Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

Dipeptidyl peptidase-4 inhibitors (DPP-4i) have an important place in the management of type 2 diabetes. The DPP-4 enzyme is ubiquitously distributed throughout the human body and has multiple substrates through which it regulates several important physiological functions. DPP-4 regulates several immune functions, including T-cell activation, macrophage function, and secretion of cytokines. Studies have reported an increase in autoimmune diseases like bullous pemphigoid, inflammatory bowel disease, and arthritis with DPP-4i use. The relationship of DPP-4i and autoimmune diseases is a complex one and warrants further research into the effect of DPP-4 inhibition on the immune system to understand the pathogenesis more clearly. Whether a particular cluster of autoimmune diseases is associated with DPP-4i use remains an important contentious issue. Nevertheless, a heightened awareness from the clinicians is required to identify and treat any such diseases. Through this review, we explore the clinical and pathophysiological characteristics of this association in light of recent evidence.     

The efficacy and safety of dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus patients with severe renal impairment: a meta-analysis

Aims/introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic agents, and have been increasingly and widely used in the treatment of diabetes mellitus (DM). However, information of DPP-4 inhibitors in type 2?DM patients with severe renal impairment (RI) is limited. Our study aimed to assess the efficacy and safety of DPP-4 inhibitors as compared to placebos or other hypoglycemic drugs in type 2?DM patients with severe RI. Materials and methods A meta-analysis was conducted to examine the literature comparing the effects of DPP-4 inhibitors on hemoglobin A1c (HbA1c) and fasting blood glucose (FBG). Randomized control trials (RCTs) including adults with type 2?DM and severe RI were analyzed. Safety was evaluated based on the percentage of patients who developed hypoglycemia and the occurrence of adverse events (AEs) as well as the incidence of peripheral edema, urinary tract infection, diarrhea, and death. Results Five RCTs including 503 patients were analyzed. Compared with a placebo or no treatment, DPP-4 inhibitors were associated with a larger decline in HbA1c (mean difference (MD)?=??0.57, 95% confidence interval (CI): ?0.73 to ?0.41; p?0.01) but not with FBG (MD?=??0.26, 95% CI: ?1.40 to 0.8; p?= 0.66). Compared with glipizide monotherapy, no significant differences in HbA1c (MD?=?0.15, 95% CI: ?0.19 to 0.49; p?= 0.38) or FBG (MD?=??0.26, 95% CI: ?1.16 to 0.64; p?= 0.57) were found. Similar odds of experiencing an AE were found in both the DPP-4 inhibitor groups and comparison groups. Conclusions In type 2?DM patients with severe RI, treatment with DPP-4 inhibitors is safe and it effectively lowers HbA1c.     

Incretin manipulation in diabetes management

Incretin-based therapies have revolutionized the medical management of type 2 diabetes mellitus(T2DM) in the 21 st century. Glucagon-like peptide-1(GLP-1) suppresses appetite and gastric motility, and has trophic effects on pancreas, cardio-protective and renal effects. GLP-1 analogues and dipeptidyl peptidase-4 inhibitors form the incretin-based therapies. Significant reduction of hemoglobin A1 c when used as monotherapy and in combination regimens, favorable effects on body weight, and low risk of hypoglycemia are their unique therapeutic benefits. Their safety and tolerability are comparable to other anti-diabetic medications. Concern about elevated risk of pancreatitis has been discarded by two recent meta-analyses. This article discusses the therapeutic manipulation of incretin system for the management of T2 DM.     

Efficacy of anagliptin as compared to linagliptin on metabolic parameters over 2 years of drug consumption: A retrospective cohort study

AIM To evaluate the comparative effectiveness of anagliptin and linagliptin on the clinical parameters in patients with type 2 diabetes mellitus(T2 DM). METHODS A 2-year retrospective cohort study was conducted in patients with T2 DM who received anagliptin and linagliptin. We enrolled 234 patients(anagliptin group, 117 patients; linagliptin group, 117 patients). RESULTS The glycemic control considerably improved 3, 6, 12, and 24 mo after the administration of both dipeptidyl peptidase-4(DPP-4) inhibitors. Following the administration of anagliptin, the diastolic blood pressure and serum total cholesterol levels decreased. However, serum high-density lipoprotein cholesterol levels increased and urinary albumin-creatinine ratio decreased following linagliptin administration. Furthermore, the liver function improved after the administration of linagliptin.CONCLUSION These findings suggest that that the efficacy of DPP-4 inhibitors on the blood pressure, lipid profile, and liver function differs between anagliptin and linagliptin.     

