Combination Of Dipeptidyl Peptidase-4 Inhibitors Research Articles

7800 Real World Incidence Of Urinary Tract Infections (UTI) & Genital Tract Infections (GTI) With SGLT2 Inhibitors Alone Or In Combination With DPP4 Inhibitors In Patients With T2D In India

Abstract Disclosure: A. Gupta: None. N. Singh: None. S. Phatak: None. A.N. Singh: None. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with urinary and genital tract infections (UTI and GTI), as they increase glucose availability in these areas, fostering bacterial growth. A study found a 26% lower occurrence of UTI and GTI in patients using a combination of Dipeptidyl Peptidase-4 inhibitors (DPP4i) and SGLT2i compared to those on SGLT2i alone. (1) The present study assessed whether patients receiving SGLT2i were at increased risk of significant UTIs & GTIs compared with those using a combination of SGLT2i & DPP-4i. A cross-sectional, multicenter, real-world study was conducted that enrolled patients with Type 2 Diabetes Mellitus (T2D) from 15th June to 30th September 2023 across 42 sites in India. The recorded data encompassed demographic information, glycemic parameters, medication use & information on hygiene practices. The sample considered for this analysis is those on SGLT2i & with or without DPPi. [Note – all patients are on other OHAs besides SGLT2i or DPP4i]. Of 10,179 patients, 2,123 were on only SGLT2i (Group A), and 8,052 were on SGLT2i and DPP4i (Group B). Group A showed a significantly higher incidence of UTI (9.09% vs. 6.11%) and GTI (6.64% vs. 5.2%). Elderly patients, especially those aged 60-69 and >70, exhibited higher UTI and GTI rates in Group A. In both genders, the incidence of UTI was higher in Group A (7.93%-males & 10.53%-females) than in Group B (5.41%-males & 7.11%-females). Amongst males, the incidence of GTI was significantly higher in Group A (5.63%) than in Group B (4.12%). In females, no significant difference was noted. Two models were developed to assess the impact of SGLT2i and insulin usage on UTI and GTI likelihood. Propensity score matching addressed confounding variables like age, gender, BMI, and comorbidities. Subsequently, logistic regression analysis focused solely on medication variables. The odds of developing UTI were calculated for various medication possibilities. As against ‘No SGLT2i’, Group A has 2.24 (CI 1.69-2.96) times higher odds of UTI, while Group B has 1.45 (CI 1.15-1.72) times. or GTI, Group A shows 3.18 (CI 2.23-4.53) times higher odds, and Group B has 2.48 (CI 1.90-3.25) times, as against ‘No SGLT2i’. In summary, DPP-4 & SGLT2 inhibitors combination therapy decreases the incidence of UTI & GTI linked to SGLT2i. Reference: (1) Fadini et al. DPP4i moderate the risk of GTI & UTI associated with SGLT2i. Diab Obes Metab. 2018 Mar;20(3):740-744. Presentation: 6/2/2024

Sodium-glucose cotransporter-2 inhibitor (SGLT2i) plus glucagon-like peptide type 1 receptor combination is more effective than SGLT2i plus dipeptidyl peptidase-4 inhibitor combination in treating obese mice metabolic dysfunction-associated steatotic liver disease (MASLD).

Monotherapy to treat obesity-associated liver insult is limited. In diet-induced obese mice showing metabolic dysfunction-associated steatotic liver disease (MASLD), we aimed to compare the combinations of sodium-glucose cotransporter-2 inhibitor (SGLT2i, empagliflozin, E), dipeptidyl peptidase-4 inhibitor (DPP4i, linagliptin, L), and glucagon-like peptide type 1 receptor agonist (GLP1RA, dulaglutide, D). Male 3-month-old C57BL/6J mice were fed for 12 weeks in a control (C, n= 10) or high-fat (HF, n= 30) diet. Then, mice were followed for three additional weeks: C, HF, HF E + L, and HF E + D (n= 10/group). HF versus C showed higher hepatic triacylglycerol (TAG, +82%), steatosis (+850%), glucose intolerance (+71%), insulin (+98%), and insulin resistance (+68%). Compared to the HF group, HF E + L showed lower glucose intolerance (-60%), insulin (-61%), insulin resistance (-46%), TAG (-61%), and steatosis (-58%), and HF E + D showed lower glucose intolerance (-71%), insulin (-58%), insulin resistance (-62%), TAG (-61%), and steatosis (-82%). The principal component analysis (PCA) placed the HF group and the HF E + D group on opposite sides, while the HF E + L group was placed between C and HF E + D. PCA separated the groups considering the metabolism-related genes (glucose and lipid), mitochondrial biogenesis, and steatosis. The two pharmacological combinations showed beneficial effects in treating obesity and MASLD. However, the combination of SGLT2i and GLP1RA showed more potent beneficial effects on MASLD than SGLT2i and DPP4i and, therefore, should be the recommended combination.

