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Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy.
Furuhashi, M, Sakuma, I, Morimoto, T, Higashiura, Y, Sakai, A, Matsumoto, M, Sakuma, M, Shimabukuro, M, Nomiyama, T, Arasaki, O, et al
Journal of atherosclerosis and thrombosis. 2022;(1):24-37
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AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. METHODS PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. RESULTS Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07). CONCLUSIONS PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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Efficacy and safety of a sodium-glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4 inhibitor: a systematic review and meta-analysis of randomised controlled trials.
De Buitléir, C, O' Connor, E, Satti, MM, Shaw, J, Liew, A
Diabetic medicine : a journal of the British Diabetic Association. 2021;(2):e14409
Abstract
AIMS: To conduct a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor dual therapy in type 2 diabetes. METHODS This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018099398). A search was conducted via PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials of relevant randomised controlled trials up until 14 August 2020 that compared sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor therapy. A random-effects model was used. RESULTS Six randomised controlled trials (1661 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on to metformin and dipeptidyl peptidase-4 inhibitor therapy, was associated with a significant reduction in HbA1c level [mean difference -8 mmol/mol, 95% CI -10, -6 (-0.7%, 95% CI -0.9, -0.6); P < 0.00001], in fasting plasma glucose level [mean difference -1.70 mmol/l, 95% CI -1.91, -1.49; P < 0.00001], in weight (mean difference -1.76 kg, 95% CI -2.04, -1.48; P < 0.00001) and in blood pressure (systolic blood pressure: mean difference -3.6 mmHg, 95% CI -4.8, -2.4; P < 0.00001; diastolic blood pressure: mean difference -1.5 mmHg; 95% CI -2.4, -0.6; P = 0.002). Genital mycotic infections (odds ratio 7.37, 95% CI 3.06, 17.76; P < 0.00001) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (odds ratio 1.16, 95% CI 0.63, 2.13; P = 0.64), in hypoglycaemia (odds ratio 1.36, 95% CI 0.61, 3.04; P = 0.45), or in discontinuation rates due to adverse events (odds ratio 1.52, 95% CI 0.78, 2.97; P = 0.22) between the two groups. CONCLUSIONS In comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c , fasting plasma glucose and weight in people with type 2 diabetes following inadequate glycaemic control with metformin and a dipeptidyl peptidase-4 inhibitor. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.
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Efficacy of DPP-4 inhibitors and SGLT2 inhibitors compared to sulphonylureas in adult patients with diabetes with low c-peptide levels with or without anti-GAD65 antibody positivity.
Sudan, A, Kalra, A, Mirza, AA, Kant, R
Diabetes & metabolic syndrome. 2021;(4):102197
Abstract
BACKGROUND AND AIMS Latent Autoimmune Diabetes of Adulthood (LADA) is different from type 2 diabetes. Present treatment protocols do not reflect that. DPP-4 and SGLT2 inhibitors have changed therapy. DPP-4 inhibitor use has shown delayed decline in beta-cell reserve in LADA. We studied patients with low c-peptide to assess relationship between c-peptide and anti-GAD65 antibody levels and compare DPP-4 inhibitors with SGLT2 inhibitors and sulphonylureas. METHODS The study was an open-label trial conducted in 156 participants with low c-peptide (<0.8 ng/mL), age > 25 years, recently diagnosed diabetes with HBA1c ≥ 6.5%. Participants were enrolled into three arms: Group A received sulphonylureas + metformin, Group B received DPP-4 inhibitors + metformin, and Group C received SGLT-2 inhibitors + metformin. Serum anti-GAD-65 antibodies were assessed using sandwich ELISA. Participants were assessed on enrolment and after three months of dual pharmacotherapy. RESULTS The three arms were comparable on enrolment. 52% of participants with low c-peptide had high anti-GAD65 antibody titers. Significant differences were observed after three months - DPP-4 inhibitors reduced HbA1c by 1.1 ± 0.3%, compared to SGLT2 inhibitors (0.8 ± 0.13%) and sulphonylureas (0.7 ± 0.3%) CONCLUSION DPP-4 inhibitors appear to provide better glycemic control than alternate therapeutic options in patients with low serum c-peptide.