二肽基肽酶-4在瘢痕疙瘩中的表达情况研究

目的:探讨二肽基肽酶-4(DPP4)在瘢痕疙瘩中的表达情况。方法:分别获取切除术后的瘢痕疙瘩组织及正常皮肤组织,然后通过蛋白免疫印迹方法、定量聚合酶链反应,比较二者DPP4基因在蛋白和mRNA水平上表达的差异。结果:与正常皮肤组织相比,DPP4蛋白在瘢痕疙瘩组织中的表达高于正常皮肤,差异有统计学意义(P<0.05),DPP4基因在mRNA水平上的表达高于正常皮肤(P<0.05)。结论:DPP4在瘢痕疙瘩中的表达上升,DPP4可能在促进成纤维细胞活化、纤维化形成方面有一定作用。     

Comparison between sitagliptin and nateglinide on postprandial lipid levels: The STANDARD study

AIM: To assess the effects of sitagliptin and nateglinide on lipid metabolism. METHODS: In a parallel group comparative open trial, patients with type 2 diabetes mellitus under treatment at the Japanese Red Cross Medical Center were randomly assigned to receive either sitagliptin (50 mg once daily) or nateglinide (90 mg three times daily before meals). Eligible patients met the following criteria: age ≥ 20 years; hemoglobin A 1c (HbA 1c ) > 6.5% despite diet and exercise; HbA 1c between 6.5% and 8.0%; fasting glucose < 7.77 mmol/L; diet and exercise therapy for more than 3 mo; and ability to read and understand the information for written informed consent. Exclusion criteria were contraindications to sitagliptin, contraindications to nateglinide, pregnancy or possible pregnancy, and severe liver/renal failure. Patients who were considered to be unsuitable by the attending physician for other reasons were also excluded. Blood samples were collected at one and three hours after intake of a test meal. The primary outcome measure was the area under the curve (AUC) of apolipoprotein (Apo) B48 at three hours postprandially. RESULTS: Twenty patients were randomly assigned to the sitagliptin group and sixteen patients were randomized to the nateglinide group. All 36 patients took the medication as directed by the physician in both groups, and they all were analyzed. Apart from antidiabetic drugs, there was no difference between the two groups with respect to the frequency of combined use of lipid-lowering, antihypertensive, and/or antiplatelet drugs. The doses of these medications were maintained during 12 wk of treatment. Detailed dietary advice, together with adequate exercise therapy, was given to the patients so that other factors apart from the two test drugs were similar in the two groups. There were no significant differences of the baseline characteristics between the two groups, except for body mass index (the sitagliptin group: 25.14 ± 3.05 kg/m 2 ; the nateglinide group: 21.39 ± 2.24 kg/m 2 ). Fasting levels of HbA 1c , glycated albumin, 1.5-anhydroglucitol, and blood glucose, as well as the blood glucose levels at one and three hours postprandially, improved in both groups after 12 wk of treatment, and there were no significant differences between the two groups. However, the glucagon level at one hour postprandially (P = 0.040) and the diastolic blood pressure (P<0.01) only showed a significant decrease in the sitagliptin group. In the nateglinide group, there was no significant change in the AUC of Apo B48, the glucagon level at one hour postprandially, the fasting triglyceride level, or the diastolic blood pressure. Body weight was unchanged in both groups. However, the AUC of Apo B48 at three hours postprandially showed a significant decrease in the sitagliptin group from 2.48 ± 0.11 at baseline to 1.94 ± 0.78 g/L per hour after 12 wk (P=0.019). The fasting triglyceride level also decreased significantly in the sitagliptin group (P = 0.035). With regard to lipid-related markers other than Apo B48 and fasting triglycerides, no significant changes were observed with respect to Apo A1, Apo B, or Apo C3 in either group. No adverse events occurred in either group. CONCLUSION: Sitagliptin significantly improves some lipid parameters while having a comparable effect on blood glucose to nateglinide. A large-scale prospective study of sitagliptin therapy is warranted.     

Antidiabetic treatment,stroke severity and outcome

Ischemic stroke is a leading cause of mortality and long-term disability worldwide. Given the detrimental effects of acute stroke, several neuroprotective agents have been evaluated in these patients. However, the benefits of the evaluated agents appear to be limited and none is currently recommended for clinical use. On the other hand, prior treatment with agents that are used for the primary and secondary prevention of stroke, including statins and antiplatelets, has been associated with better outcome in patients who experience an acute stroke. In contrast, there are limited data as to whether prior treatment with antidiabetic agents is beneficial in diabetic patients who suffer a stroke. In this context, the findings of a recent study that showed reduced stroke size following pretreatment with linagliptin, a dipeptidyl peptidase-4(DDP-4) inhibitor, compared with glimepiride, in both diabetic and non-diabetic mice, appear promising. Despite these preclinical findings suggesting neuroprotective effects of DPP-4 inhibitors in acute stroke, it is still unclear whether these actions will also be observed in humans. Of note, two recent large randomized, placebo-controlled studies did not show any effect of DPP-4 inhibitors on cardiovascular events, including stroke. Several other ongoing trials are evaluating the effects of DPP-4 inhibitors on cardiovascular morbidity and mortality. These studies also provide a major opportunity to assess whether patients treated with this class of antidiabetic agents will suffer from less severe strokes and whether their outcome after stroke will be more favorable.     

