A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin.

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial.

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

SGLT2 inhibitor versus carbohydrate-restricted isocaloric diet: reprogramming substrate oxidation in type 2 diabetes.

OBJECTIVE: Based on the whole-body energy metabolism and insulin action, the difference between increased excretion of carbohydrate in urine by SGLT2i and reduced same amount of oral carbohydrate intake are scarce. This study aimed to compare the effect of carbohydrate availability with reduced oral intake (carbohydrate-restricted isocaloric diet: CRIC diet) or lost in urine, as urinary glucosuria on sodium/glucose cotransporter-2 inhibitor (SGLT2i) treatment, focus on the insulin requirement and the macronutrient oxidation within insulin treated type 2 diabetes. METHODS: This is randomized 3-arm open-label prospective study. Subjects treated with titrated basal-bolus insulin regimen subsequent to three diet regimens, control diet (CON), administration of canagliflozin 100 mg/day to CON (SGLT2i), or CRIC diet, with a week admission to the endocrinology ward followed by 12 weeks outpatients' management. The main outcome measures including the total insulin dose (TID) required to achieve euglycemia, fasting and postprandial energy expenditure (EE) and respiratory quotient (RQ) at 1-week and 12-week. RESULTS: We enrolled 23 patients with type 2 diabetes (male/female: 14/9, age: 53.6 ± 14.2 years, body mass index: 26.9 ± 4.8 kg/m2, HbA1c: 12.5 ± 1.6%). The TID was similar with CON and SGLT2i at both 1 and 12-weeks. Although comparable net carbohydrate availability in SGLT2i and CRIC groups, the TID was significantly higher in the CRIC (p = 0.02) compare to the SGLT2i at both 1 and 12-weeks. Fasting EE was similar in all groups, postprandial EE was significantly elevated in the SGLT2i and CRIC groups compared to the CON group (p = 0.03 and 0.04). Compare to the CON, lower basal fasting RQ (p = 0.049) and decreased delta-RQ (postprandial RQ/fasting RQ) indicated continuous lipid substrate utilization in the SGLT2i (p = 0.04) and CRIC (p = 0.03) groups. CONCLUSION: The CRIC diet resulted in a similar fasting and postprandial EE and substrate oxidation compared to the SGLT2i. The increased insulin requirement in the CRIC diet indicates that a relatively highly lipid and protein consumption, compared to the SGLT2i and CON, may influence insulin requirement.

Dipeptidyl peptidase-4 inhibitor improves glycemic variability in multiple daily insulin-treated type 2 diabetes: a prospective randomized-controlled trial.

AIMS: To improve glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) treatment in diabetes. To evaluate the GV improvement in MDI treated type 2 diabetes (T2D) with low-dose metformin 750 mg/day (LMET), which was popular in the clinical practice in Japan, we compared the effect of adding vildagliptin 100 mg/day (LMET + DPP4i treatment) or increased metformin dose to 1500 mg/day (HMET treatment), in the setting of continuous glucose monitoring (CGM) analysis. MATERIALS AND METHODS: Single-center, open-label, 12 weeks-two period cross-over design. Twenty T2D with inadequately controlled (7.0% < HbA1c ≤ 9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM indices, performed after each 12 week treatment periods. RESULTS: There was no significant difference in both LMET + DPP4i treatment and HMET treatment, in terms of HbA1c, body weight changes, and total daily dose of insulin to achieve the targeted glycemia. LMET + DPP4i treatment compared to HMET treatment, significantly reduced the calculated GV value, mean (7.15 ± 1.30 vs 7.82 ± 1.60, p = 0.04), standard deviation (1.78 ± 0.55 vs 2.27 ± 1.11, p = 0.03), continuous overlapping net glycemic action (6.44 ± 1.28 vs 7.12 ± 1.69, p < 0.05), J-Index (26.7 ± 11.0 vs 34.9 ± 19.8, p < 0.05), high blood glucose index (3.01 ± 1.96 vs 6.73 ± 4.85, p = 0.02), and mean amplitude of glycemic excursions (4.53 ± 1.35 vs 5.50 ± 2.34, p = 0.03). CONCLUSION: The GV metrics regarding daily and nocturnal hypoglycemia were not significantly different between LMET + DPP4i treatment and HMET treatment. LMET + DPP4i treatment decreased GV associated with hyperglycemia. Adding DPP-4-inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI compared to additional high-dose metformin. National Clinical Trial registration in Japan, number is JPRN-UMIN000024663. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00513-6.