Efficacy and Safety of DPP-4 Inhibitors and Metformin Combinations in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis.

Several oral antidiabetic regimens are available for treating type 2 diabetes mellitus (T2DM), dipeptidyl peptidase-4 inhibitors (DPP4i) being one of them. We conducted a network meta-analysis (NMA) comparing DPP4i plus metformin (Met) combination with other Met-based oral antidiabetic drug (OAD) combinations used in treating patients with T2DM. We searched PubMed and Embase from inception until 19th April, 2022 for phase II and phase III trials in patients with T2DM on Met-based traditional OADs. The primary outcome was assessed by change in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour post-prandial blood glucose (2h-PPG). The secondary safety outcomes assessed were hypoglycemic events, serious adverse events (SAEs), cardiovascular (CV) events, and gastrointestinal (GI) events. Sixty-two trials were included in the analysis. The combination of DPP4i + Met revealed a comparable mean reduction in HbA1c levels to the glinides (Gli) + Met combination (mean difference [MD]: -0.03%, 95% CI: 0.69, -0.65), although the difference was not statistically significant. The mean HbA1c reduction with DPP4i + Met was greater than with sulfonylureas (SU) + Met (MD: -0.05, 95% CI: -0.29, 0.39), thiazolidinedione (TZD) + Met (MD: -0.69, 95% CI: -1.39, -0.02), and SU + TZD (MD: 0.21; 95% CI: -1.30, 1.71), with no statistical significance. DPP4i + Met demonstrated a non-significant lower incidence of CV events in comparison to TZD + Met (RR: 1.01, 95% CI: 0.46, 2.45) and SU + Met (RR: 1.06, 95% CI: 0.61, 2.06). DPP4i in combination with Met was efficacious and had a well-tolerated safety profile compared with other traditional OADs. This combination can be considered as a suitable treatment option for patients with T2DM.

Sodium Glucose Cotransporter-2 Inhibitors as an Add-on Therapy to Metformin Plus Dipeptidyl Peptidase-4 Inhibitor in Patients with Type 2 Diabetes.

PurposeTo date, no study has compared the effects of adding sodium glucose cotransporter-2 (SGLT-2) inhibitors to the combination of metformin plus dipeptidyl peptidase-4 (DPP-4) inhibitors to the effects of adding other conventional anti-diabetic drugs (ADDs) to the dual therapy. We aimed to compare the effect of adding SGLT-2 inhibitors with that of adding sulfonylurea (SU) in type 2 diabetes (T2D) patients inadequately controlled with metformin plus DPP-4 inhibitors.Materials and MethodsThis study was designed to evaluate the non-inferiority of SGLT-2 inhibitor to SU as an add-on therapy to the dual combination of metformin plus DPP-4 inhibitors. A total of 292 T2D patients who started SU or SGLT-2 inhibitors as an add-on therapy to metformin plus DPP-4 inhibitors due to uncontrolled hyperglycemia, defined as glycated hemoglobin (HbA1c) ≥7%, were recruited. After propensity score matching, 90 pairs of patients remained, and 12-week changes in HbA1c levels were reviewed to assess glycemic effectiveness. Data from these patients were analyzed retrospectively.ResultsAfter 12 weeks of triple therapy, both groups showed significant changes in HbA1c levels, with a mean of -0.9% in each group. The inter-group difference was 0.01% [95% confidence interval (CI): -0.26–0.27], and the upper limit of the 95% CI was within the limit for non-inferiority (0.40%). There were no inter-group differences in the changes of liver enzyme levels and kidney function.ConclusionAdding SGLT-2 inhibitors is not inferior to adding SU as a third-line ADD to metformin plus DPP-4 inhibitor combination therapy.