Recent advances in new-onset diabetes mellitus after kidney transplantation

A common challenge in managing kidney transplant recipients (KTR) is post-transplant diabetes mellitus (PTDM) or diabetes mellitus (DM) newly diagnosed after transplantation, in addition to known pre-existing DM. PTDM is an important risk factor for post-transplant cardiovascular (CV) disease, which adversely affects patient survival and quality of life. CV disease in KTR may manifest as ischemic heart disease, heart failure, and/or left ventricular hypertrophy. Available therapies for PTDM include most agents currently used to treat type 2 diabetes. More recently, the use of sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and dipeptidyl peptidase 4 inhibitors (DPP4i) has cautiously extended to KTR with PTDM, even though KTR are typically excluded from large general population clinical trials. Initial evidence from observational studies seems to indicate that SGLT2i, GLP-1 RA, and DPP4i may be safe and effective for glycemic control in KTR, but their benefit in reducing CV events in this otherwise high-risk population remains unproven. These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status, pre-existing burden of peripheral vascular disease, urinary tract infections due to immunosuppression and a surgically altered urinary tract, erythrocytosis from calcineurin inhibitors, and reduced kidney function from acute or chronic rejection.     

Insulin plus incretin:A glucose-lowering strategy for type 2-diabetes简

There are many advantages of combining incretin therapy [glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] with insulin therapy as a glucose-lowering strategy in type 2 diabetes. One important advantage is the complementary mode of the mechanistic action of incretin and insulin therapy. Another advantage is the reduction in risk of hypoglycemia and weight gain when adding incretin therapy to insulin. Several clinical trials have studied the addition of GLP-1 receptor agonists [exenatide BID (twice daily), lixisenatide, albiglutide] or DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, alogliptin, linagliptin) to ongoing insulin therapy or adding insulin to ongoing therapy with a GLP-1 receptor agonist (liraglutide). These studies show improved glycemia in the presence of limited risk for hypoglycemia and weight gain with the combination of incretin therapy with insulin. This article reviews the background and clinical studies on this combination.     

Interactions between diabetes and COVID-19: A narrative review

Diabetes, whether due to pancreatic beta cells insufficiency or peripheral resistance to insulin, has been suggested as a risk factor of developing severe acute respiratory disease coronavirus-2 (SARS-CoV-2) infections. Indeed, diabetes has been associated with a higher risk of infections and higher risk of developing severe forms of coronavirus disease 2019 (COVID-19) related pneumonia. Diabetic patients often present associated comorbidities such as obesity, hypertension and cardiovascular diseases, and complications of diabetes, including chronic kidney disease, vasculopathy and relative immune dysfunction, all of which make them more susceptible to infectious complications. Moreover, they often present low-grade inflammation with increased circulating interleukin levels, endothelial susceptibility to inflammation and dysfunction, and finally, hyperglycemia, which increases this risk. Additionally, corticosteroids, which count among the few medications which showed benefit on survival and mechanical ventilation requirement in COVID-19 pneumonia in large randomized controlled trials, are associated to new onsets of diabetes, and metabolic disorders in patients with previous history of diabetes. Finally, SARS-CoV-2 via the alternate effects of the renin-angiotensin system, mediated by the angiotensin-converting-enzyme 2, was also associated with insulin resistance in key tissues involved in glucose homeostasis, such as liver, skeletal muscles, and adipose tissue; and also, with impaired insulin secretion by pancreatic β-cells. In this work, we reviewed all elements which may help understand how diabetes affects patients with COVID-19, how treatments affect outcomes in patients with COVID-19, how they may cause new onsets of diabetes, and finally review how SARS-CoV-2 may inherently be a risk factor of developing diabetes, through immune-mediated diabetogenic mechanisms.     

Treatment of type 2 diabetes,lifestyle, GLP1 agonists and DPP4 inhibitors

In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes.Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality.Drugs which inhibit glucose re-absorption in the kidney,sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.     

Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1

AIM: To investigate whether active glucagon-like peptide-1(GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus(GLP-1 FEST:UMIN000010645). METHODS: Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c(Hb A1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. RESULTS: At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of Hb A1c(7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of Hb A1c(7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significantexplanatory variable for an Hb A1 c decrease of ≥ 0.5%, and its odds ratio is 4.5(1.40-17.6)(P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for Hb A1 c level before administration, patients' medical history, medications, insulin secretion and insulin resistance.CONCLUSION: Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.     