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.

Sustained fasting glucose oxidation and postprandial lipid oxidation associated with reduced insulin dose in type 2 diabetes with sodium-glucose cotransporter 2 inhibitor: A randomized, open-label, prospective study.

AIMS/INTRODUCTION: Hyperglycemia impairs energy substrate oxidation as a result of glucotoxicity. We examined whether the reduction of plasma glucose using a sodium-glucose cotransporter 2 inhibitor, in inpatient diabetes management, has any effect on: (i) treatment period and basal-bolus dosage of insulin that achieve euglycemia; (ii) fasting/postprandial energy expenditure (EE); and (iii) energy substrate oxidation. MATERIALS AND METHODS: This was a randomized, open-label, 7-day prospective study. Participants were type 2 diabetes patients with hyperglycemia, aged >20 years, with glycated hemoglobin >10%, daily mean preprandial blood glucose >11 mmol/L (200 mg/dL) and no previous antidiabetic medication. A total of 18 type 2 diabetes patients were randomized (1:1) to basal-bolus insulin titration algorithm (INS) alone or INS + dapagliflozin 5 mg/day (INS/DAPA). The main outcome measures were total daily insulin dose to achieve euglycemia, as well as EE and respiratory quotient during fasting and postprandial states, measured by indirect calorimetry. RESULTS: The rate of euglycemia was higher in the INS/DAPA compared with INS group (100 vs 55.6%, P = 0.04), whereas the total daily dose of insulin was 19% lower and was accompanied by a decreased basal-bolus ratio (P = 0.02). Fasting and postprandial EE elevation were similar in both groups. The post-treatment fasting respiratory quotient significantly increased in the INS/DAPA group (0.72 ± 0.05 vs 0.79 ± 0.08, P = 0.04), and the postprandial respiratory quotient elevation was abolished; the opposite trend was observed in the INS group (P < 0.02). CONCLUSIONS: INS/DAPA sustained fasting carbohydrate oxidation, postprandial lipid-derived EE (failed to increase carbohydrate-derived EE) and reduced basal insulin requirement might be related to further bodyweight loss. CLINICAL TRIAL REGISTRY: National University Hospital Medical Information Network UMIN000018997.

Glycemic Variability in Type 1 Diabetes Compared with Degludec and Glargine on the Morning Injection: An Open-label Randomized Controlled Trial.

INTRODUCTION: Optimal adjustment of basal insulin to overcome hypoglycemia and glycemic variability (GV) depends on its duration of action and peak-less profile. Owing to the ability of long-acting basal insulin to avoid hypoglycemia, we titrated pre-meal glucose to normal fasting blood glucose, 80-110 mg/dL (4.5-6.1 mmol/L), and post-meal glucose to 80-140 mg/dL (4.5-7.8 mmol/L). The purpose of this study was to evaluate two basal insulin analogues degludec (IDeg) and glargine (IGlar), injected in the morning, for GV using continuous glucose monitoring (CGM) in type 1 diabetes (T1DM). METHODS: In this crossover study, 20 Japanese patients with T1DM (age 54 ± 16 years, disease duration 16 ± 8 years, BMI 24 ± 4 kg/m2, HbA1c 7.4 ± 0.8%) were randomized into one of two different starting regimens, and CGM was conducted on three consecutive days during the last week of each 12-week titration period. Treatment satisfaction was assessed at the end of each treatment period using the Diabetes Therapy-Related Quality of Life Questionnaire (DTR-QOL). RESULTS: There were no differences in HbA1c, total insulin dosage, body weight changes, and basal to bolus ratio between the IDeg and IGlar arms. The day-to-day variability in fasting interstitial GV on the CGM curves was significantly less in the IDeg than IGlar treatment period (25.9 ± 22.0 vs. 43.8 ± 30.1 mg/dl, p = 0.04). Other markers of GV, calculated by the EasyGV software, including mean amplitude of glycemic excursions (MAGE), J-index, total and nocturnal hypoglycemia were not different between the two treatment periods. The score of "satisfaction with treatment", a subdomain of the DTR-QOL system, was higher in the IDeg period. CONCLUSION: Thus, the morning injection of the two long-acting insulin analogues seemed similar with regard to the magnitude of hypoglycemia in T1DM, but treatment with IDeg was associated with lower day-to-day variation in glucose level. These results suggest that IDeg is safe with minimal morning GV in patients with T1DM. CLINICAL TRIAL REGISTRATION: Japanese Clinical Trials Registry, UMIN000012358.