Fixed-Dose Combination of Dipeptidyl Peptidase-4 Inhibitors Plus Metformin in Patients with Type 2 Diabetes: A Review on Safety and Efficacy

There is a significant increase noted in the incidence and prevalence of Type 2 diabetes mellitus (T2DM). The global number of diabetic patients is projected by the International Diabetes Federation (IDF) to reach 552 million. T2DM disease has chronic and progressive nature. More than fifty percent of patients do not attain adequate glycemic control despite initial sufficient monotherapy. To maintain target glycated hemoglobin (HbA1c) levels (<7%), dose adjustment and adoption of several diabetes therapies become necessary in many cases. Compared to monotherapy, a fixed drug combination of oral agents and metformin has proven to be more efficacious to maintain levels of blood glucose and HbA1c. The combination of dipeptidyl peptidase-4 inhibitors (DDPIs) and metformin has been explicated to effectively decrease HbA1c to a relatively higher degree compared to the use of either agent individually. This combination addresses various pathophysiological processes involved in T2DM pathogenesis. Additionally, the concerned combination is safe and associated with a lower risk of hypoglycemia. Moreover, it is well-tolerated and prescribed as an easy-to-use single pill to improve patient compliance. This review provides an overview of the pharmacology, efficacy, and safety of fixed drug combinations of DDPIs and metformin according to current practice.

Optimizing the treatment of newly diagnosed type 2 diabetes mellitus with combination of dipeptidyl peptidase-4 inhibitors and metformin: An expert opinion.

The expanding burden of Type 2 Diabetes Mellitus (T2DM) in today's world, with respect to incidence, prevalence, and cost incurred, is an existential risk to society. Various guidelines recommend individualization of treatment. This expert opinion aims to review the recent evidences and reach a consensus on the preferable combination therapy for use in newly diagnosed Indian T2DM patients with HbA1C >7.5%. The core committee included seventeen diabetes specialists. Three statements were developed, discussed, and rated by specialists and recommendations were noted. Specialists were requested to rate the statements using a 9-point Likert's scale with score of 1 being “Strongly Disagree” and 9 being “Strongly Agree”. Statement-specific scores of all the specialists were added and mean score of ≥7.00 was considered to have achieved a consensus. Statements used to meet the consensus were: Statement 1. Majority of newly-diagnosed Indian diabetics have HbA1C >7.5%; Statement 2. Patients with HbA1C >7.5% may be initiated with dual therapy of dipeptidyl peptidase-4 inhibitors (DPP4Is) + Metformin; and Statement 3. In Indian patients with HbA1C >7.5% at diagnosis, DPP4Is + Metformin may be considered as a first-line therapy. Literature review revealed that HbA1C level at the time of diagnosis in majority of Indian T2DM patients is >7.5%. Consensus was reached that dual anti-diabetic therapy should be initiated in patients with HbA1C >7.5%. DPP4Is + Metformin is the preferred cost-effective option and may be considered as a first-line therapy in Indian T2DM patients with HbA1C >7.5% at diagnosis.

Early combination therapy of empagliflozin and linagliptin exerts beneficial effects on pancreatic \u03b2 cells in diabetic db/db mice

Effects of combination therapy of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor on β-cells are still unclear, although combination agent of these two drugs has become common in clinical practice. Therefore, we aimed to elucidate the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cell mass and function and compared their effects between in an early and advanced phase of diabetes. We used 7-week-old db/db mice as an early phase and 16-week-old mice as an advanced phase and treated them for 2 weeks with oral administration of linagliptin, empagliflozin, linagliptin + empagliflozin (L + E group), and 0.5% carboxymethylcellulose (Cont group). Blood glucose levels in Empa and L + E group were significantly lower than Cont group after treatment. In addition, β-cell mass in L + E group was significantly larger than Cont group only in an early phase, accompanied by increased Ki67-positive β-cell ratio. In isolated islets, mRNA expression levels of insulin and its transcription factors were all significantly higher only in L + E group in an early phase. Furthermore, mRNA expression levels related to β-cell differentiation and proliferation were significantly increased only in L + E group in an early phase. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor exerts more beneficial effects on β-cell mass and function, especially in an early phase of diabetes rather than an advanced phase.

Urinary exosomal microRNA profiling in type 2 diabetes patients taking dipeptidyl peptidase-4 inhibitor compared with sulfonylurea.

BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to have kidney-protective benefits. To elucidate how antidiabetic agents prevent diabetic kidney disease progression, it is important to investigate their effect on the kidney environment in type 2 diabetes mellitus (DM) patients. Herein, we investigated the expression pattern of urinary exosome-derived microRNA (miRNA) in patients taking a combination of DPP-4 inhibitor and metformin (DPP-4 inhibitor group) and compared them with patients taking a combination of sulfonylurea and metformin (sulfonylurea group).MethodsThis was a prospective study involving 57 patients with type 2 DM (DPP-4 inhibitor group, n = 34; sulfonylurea group, n = 23) and healthy volunteers (n = 7). We measured urinary exosomal miRNA using the NanoString nCounter miRNA array (NanoString Technologies) across the three groups (n = 4 per each group) and validated findings using real-time polymerase chain reaction.ResultsTwenty-one differentially expressed candidate miRNAs were identified, and six (let-7c-5p, miR-23a-3p, miR-26a-3p, miR-30d, miR-205, and miR-200a) were selected for validation. Validation showed no significant difference in miRNA expression between the DPP-4 inhibitor and sulfonylurea groups. Only miR-23a-3p was significantly overexpressed in the diabetes group compared with the control group (DPP-4 inhibitor vs. control, p = 0.013; sulfonylurea vs. control, p = 0.007). This trend was consistent even after adjusting for age, sex, and body mass index.ConclusionThere was no significant difference in urine exosome miRNA expression between diabetic participants taking DPP-4 inhibitor and those taking sulfonylurea. The miR-23a levels were higher in diabetic participants than in nondiabetic controls.

Cytokine storm modulation in COVID-19: a proposed role for vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i).

A dysregulated immune response characterized by the hyperproduction of several pro-inflammatory cytokines (a.k.a. ‘cytokine storm’) plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this Perspective article we discuss the evidence for synergistic anti-inflammatory and immunomodulatory properties exerted by vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors, the latter being a class of antihyperglycemic agents used for the treatment of Type 2 diabetes, which have also been reported as immunomodulators. Then, we provide the rationale for investigation of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as an immunomodulation strategy to ratchet down the virulence of SARS-CoV-2, prevent disease progression and modulate the cytokine storm in COVID-19.

2054-P: Combination of Dipeptidyl Peptidase-4 (DPP-4) Inhibitor and Sodium–Glucose Cotransporter 2 (SGLT2) Inhibitor Substantially Protects Pancreatic ß-Cells Especially in Early Phase of Diabetes Rather than Advanced Phase

In diabetes treatment, it is important to protect pancreatic β-cells in addition to correct hyperglycemia. Although DPP-4 inhibitor and SGLT2 inhibitor are widely used nowadays, there is no report about β-cell protective effect by combination of both inhibitors. In this study, we examined the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cells and compared their effects between in early and advanced phase of diabetes. We used 7-week-old BKS. Cg-+ Leprdb/Jcl (db/db) mice as early phase and 16-week-old mice as advanced phase, and treated them for 2 weeks with oral administration of linagliptin 3 mg/kg (Lina group), empagliflozin 30mg/kg (Empa group), linagliptin + empagliflozin (L+E group), and 0.5% carboxymethylcellulose (Cont gourp). After 2-week treatment, blood glucose levels in Empa and L+E group were significantly lower than Cont group. OGTT after 1-week treatment showed that blood glucose levels were significantly lower in Empa and L+E group in both phases, and slightly lower in Lina group only in early phase. After 2-week treatment, islets size in L+E group was significantly larger than Cont group only in early phase. In GSIS using isolated islets, insulin levels in Lina, Empa and L+E group were significantly higher than Cont group in both phases. Furthermore, mRNA expression levels of ins1, ins2 and their transcription factors mafa, pdx-1, neurod and nkx6.1 were all higher in Lina and L+E group in early phase. Contrarily, mRNA expression levels of caspase3, 8 were lower in Lina and L+E group, and jnk and c-jun levels were lower in Empa and L+E group in early phase. Intriguingly, such changes were not observed in advanced phase. It seemed that DPP-4 inhibitor and SGLT2 inhibitor exerted beneficial effects on β-cells through some different mechanism. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor protects β-cells in early phase of diabetes. Disclosure Y. Fushimi: None. A. Obata: None. J. Sanada: None. Y. Nogami: None. T. Ikeda: None. Y. Obata: None. M. Shimoda: None. S. Nakanishi: None. T. Mune: None. K. Kaku: Advisory Panel; Self; Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc. Consultant; Self; Sanwa Kagaku Kenkyusho. Research Support; Self; Taisho Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Kaneto: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: A Surveillance Epidemiology and Endpoint Research Medicare study

