP, whereas SC tended to underestimate the severity. An average of 1 min 19 s was required to send one edited 9-field photography (average size 259+/-30 KB) over the Internet. Twelve of these eyes were diagnosed as diabetic retinopathy on a desktop monitor whereas SC gave only seven. CONCLUSION: This new 9-field fundus photography system can be appropriate for the screening and follow-up of diabetic retinopathy in adult and adolescent diabetic subjects, especially when applied to telemedicine over the Internet.

HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes.

Patients with type 2 diabetes are known to have abnormalities in their remnant metabolism and low density lipoprotein (LDL) subfraction pattern, with a preponderance of small dense LDL. The effects of pitavastatin, a newly synthesized 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, on lipoprotein profiles in patients with type 2 diabetes were determined. Thirty-three patients were treated with pitavastatin with a daily dose of 2 mg for 8 weeks. After treatment, triglyceride, total and LDL cholesterol were significantly reduced by 28.7 +/- 36.7%, 25.2 +/- 14.3% and 36.1 +/- 14.3%, respectively. Remnant-like particle cholesterol (RLP-C), an independent risk factor for CAD which is known to be elevated in diabetic patients, was also significantly reduced (-30.9 +/- 30.5%) by the treatment and this decrease correlated well with the decrease in triglyceride level. The proportion of small dense LDL, which is known for its atherogenisity, decreased from 29.9 +/- 26.2% to 19.7 +/- 22.7% and the mean LDL particle size significantly increased from 26.36 +/- 1.13 nm to 27.10 +/- 1.36 nm. Pitavastatin, which is known to improve triglyceride levels and cholesterol levels, also improves RLP-C level and LDL subfraction profiles, and this in turn may reduce the cardiovascular risk in patients with type 2 diabetes and dyslipidemia.

Asymptomatic insulinoma: a case report and autopsy series.

AIMS: We investigated the prevalence and characterization of asymptomatic pancreatic tumors in response to our experience of asymptomatic insulinoma. METHODS: A patient with a moderately low glucose level and pancreatic incidentaloma detected by CT was examined. Pancreas specimens from 423 autopsy cases were also pathologically examined systematically by hematoxylin-eosin staining. RESULTS: The examined patient showed no profile characteristic of insulinoma by fasting or loading tests, however, ASVS led to diagnosis of insulin-producing tumor. The tumor was resected with the pancreatic body and tail and revealed to be 10 mm in diameter, with 98.5% of the cells positive for insulin. Pathological evaluation confirmed a well-differentiated endocrine pancreatic tumor, which was suggestive of an incidentally detected asymptomatic insulinoma. Microscopic evaluations of pancreatic specimens from 423 autopsy cases revealed pancreatic monotonous lesions in 6 cases (1.42%). In 4 autopsy specimens large enough for immuno-histochemical evaluation, the lesions were positive for glucagon but negative for insulin. CONCLUSIONS: As concerns the present study, retrospective immunohistochemical investigation in autopsy cases revealed the presence of asymptomatic glucagonoma but no asymptomatic insulinoma. Advances in diagnostic imaging, however, might raise the probability of detecting early asymptomatic stages of insulinoma incidentally. ASVS appears to be sensitive even for asymptomatic incidental insulinomas.

Knowledge and Demand for Information about Islet Transplantation in Patients with Type 1 Diabetes.

This cross-sectional study based on self-administrated questionnaire was conducted to investigate knowledge, related factors, and sources of information regarding islet transplantation in patients with type 1 diabetes in Japan. Among 137 patients who provided valid responses, 67 (48.9%) knew about islet transplantation. Their main source of information was newspapers or magazines (56.7%) and television or radio (46.3%). However, 85.8% of patients preferred the attending physician as their source of information. Although more than half of the patients were correctly aware of issues related to islet transplantation, the following specific issues for islet transplantation were not understood or considered, and there was little knowledge of them: need for immunosuppressants, lifestyle and dietary adaptations, fewer bodily burdens, and complications. The experience of hypoglycaemia, a high level of academic background, frequent self-monitoring of blood glucose, and the use of continuous subcutaneous insulin infusion were related to higher knowledge about islet transplantation.