Se Hee Min

Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta‐analysis

Both sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase‐4 (DPP4) inhibitors can be used to treat patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with insulin therapy, and yet there has been no direct comparison of these two inhibitors.

Efficacy and safety of the addition of a dipeptidyl peptidase-4 inhibitor to insulin therapy in patients with type 2 diabetes: A systematic review and meta-analysis

AIMS To compare the efficacy and safety of the addition of a dipeptidyl peptidase-4 (DPP-4) inhibitor or a placebo in patients with type 2 diabetes inadequately controlled with insulin. METHODS We searched randomised controlled trials (RCTs) from MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and the ClinicalTrials.gov online registry. Studies of at least 12week treatment duration were eligible if they were RCTs in patients with type 2 diabetes comparing addition of a DPP-4 inhibitor to insulin therapy (INS/DPP4i) with addition of a placebo to insulin therapy (INS/PCB) and contained information on the change in glycated haemoglobin (HbA1c) from baseline. RESULTS Of 3105 potentially relevant published articles and 206 registered trials, 9 studies were included for meta-analysis. Compared to INS/PCB, INS/DPP4i exhibited a greater reduction in HbA1c (weighted mean difference [WMD] -0.58%; 95% CI -0.70, -0.46) and fasting plasma glucose (WMD -0.59mmol/L; 95% CI -0.79, -0.40) with less daily insulin doses (WMD -1.86IU; 95% CI -3.27, -0.45) and with no difference in weight gain (WMD -0.04kg; 95% CI -0.25, 0.16). The risk of hypoglycaemia was similar between INS/DPP-4i and INS/PCB (the RR in favour of INS/PCB was 0.94; 95% CI 0.84, 1.05). CONCLUSIONS Compared to placebo, DPP-4 inhibitors exhibit a better glycaemic control without further increasing the risk of weight gain and hypoglycaemia in patients with type 2 diabetes inadequately controlled with insulin.

Hemoglobin Glycation Index Is Associated With Cardiovascular Diseases in People With Impaired Glucose Metabolism

Context There is a substantial interindividual variation in the association between glycated hemoglobin (HbA1c) and plasma glucose concentrations. Its impact on cardiovascular disease (CVD) has not been comprehensively evaluated. Objective We examined associations between interindividual variations in HbA1c, which was estimated as the hemoglobin glycation index (HGI), and CVD. Design, Setting, and Participants We performed a cross-sectional analysis with 1248 treatment-naïve subjects with prediabetes or diabetes. The HGI was defined as the measured HbA1c minus predicted HbA1c, which was calculated from the linear relationship between HbA1c and fasting plasma glucose levels. Main Outcome Measures The prevalence of composite and individual CVDs including coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Results The overall prevalence of composite CVD was 10.3% and individual prevalences of CAD, stroke, and PAD were 5.7%, 5.1%, and 1.3%, respectively. All prevalences significantly increased from the first to third tertile of HGI. In multivariate analysis, the highest HGI tertile was independently associated with composite CVD [odds ratio (95% confidence interval): 2.81 (1.59-4.98)], and individual CAD [2.30 (1.12-4.73)], stroke [3.40 (1.50-7.73)], and PAD [6.37 (1.18-34.33)] after adjustment for other CVD risk factors including HbA1c levels. Two consecutive measurements of HGI obtained on different days showed good correlation (r = 0.651, P < 0.001) and high concordance rate in the tertile classification (69.1%). Conclusions High HGI was independently associated with overall and individual CVDs. This result suggests that discrepancy between HbA1c and fasting glucose levels can reflect vascular health in subjects with impaired glucose metabolism.

Normal Glucose Tolerance with a High 1-Hour Postload Plasma Glucose Level Exhibits Decreased β-Cell Function Similar to Impaired Glucose Tolerance.

Background Subjects with normal glucose tolerance (NGT) who have a high 1-hour postload plasma glucose level (≥155 mg/dL; NGT 1 hour-high) have been shown to be at higher risk for type 2 diabetes than subjects with NGT 1 hour-low postload plasma glucose level (<155 mg/dL). We compared β-cell function in subjects with NGT 1 hour-high, NGT 1 hour-low, and impaired glucose tolerance (IGT). Methods We classified subjects into NGT 1 hour-low (n=149), NGT 1 hour-high (n=43), and IGT (n=52). The β-cell function was assessed based on insulinogenic index (IGI), oral disposition index (DI), and insulin secretion-sensitivity index-2 (ISSI-2). Results Insulin sensitivity was comparable between the subjects with NGT 1 hour-high and NGT 1 hour-low. The β-cell function with/without adjusting insulin sensitivity was significantly different among the three groups. The IGI (pmol/mmol) was 116.8±107.3 vs. 64.8±47.8 vs. 65.8±80.6 (P=0.141), oral DI was 3.5±4.2 vs. 1.8±1.4 vs. 1.8±3.1 (P<0.001), and ISSI-2 was 301.2±113.7 vs. 213.2±67.3 vs. 172.5±87.5 (P<0.001) in NGT 1 hour-low, NGT 1 hour-high, and IGT, respectively. Post hoc analyses revealed that oral DI and ISSI-2 were significantly different between NGT 1 hour-low and NGT 1 hour-high but comparable between NGT 1 hour-high and IGT. Conclusion Among Korean subjects with NGT, those who have a higher 1-hour postload glucose level have a compromised insulin-sensitivity adjusted β-cell function to a similar degree as IGT subjects.

Effects of gemigliptin, a dipeptidyl peptidase-4 inhibitor, on lipid metabolism and endotoxemia after a high-fat meal in patients with type 2 diabetes

We aimed to investigate the effects of gemigliptin, a dipeptidyl peptidase‐4 inhibitor, on postprandial lipoprotein levels and endotoxemia in a randomized, double‐blind, placebo‐controlled, crossover study. Ten people with type 2 diabetes mellitus (T2DM), inadequately controlled with oral antidiabetic medications and/or lifestyle modification, were randomized to gemigliptin or placebo for 4 weeks. At the end of each treatment phase, the study participants underwent a high‐fat meal tolerance test and needle aspiration of abdominal subcutaneous adipose tissue. The median (range) fasting and total area under the curve of apolipoprotein B48 (ApoB48) were significantly lower with gemigliptin than with placebo (2.9 [1.5‐15.8] µg/mL vs 4.2 [1.3‐23.4] µg/mL; P = .020; 35.3 [14.4‐87.4] µg/mL × hour vs 42.2 [17.5‐109.0] µg/mL × hour; P = .020, respectively), whereas apolipoprotein B100 showed no significant difference. Serum endotoxin levels were undetectable in 70% of the samples, so we were not able to evaluate the effect of gemigliptin on endotoxemia. The gene expression of inflammatory cytokines in subcutaneous adipose tissue was not affected by gemigliptin. Gemigliptin reduced ApoB48 levels after a high‐fat meal in participants with T2DM. Whether systemic endotoxin levels can be reduced by gemigliptin requires further investigation.

Comprehensive assessment of lipoprotein subfraction profiles according to glucose metabolism status, and association with insulin resistance in subjects with early-stage impaired glucose metabolism

BACKGROUND Early detection of atherogenic dyslipidemia is crucial. We investigated lipoprotein subfraction parameters according to glucose metabolism status. METHODS We recruited 1255 lipid-lowering drug-naïve subjects with normal fasting glucose (NFG; n=200, 15.9%), impaired fasting glucose (IFG; n=443, 35.3%), or type 2 diabetes (T2D; n=612, 48.8%). Lipoprotein subfractions (1-7) were determined by polyacrylamide gel electrophoresis, separating low-density lipoprotein (LDL) into large buoyant LDL (lbLDL, LDL1-2) and small dense LDL (sdLDL, LDL3-7). Lipoprotein subfraction parameters including the sdLDL% (LDL3-7/LDL1-7), the sdLDL/lbLDL ratio (LDL3-7/LDL1-2), and weighted LDL subfraction (LDLSF) scores, were compared between groups. Their associations with insulin resistance, estimated using the homeostasis model assessment of insulin resistance, were examined. RESULTS The concentrations of sdLDL particles were significantly higher in subjects with T2D and IFG than in those with NFG (15.78±13.47mg/dl and 14.60±14.33mg/dl, respectively, vs. 12.22±12.31mg/dl). Compared with those with NFG, subjects with IFG or T2D had significantly a higher sdLDL% (15.98±15.26% vs. 19.50±16.21% or 21.46±16.81%, respectively), a higher sdLDL/lbLDL ratio (0.24±0.30 vs. 0.31±0.37 or 0.35±0.39), and a higher LDLSF score (2.08±0.91 vs. 2.30±1.14 or 2.36±1.17). These lipoprotein subfraction parameters had stronger associations with insulin resistance compared to conventional lipid profiles in the IFG and T2D groups. CONCLUSIONS Atherogenic dyslipidemia is initiated in an early stage of impaired glucose metabolism, when early intervention might be required.

Combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor in type 2 diabetes: a systematic review with meta-analysis

Sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors have complementary mode of action. For the meta-analysis comparing the efficacy and safety between SGLT2 inhibitor plus DPP4 inhibitor (SGLT2i/DPP4i) and placebo plus DPP4 inhibitor (PCB/DPP4i) in patients with type 2 diabetes mellitus (T2DM), we selected randomized controlled trials from electronic databases by predefined criteria. The primary outcome of interest was the change in glycated hemoglobin A1c (HbA1c) from baseline. Of 605 potentially relevant studies, 7 eligible RCTs comprising 2,082 patients were included.SGLT2i/DPP4i showed a greater reduction in HbA1c (weighted mean difference −0.6%, 95% CI −0.7 to −0.5%), fasting plasma glucose, 2 h postprandial plasma glucose, and body weight compared to PCB/DPP4i. The risk of hypoglycemia increased in SGLT2i/DPP4i compared to that in PCB/DPP4i only when insulin or sulfonylureas were included as a background therapy. The risk of urinary tract infection was not increased in SGLT2i/DPP4i; however, the risk of genital infection increased upon adding SGLT2 inhibitors to pre-existing DPP4 inhibitors. In conclusion, compared to PCB/DPP4i, SGLT2i/DPP4i achieved better glycemic control and greater weight reduction without increasing the risk of hypoglycemia and urinary tract infection in patients with inadequately controlled T2DM.

Independent Association of Serum Aldosterone Level with Metabolic Syndrome and Insulin Resistance in Korean Adults

Background and Objectives A relationship between renin-angiotensin system (RAS) components and metabolic syndrome (MetS) has been suggested, but not elucidated clearly. We examined the levels of RAS components in patients with and without MetS and their association with MetS in Korean population. Methods This study was approved by the review boards of the participating institutions and endorsed by the Korean Society of Lipid and Atherosclerosis. We screened 892 Koreans aged ≥20 years who underwent evaluation of hypertension, diabetes, or dyslipidemia at 6 tertiary hospitals in 2015–2016. After excluding patients who were taking diuretics, β-blockers, or RAS blockers, or suspected of primary aldosteronism, 829 individuals were enrolled. Anthropometric and biochemical parameters including aldosterone, plasma renin activity (PRA), and aldosterone-to-PRA ratio were evaluated. The homeostasis model assessment for insulin resistance (HOMA-IR) were used for evaluating insulin resistance. Results The mean age of the participants was 52.8±12.8 years, 56.3% were male, and their mean systolic and diastolic blood pressures were 133.9±20.0 and 81.2±14.6 mmHg, respectively. The levels of serum aldosterone, but not PRA, were significantly higher in subjects with MetS than in those without (20.6±33.6 vs. 15.3±12.2 ng/dL, p<0.05), and positively correlated with waist circumference, blood pressure, triglycerides, and glycated hemoglobin. The levels of aldosterone were independently associated with the number of MetS components and HOMA-IR after adjusting for conventional risk factors. Conclusions Serum aldosterone levels were higher in Korean adults with MetS than in those without. This finding suggests that increased aldosterone level might be closely associated with insulin resistance.

Efficacy and safety of combination therapy with an α-glucosidase inhibitor and a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta-analysis

The combination of dipeptidyl peptidase‐4 (DPP4) inhibitors and α‐glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose‐lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI.

Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes

BACKGROUND Euglycaemic ketoacidosis has been reported after sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. However, the degree of ketonaemia and its metabolic effects have not been well investigated. Our study examined the degree of ketonaemia induced by SGLT2 inhibition and its association with metabolic profiles in type 2 diabetes mellitus (T2DM). METHODS Biochemical parameters, including insulin, glucagon, free fatty acid (FFA), β-hydroxybutyrate (BHB) and acetoacetate (ACA) levels, were measured in 119 T2DM patients after dapagliflozin treatment for>3 months, and compared with a matched control group. RESULTS Levels of total ketones, BHB and ACA were significantly higher in the dapagliflozin group than in the control group: 283.7±311.0 vs 119.8±143.8μmol/L; 188.3±226.6 vs 78.0±106.7μmol/L; and 94.1±91.3 vs 41.8±39.1μmol/L, respectively (all P<0.001). After dapagliflozin treatment, BHB was higher than the upper limit of normal (>440μmol/L) in 13 (10.9%) patients who had no relevant symptoms. BHB level after dapagliflozin treatment correlated positively with HbA1c (r=0.280), FFA levels (r=0.596) and QUICKI (r=0.238), and negatively with BMI (r=-0.222), insulin-to-glucagon ratio (r=-0.199) and HOMA-IR (r=-0.205; all P<0.05). On multivariable linear regression analysis, QUICKI was independently associated with BHB level. CONCLUSION Ketone levels were higher in T2DM patients treated with dapagliflozin than in controls, but with no clinical symptoms or signs of ketonaemia. Low-grade ketonaemia after dapagliflozin treatment may also be associated with improved insulin sensitivity.