Incretin-based therapies in prediabetes: Current evidence and future perspectives

The prevalence of type 2 diabetes(T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance(NGT) and the clinical entity of T2 D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2 D. The huge burden resulting from the complications of T2 D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists, on β-cell function in patients with T2 D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2 D.     

Novel glucose-lowering drugs for non-alcoholic fatty liver disease

BACKGROUNDThe efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown.AIMTo evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments.METHODSElectronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline.RESULTSNineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups.CONCLUSIONTreatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.     

Dipeptidyl peptidase-4 activity,lipopolysaccharide, C-reactive protein,glucose metabolism,and gut peptides 3 months after bariatric surgery

BackgroundBariatric surgery induces weight loss, but changes in glucose metabolism, gut peptides, and inflammatory biomarkers still have conflicting results.SettingsUniversity hospital.ObjectivesWe investigated glucose metabolism, gut hormones, and inflammatory profile after bariatric surgery and medical treatment.MethodsForty patients with obesity were recruited and were subjected to Roux-en-Y gastric bypass (n = 15; Bariatric Surgery Group - BSG) or received medical care (n = 20; MG). Sleeve gastrectomy was performed in five patients who were excluded from analysis. Glucose, insulin, homeostatic model for the assessment of insulin resistance (HOMA-IR), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon, ghrelin, dipeptidyl peptidase-4 (DPP-4) activity, circulating lipopolysaccharide (LPS), LPS-binding protein (LPB) and high-sensitivity C-reactive protein (hs-CRP) were evaluated before and three months after each treatment. Except for HOMA-IR, hs-CRP, and LBP, all variables were assessed at fasting and 30- and 60-minutes after a standard meal.ResultsAfter 3 months, both groups lost weight. However, BSG had a more extensive reduction than MG (respectively, 17.6% vs. 4.25%; P < 0.01). Except for LPS levels, higher on BSG than MG (1.38 ± 0.96 vs. 0.83 ± 0.60 EU/ml, P < 0.01), groups were similar before treatment. In respect to metabolic/hormonal changes, the BSG showed higher glucose, insulin, GLP-1, and GIP levels at 30-min and also GLP-1 at 30- and 60-minutes. DPP-4 activity, HOMA-IR, and fasting LBP did not change. LPS levels at 60-minutes decreased after surgery in the BSG. hs-CRP decreased on BSG compared to MG.ConclusionsBariatric surgery resulted in more extensive effects on glucose metabolism, gut hormones, and inflammation.     

Cystic fibrosis-related diabetes: The unmet need

Cystic fibrosis(CF) is a common autosomal recessive disease. Life expectancy of patients with CF continues to improve mainly driven by the evolving therapies for CF-related organ dysfunction. The prevalence of CF-related diabetes(CFRD)increases exponentially as patients' age. Clinical care guidelines for CFRD from2010, recommend insulin as the mainstay of treatment. Many patients with CFRD may not require exogenous insulin due to the heterogeneity of this clinical entity.Maintenance of euglycemia by enhancing endogenous insulin production,secretion and degradation with novel pharmacological therapies like glucagonlike peptide-1 agonist is an option that remains to be fully explored. As such, the scope of this article will focus on our perspective of glucagon-like peptide-1 receptor agonist in the context of CFRD. Other potential options such as sodiumglucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors and their impact on this patient population is limited and further studies are required.     

Clinical effects of antidiabetic drugs on psoriasis: The perspective of evidence-based medicine

Psoriasis and diabetes shared common underlying pathophysiological mechanisms. Emerging data suggested that antidiabetic medications may improve the psoriasis severity in patients with diabetes mellitus. Several hypoglycemic agents including thiazolidinediones, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and biguanides have been reported to make a remarkable reduction in the Psoriasis Area and Severity Index score from baseline. This antipsoriatic effect could be mediated not only by the glucoselowering action of these agents but also via inhibition of keratinocyte over proliferation, increase expression of differentiation markers, suppression the immune inflammatory pathway, and blocking the calcium channels and mitogen-activated protein kinase signaling pathways. On the other hand, there was no significant increase in adverse reactions associated with the treatment of pioglitazone or metformin. However, previous studies often had the relatively short duration of the trials, and did not have enough power to assess recurrence of psoriasis. Potential bias in the study and missing data could undermine the reliability of the results. Therefore, the appropriately randomized controlled studies with large sample sizes and long-term durations in various psoriasis patients are warranted for further support.     

Crosstalk between gut microbiota and antidiabetic drug action

Type 2 diabetes(T2 D) is a disorder characterized by chronic inflated blood glucose levels(hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2 D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin, α-glucosidase inhibitors, glucagon-like peptide-1 agonists,peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2 D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2 D,and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria,responsible for losing weight and suppressing inflammation.