BackgroundDipeptidyl peptidase 4 (DPP4) is a cell surface protein that can act as a tumor suppressor or activator, depending upon the level of expression and interaction with the microenvironment and chemokines. DPP4 inhibitors are used to treat diabetes.MethodsWe conducted this Surveillance Epidemiology and Endpoint Research‐Medicare database study to evaluate the role of DPP4 inhibitors on the overall survival (OS) of diabetic patients diagnosed with colorectal (CRC) and lung cancers.ResultsDiabetic patients with CRC or lung cancer who were treated with DPP4 inhibitors exhibited a statistically significant survival advantage (hazard ratio [HR] of 0.89; CI: 0.82‐0.97, P = 0.007) that remained significant after controlling for all other confounders. When DPP4 inhibitors were used in combination of metformin which is known to suppress cancer, the survival advantage was even more pronounced (HR of 0.83; CI: 0.77‐0.90, P < 0.0001). Data were then analyzed separately for two cancer types. In the CRC‐only cohort, the use of DPP4 inhibitors alone had a positive trend but did not meet statistically significant threshold (HR of 0.87; CI: 0.75‐1.00, P = 0.055), while the combined use of DPP4 inhibitors and metformin was associated with statistically significant survival advantage (HR of 0.77; CI: 0.67‐0.89, P = 0.003). Similarly, for the lung cancer cohort, use of DPP4 alone was not found to be statistically significant (HR of 0.93; CI: 0.83‐1.03, P = 0.153), whereas lung cancer patients treated with the combination of DPP4 inhibitors and metformin showed statistically significant survival advantage (HR of 0.88; CI: 0.80‐0.97, P = 0.010).ConclusionsDPP4 inhibition in CRC and lung cancer is associated with improved OS, which possibly may be due to the effect of DPP4 inhibition on immunoregulation of cancer.

Combined treatment of dipeptidyl peptidase-4 inhibitor and exercise training improves lipid profile in KK/Ta mice.

What is the central question of this study? Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice. What is the main finding and its importance? The combination of a DPP-4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36. The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP-4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP-4 inhibitor, enhances the preventive effect of exercise-induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high-fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K-A, KK/Ta mice with alogliptin (0.01%); K-Ex, KK/Ta mice with exercise training (3 days week-1 , 15-20m min-1 for 30min); and K-Ex+A, KK/Ta mice with alogliptin and exercise training (n=8 or 9 mice per group). After 8weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K-Ex+A group than in the K group. The liver expression level of PPAR-γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K-Ex+A and B groups than in the K group. Thus, combined therapy of a DPP-4 inhibitor with exercise training was effective against high-fat diet-induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP-4 inhibitor.

DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs.

Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H2O metabolism, and attenuating insulin resistance (IR).

Investigation of a Dipeptidyl Peptidase-4 Inhibitor/Thiazolidinedione Combination Drug for Patients With Type 2 Diabetes and Poor Glycemic Control: Difficulty With Patient Enrollment

BackgroundOne of the treatment options for type 2 diabetes mellitus (DM) is a combination drug (CD) that contains the dipeptidyl peptidase-4 inhibitor (DPP4I) alogliptin (AG) together with pioglitazone (PG). This CD can improve impaired insulin secretion and insulin resistance, which are the two major pathologic factors for type 2 DM, and is also expected to increase adherence to treatment. We conducted a multicenter open-label prospective study to examine the usefulness of this CD for routine management of type 2 DM.MethodsIn type 2 DM patients with poor glycemic control who had been taking a DPP4I for ≥ 1 month, PG (15 mg/day) was added (first point). When the safety of PG was confirmed after 1 - 3 months, the DPP4I and PG were switched to the CD containing AG (25 mg) and PG (15 mg) (second point). Three months after switching to the CD was defined as the final point. Evaluation of objective findings, laboratory test results, and medication adherence was performed at these three points.ResultsNineteen subjects completed the study, but this was far short of the target (160 subjects). Compared to the first point, white blood cell count (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), and fasting blood glucose (FBG) all showed a significant decrease at both the second and final points. No change in medication adherence was observed throughout the study period. The most notable point about this study was the extremely small number of subjects enrolled. As a possible explanation, we considered whether the preferences of the study doctors for antidiabetic drugs differed between specialties. The study doctors were mainly gastroenterologists, followed by endocrinologists/diabetologists and cardiologists in equal numbers. As an additional investigation, we determined the percentages of specialist doctors prescribing DPP4Is, sodium-glucose cotransporter-2 inhibitors (SGLT2Is), PG, or biguanides (BGs) as the main treatment for DM in 1 month at our hospital. We found that a low percentage of endocrinologists/diabetologists prescribing PG compared to other drugs, while cardiologists prescribed PG frequently.ConclusionsIt was confirmed that the combination of DPP4I with PG was effective for the treatment of type 2 DM and improving metabolic function. Our data also showed that prescription of antidiabetic drugs differed between specialties, suggesting differences in their response to the results of various clinical studies and adverse reaction reports.

Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Dipeptidyl Peptidase-4 Inhibition

Type 2 diabetes is characterized by absolute or relative hypoinsulinemia and hyperglucagonemia. Dipeptidyl peptidase 4 inhibitors (DPP-4i) augment insulin secretion and decrease glucagon secretion, but if glucagon is removed from the metabolic equation, the effect of DPP-4i is unknown. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, patients with type 2 diabetes (n=12, age [mean (SD)]: 60.9 (7.8) years, BMI 34.6 (7.1) kg/m2; HbA1c 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration of 1) placebo, 2) DPP-4i (5 mg linagliptin) 2 hours before the meal, 3) glucagon receptor antagonist (GRA) (300 mg LY2409021) 12 hours before the meal, and 4) GRA + DPP-4i. Compared to placebo, fasting plasma glucose (FPG) was lowered by GRA but not DPP-4i. Adding DPP-4i to GRA did not lower FPG further. Compared to placebo, DPP-4i increased insulin responses to the meal (C-peptide AUC) (P&amp;lt;0.01), but did not result in a difference in plasma glucose excursions (Figure). GRA alone lowered glucose AUC, and the combination of GRA and DPP-4i lowered glucose AUC further. In conclusion, the combination of DPP-4i and GRA has additive effects on postprandial glucose excursions. This seems to be driven by the efficient reduction in FPG by GRA combined with additional reduction in postprandial glucose excursions by DPP-4i. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. E. Nielsen-Hannerup: None. H. Maagensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Engglis

Using the concept of inhibition of dipeptidyl peptidase-4 (DPP-4) as a new treatment for type 2 diabetes mellitus (T2DM) is based on the inhibition of bioactive peptide inactivation process. Most clinical trials on DPP-4 inhibition are based on vildagliptin, sitagliptin, saxagliptin, and linagliptin. The drugs may improve glycemic control when they are given as a combination with other oral hyperglycemic agents or when they are given to patients who received metformin and still had inadequate glycemic control. Studies showed that vildagliptin was well-tolerated if it was given as add-on treatment to metformin for 24 weeks duration. In addition, vildagliptin showed significant clinical improvement proven by the associated decrease in HbA1c and fasting glucose levels. Sitagliptin in initial combination therapy with metformin decreased HbA1c level by 2.1% after 24 weeks of treatment. It was reported that DPP-4 inhibitor saxagliptin increased glycemic control when it was added to metformin. The study included 743 patients with an average HbA1c level of 8.0% when they were treated with metformin alone. After 24 weeks of treatment, saxagliptin decreased HbA1c level by 0.7%. A multicenter, randomized, placebo-controlled, double-blind, parallel-group study examined the efficacy and tolerability of linagliptin as treatment adjunctive to metformin in patients T2DM. The primary end point was changed in HbA1c from baseline to 24 weeks of treatment. The mean adjusted change from baseline in HbA1c in the linagliptin group was 0.49% compared with an increase of 0.15% in the placebo group, with 26% and 9% of participants in the linagliptin and placebo groups, respectively, achieving an HbA1c 7.0% at 24 weeks. The combination of DPP-4 inhibitors and metformin has been shown to be well-tolerated with a very low risk of hypoglycemia. Therefore, DPP-4 inhibitors and metformin combination is an efficient, safe, and well-tolerated therapy for T2DM.

Risk of fractures and diabetes medications: a nationwide cohort study.