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Islet Function and Insulin Sensitivity in Latent Autoimmune Diabetes in Adults Taking Sitagliptin: A Randomized Trial.
Yang, L, Liang, H, Liu, X, Wang, X, Cheng, Y, Zhao, Y, Liu, L, Huang, G, Wang, X, Zhou, Z
The Journal of clinical endocrinology and metabolism. 2021;(4):e1529-e1541
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CONTEXT The long-term effects of dipeptidyl peptidase-4 inhibitors on β-cell function and insulin sensitivity in latent autoimmune diabetes in adults (LADA) are unclear. OBJECTIVE To investigate the effects of sitagliptin on β-cell function and insulin sensitivity in LADA patients receiving insulin. DESIGN AND SETTING A randomized controlled trial at the Second Xiangya Hospital. METHODS Fifty-one patients with LADA were randomized to sitagliptin + insulin (SITA) group or insulin alone (CONT) group for 24 months. MAIN OUTCOME MEASURES Fasting C-peptide (FCP), 2-hour postprandial C-peptide (2hCP) during mixed-meal tolerance test, △CP (2hCP - FCP), and updated homeostatic model assessment of β-cell function (HOMA2-B) were determined every 6 months. In 12 subjects, hyperglycemic clamp and hyperinsulinemic euglycemic clamp (HEC) tests were further conducted at 12-month intervals. RESULTS During the 24-month follow-up, there were no significant changes in β-cell function in the SITA group, whereas the levels of 2hCP and △CP in the CONT group were reduced at 24 months. Meanwhile, the changes in HOMA2-B from baseline were larger in the SITA group than in the CONT group. At 24 months, first-phase insulin secretion was improved in the SITA group by hyperglycemia clamp, which was higher than in the CONT group (P < .001), while glucose metabolized (M), insulin sensitivity index, and M over logarithmical insulin ratio in HEC were increased in the SITA group (all P < .01 vs baseline), which were higher than in the CONT group. CONCLUSION Compared with insulin intervention alone, sitagliptin plus insulin treatment appeared to maintain β-cell function and improve insulin sensitivity in LADA to some extent.
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Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study.
Cho, KY, Nomoto, H, Nakamura, A, Kawata, S, Sugawara, H, Takeuchi, J, Nagai, S, Omori, K, Tsuchida, K, Miya, A, et al
Journal of diabetes investigation. 2021;(8):1417-1424
Abstract
AIMS/INTRODUCTION We recently reported the beneficial effect of the combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. MATERIALS AND METHODS The CALMER study was a multicenter, open-label, prospective, randomized, parallel-group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. RESULTS All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2-82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (-14.8% vs -7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05). CONCLUSIONS Sodium-glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase-4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy.
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Begelomab for severe refractory dermatomyositis: A case report.
De Lorenzo, R, Sciorati, C, Monno, A, Cavalli, S, Bonomi, F, Tronci, S, Previtali, S, Rovere-Querini, P
Medicine. 2021;(9):e24372
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RATIONALE Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody. PATIENT CONCERNS A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia. DIAGNOSIS Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed. INTERVENTIONS The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26. OUTCOMES Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life. CONCLUSION Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
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Efficacy and Safety of Miglitol- or Repaglinide-Based Combination Therapy with Alogliptin for Drug-Naïve Patients with Type 2 Diabetes: An Open-Label, Single-Center, Parallel, Randomized Controlled Pilot Study.
Okajima, F, Sugihara, H, Emoto, N
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi. 2021;(1):71-79
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BACKGROUND Combination therapy with an alpha-glucosidase inhibitor or glinide plus a dipeptidyl peptidase-4 inhibitor is thought to be effective for glycemic control because of its effects on postprandial hyperglycemia. However, no studies have directly compared these two combination therapies in relation to efficacy and safety. METHODS Eighteen patients with type 2 diabetes were studied. All had diabetes not adequately controlled with diet and exercise therapy, an HbA1c level of ≥7.5%, and were not receiving any medication for diabetes. The patients were randomized to either miglitol- or repaglinide-based combination therapy with alogliptin. Patients received miglitol or repaglinide monotherapy for 3 months (the miglitol and repaglinide groups, respectively), after which alogliptin was added to each group as combination therapy for 3 months. A meal tolerance test (MTT) was performed before the start of treatment and at the end of monotherapy and combination therapy. RESULTS During the study period, decreases in HbA1c and glycated albumin were significantly greater in the repaglinide group than in the miglitol group; however, there was no significant difference between treatment groups at the end of the study. At the end of monotherapy, insulin secretion relative to glucose elevation (ISG0-30: area under the curve of insulin from 0 to 30 min during MTT [AUC0-30 of IRI]/AUC0-30 of plasma glucose) was significantly higher only in the repaglinide group; ISG0-30 did not significantly increase in either group after the addition of alogliptin. CONCLUSIONS The addition of alogliptin to repaglinide monotherapy did not cause glucose-independent inappropriate insulin secretion and did not appear to increase the incidence of hypoglycemia.
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The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes.
Yaribeygi, H, Farrokhi, FR, Abdalla, MA, Sathyapalan, T, Banach, M, Jamialahmadi, T, Sahebkar, A
Journal of diabetes research. 2021;:6518221
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.
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A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease.
Dougherty, JA, Guirguis, E, Thornby, KA
The Annals of pharmacotherapy. 2021;(1):65-79
Abstract
OBJECTIVE To evaluate glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl-peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT) inhibitors to treat nondiabetic and type 2 diabetes mellitus (T2DM) nonalcoholic fatty liver disease (NAFLD) as it relates to improvement in hepatosteatosis (HS) or steatohepatitis (SH). DATA SOURCES MEDLINE and CINAHL were searched from inception through May 1, 2020. Search terms included nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, fatty liver, dipeptidyl-peptidase IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose transporter 2 inhibitors. STUDY SELECTION AND DATA EXTRACTION Full-text observational and randomized controlled studies in English were included. Patients diagnosed with NAFLD, treated with GLP-1 RAs, DPP-4 inhibitors, and SGLT2 inhibitors, with measures to evaluate HS or SH were evaluated. DATA SYNTHESIS Eight GLP-1 RA trials were reviewed; 7 GLP-1 RA trials showed improvement in HS. Two studies demonstrated improvement in liver histology in patients with SH. Seven SGLT2 inhibitor studies were reviewed; 6 studies demonstrated improvements in NAFLD. Five studies showed improvements in HS, whereas 1 displayed improvement in liver histology in NASH. Six studies that included DPP-4 inhibitors were evaluated, and only 2 demonstrated improvement in NASH. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Based on evidence reviewed, GLP-1 RAs and SGLT2 inhibitors decreased HS and SH in NAFLD patients, whereas DPP-4 inhibitor therapy was not effective for patients with HS. CONCLUSIONS Based on study data utilizing imaging studies and biopsy results, GLP-1 RAs or SGLT2 inhibitors can benefit NAFLD T2DM patients. Clinical trials with larger patient populations may augment these results.
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Impact of endogenous insulin secretion on the improvement of glucose variability in Japanese patients with type 2 diabetes treated with canagliflozin plus teneligliptin.
Miya, A, Nakamura, A, Cho, KY, Kawata, S, Nomoto, H, Nagai, S, Sugawara, H, Taneda, S, Tsuchida, K, Omori, K, et al
Journal of diabetes investigation. 2021;(8):1395-1399
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AIMS/INTRODUCTION To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion. MATERIALS AND METHODS A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (ΔMAGE) was carried out in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median. RESULTS ΔMAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2 ± 28.3 vs -20.0 ± 24.6, respectively; P = 0.60). However, ΔMAGE was not ameliorated in the low CPR SWITCH group, and the ΔMAGE was significantly smaller than that in the high CPR COMB group (P < 0.01). CONCLUSIONS COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.