The effects of diabetes medications on risk of fracture were investigated using the South Korea nationwide claims database. We demonstrated that the use of dipeptidyl peptidase-4 inhibitor could be associated with decreased risk of fracture. Thiazolidinedione use was associated with about 60% increased risk of fracture in real clinical practice. The effects of diabetes medication on fracture have important clinical health consequences, since most diabetes patients are at high risk of fracture. We aimed to investigate the effect of diabetes medication on fracture risk. The nationwide medical claim database in South Korea was investigated. Among 2,886,555 subjects with antidiabetes prescriptions, 207,558 subjects aged 50years and older, who initiated diabetes medication from 2008 to 2011, were analyzed. The subjects were classified based on diabetes medication classes: non-user (insufficient exposure), metformin (MET), sulfonylurea (SU), alpha-glucosidase inhibitor (AGI), MET + SU, MET + thiazolidinedione (TZD), MET + dipeptidyl peptidase-4 inhibitor (DPP4-I), and SU + TZD. A total of 5996 fractures were observed. The fracture rate varied significantly across type of diabetes medications, with MET + DPP4-I combination group having the lowest rate and SU + TZD combination group having the highest rate. Compared to non-users, MET + DPP4-I inhibitor combination group had significantly reduced composite fracture risk (hazard ratio (HR) = 0.83, P = 0.025) and significantly reduced vertebral fracture risk (HR = 0.73, P = 0.013) in the unadjusted analysis. Compared to MET + SU users, MET + DPP4-I users showed a trend of lower non-vertebral fracture risk (HR = 0.82, P = 0.086) after adjusting for all confounding variables. Patients using TZD had significantly increased risk of fracture (HR = 1.59, P < 0.001) compared with patients not using TZDs adjusting for all confounding variables. The results of this nationwide study showed a trend that DPP4 inhibitor might have a protective effect on bone metabolism compared with SU, when added to MET. Clinicians should take these results into consideration when prescribing diabetes medication, especially in elderly patients or those at high risk or fracture.

The combination of DPP-4 inhibitors versus sulfonylureas with metformin after failure of first-line treatment in the risk for major cardiovascular events and death.

To determine whether the combination of dipeptidyl-peptidase 4 (DPP-4) inhibitors vs. sulfonylureas with metformin after failure of first-line treatment is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction and stroke) and for all-cause mortality. Using the UK Clinical Practice Research Datalink, a cohort of patients newly treated with metformin or sulfonylurea monotherapy between January 1, 1988, and December 31, 2011, was identified and was followed until December 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to compare the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination so as to study the risk for a composite endpoint consisting of myocardial infarction, stroke and all-cause mortality. The models were adjusted for high-dimensional propensity score deciles. The cohort consisted of 11,807 patients that included 2286 on a DPP-4 inhibitor-metformin combination and 9521 on a sulfonylurea-metformin combination. The crude incidence rates (95% CIs) of the composite endpoint were 1.2% (0.8% to 1.7%) and 2.2% (1.9% to 2.5%) per year for the DPP-4 inhibitor-metformin and sulfonylurea-metformin combinations, respectively. In the high-dimensional propensity score-adjusted model, the use of the DPP-4 inhibitor-metformin combination was associated with a 38% decreased risk for the composite endpoint (adjusted HR: 0.62; 95% CI 0.40 to 0.98), compared with the sulfonylurea-metformin combination. The use of a DPP-4 inhibitor combination with metformin, compared with a sulfonylurea-metformin combination, was associated with decreased risks for major cardiovascular events and all-cause mortality.

Potential for combination of dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors for the treatment of type 2 diabetes.

In individuals with advanced type 2 diabetes (T2DM), combination therapy is often unavoidable to maintain glycaemic control. Currently metformin is considered the first line of defence, but many patients experience gastrointestinal adverse events, necessitating an alternative treatment approach. Established therapeutic classes, such as sulphonylureas and thiazolidinediones, have some properties undesirable in individuals with T2DM, such as hypoglycaemia risk, weight gain and fluid retention, highlighting the need for newer agents with more favourable safety profiles that can be combined and used at all stages of T2DM. New treatment strategies have focused on both dipeptidyl peptidase (DPP)-4 inhibitors, which improve hyperglycaemia by stimulating insulin secretion in a glucose-dependent fashion and suppressing glucagon secretion, and sodium-glucose co-transporter-2 (SGLT2) inhibitors, which reduce renal glucose reabsorption and induce urinary glucose excretion, thereby lowering plasma glucose. The potential complimentary mechanism of action and good tolerance profile of these two classes of agents make them attractive treatment options for combination therapy with any of the existing glucose-lowering agents, including insulin. Together, the DPP-4 and SGLT2 inhibitors fulfill a need for treatments with mechanisms of action that can be used in combination with a low risk of adverse events, such as hypoglycaemia or weight gain.

Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin.