Identification, characterization, and insights into the mechanism of novel dipeptidyl peptidase-IV inhibitory peptides from yak hemoglobin by in silico exploration, molecular docking, and in vitro assessment.

Dipeptidyl peptidase IV (DPP-IV) inhibitory peptides were screened and identified from yak hemoglobin for the first time by in silico analysis, molecular docking, and in vitro evaluation. Results showed that yak hemoglobin had a high potential to produce DPP-IV inhibitory peptides based on the sequence alignment and bioactive potential evaluation. Furthermore, "pancreatic elastase + stem bromelain" was the optimal combined-enzymatic strategy by simulated proteolysis. Additionally, 25 novel peptides were found from its simulated hydrolysate, among which 10 peptides had high binding affinities with DPP-IV by molecular docking. Most of these peptides were also in silico characterized with favorable physicochemical properties and biological potentials, including relatively low molecular weight, high hydrophobicity, several net charges, good water solubility, nontoxicity, acceptable sensory quality, and good human intestinal absorption. Finally, six novel DPP-IV inhibitory peptides were identified via in vitro assessment, among which EEKA (IC50 = 235.26 µM), DEV (IC50 = 339.45 µM), and HCDKL (IC50 = 632.93 µM) showed the strongest capacities. The hydrogen bonds and electrostatic attractions formed with core residues within the S2 pocket of DPP-IV could be mainly responsible for their inhibition performances. This work provided a time-saving method and broadened application for yak by-products development as sources of functional foods.

Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are commonly at high risk for developing cognitive dysfunction. Antidiabetic agents might be repurposed for targeting cognitive dysfunction in addition to modulation on glucose homeostasis. This study aimed to evaluate the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on cognitive function in T2DM. METHODS: PubMed, Embase, Cochrane Library and Web of Science were systematically searched from inception to September 30, 2023. Weighted mean differences were calculated using the Mantel-Haenszel (M-H) fixed or random effects model based on the degree of heterogeneity among studies. Heterogeneity was evaluated using a Chi-squared test and quantified with Higgins I2. Sensitivity analysis was performed with the leave-one-out method, and publication bias was evaluated according to Begg's and Egger's tests. RESULTS: Six clinical trials involving 5,178 participants were included in the pooled analysis. Administration of DPP-4i generally correlated with an increase of Mini-Mental State Examination (MMSE) scores (1.09, 95% CI: 0.22 to 1.96). DPP-4i alleviated cognitive impairment in the copying skill subdomain of MMSE (0.26, 95% CI: 0.12 to 0.40). Treatment with DPP-4i also resulted in an increase of Instrumental Activities of Daily Living (IADL) scores (0.82, 95% CI: 0.30 to 1.34). However, DPP-4i produced no significant effects on Barthel Activities of Daily Living (BADL) scores (0.37, 95% CI: -1.26 to 1.99) or other test scores. CONCLUSIONS: DPP-4i treatment favourably improved cognitive function in patients with T2DM. Further trials with larger samples should be performed to confirm these estimates and investigate the association of different DPP-4i with cognitive function among diabetic patients. TRIAL REGISTRATION IN PROSPERO: CRD42023430873.

Pharmacoeconomic evaluation of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus: a systematic literature review.

INTRODUCTION: Dipeptidyl peptidase-4 inhibitors (DPP-4i) are widely used oral antidiabetic agents that exert antihyperglycemic effects in type 2 diabetes mellitus (T2DM) without increased risk of weight gain or hypoglycemic events. The objective of this paper was to systematically review the latest evidence that was associated with the pharmacoeconomic evaluation of DPP-4i for the treatment of patients with T2DM. AREAS COVERED: We conducted a systematic literature search of eligible articles published since inception up to March 2021 in Web of Science, MEDLINE (via PubMed), and ECONLIT. Fifty-four eligible articles were included in our review, in which DPP-4i were compared to metformin (4 studies), sulphonylurea (SU) (16 studies), alpha-glucosidase inhibitors (AGI) (3 studies), thiazolidinediones (TZD) (4 studies), other DPP-4i (3 studies), sodium-glucose co-transporter-2 inhibitors (SGLT-2i) (10 studies), glucagon-like peptide 1 receptor agonist (GLP-1RA) (18 studies), insulin (5 studies), and other antidiabetic therapies (5 studies). EXPERT OPINION: This study provided the updated evidence of systematic pharmacoeconomic evaluation associated with DPP-4i for the treatment of patients with T2DM. The evidence from the literature suggested that DPP-4i may be more cost-effective compared to SU and insulin as second-line therapy after metformin but not a cost-effective alternative compared to SGLPT-2i and GLP-1RA.

Dispensation Patterns of Glucose-Lowering Drugs in Newly Diagnosed Type 2 Diabetes: Routine Data Analysis of Insurance Claims in Germany.

AIMS: To describe dispensation patterns of glucose-lowering drugs in newly diagnosed type 2 diabetes in Germany. MATERIALS AND METHODS: Based on claims data from four statutory health insurances (German Pharmacoepidemiological Research Database,>25 million insurants), all individuals with newly diagnosed type 2 diabetes were identified. Eligible patients had a first diagnosis for type 2 diabetes between January 2012 and December 2016. We analyzed the dispensation patterns of first-line glucose-lowering therapies initiated in the year after diabetes diagnosis and patterns of second-line therapies dispensed one year after first-line treatment. RESULTS: A total of 356,647 individuals with newly diagnosed type 2 diabetes were included (average age [SD]: 63.5 [13.4] years; 49.3% males). Of the 31.6% of individuals who were pharmacologically treated in the year after diagnosis, metformin monotherapy was most frequently dispensed (73.1%), followed by dual therapy of metformin and dipeptidyl peptidase-4 inhibitors (DPP-4is) (6.4%), and monotherapy with DPP-4is (2.9%). From 2012 through 2016, sulfonylurea dispensations were reduced by more than 50%. Dispensations for combination therapies with DPP-4is increased up to 10.6%. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors contributed to 2% of all treatments. After a median of 5 months, 20.0% of individuals on pharmacological therapy initiated second-line glucose-lowering treatment. CONCLUSIONS: Data from German statutory health insurances (2012 to 2016) showed that most individuals with newly diagnosed type 2 diabetes were dispensed metformin monotherapy in line with diabetes care guidelines. A substantial decrease in the use of sulfonylureas was observed after the introduction of DPP-4i and GLP-1 receptor agonists.

In Silico and In Vitro Assessment of Portuguese Oyster (Crassostrea angulata) Proteins as Precursor of Bioactive Peptides.

In this study, the potential bioactivities of Portuguese oyster (Crassostrea angulata) proteins were predicted through in silico analyses and confirmed by in vitro tests. C. angulata proteins were characterized by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and identified by proteomics techniques. Hydrolysis simulation by BIOPEP-UWM database revealed that pepsin (pH > 2) can theoretically release greatest amount of bioactive peptides from C. angulata proteins, predominantly angiotensin I-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) inhibitory peptides, followed by stem bromelain and papain. Hydrolysates produced by pepsin, bromelain and papain have shown ACE and DPP-IV inhibitory activities in vitro, with pepsin hydrolysate (PEH) having the strongest activity of 78.18% and 44.34% at 2 mg/mL, respectively. Bioactivity assays of PEH fractions showed that low molecular weight (MW) fractions possessed stronger inhibitory activity than crude hydrolysate. Overall, in vitro analysis results corresponded with in silico predictions. Current findings suggest that in silico analysis is a rapid method to predict bioactive peptides in food proteins and determine suitable enzymes for hydrolysis. Moreover, C. angulata proteins can be a potential source of peptides with pharmaceutical and nutraceutical application.

Bullous pemphigoid induced by dipeptidyl peptidase-4 (DPP-4) inhibitors: a pharmacovigilance-pharmacodynamic/pharmacokinetic assessment through an analysis of the vigibase®.

Objectives: To examine the signals of bullous pemphigoid (BP) with dipeptidyl peptidase-4 inhibitors (DPP-4i) in VigiBase® and the potential role of their pharmacodynamic/pharmacokinetic parameters in the occurrence of BP. Methods: Case/non-case analyses were performed in VigiBase® to examine the signal of BP [reporting odds ratio (ROR)] for gliptins. Secondly, the authors performed linear regression analyses to explore the association between DPP-4i signals for BP and their affinities toward different target enzymes (DPP-2, DPP-4, DPP-8, and DPP-9) and their volume of distribution (Vd). Results: A significant BP signal was found for DPP-4i. The ROR for pooled DPP-4i was 179.48 (95% CI: 166.41-193.58). The highest ROR was found for teneligliptin 975.04 (801.70-1185.87) and lowest for saxagliptin 18.9 (11.5-30.9). Linear regression analyses showed a considerable trend to significance for the linear correlation between the BP signal and gliptin affinity at DPP-4 (slope = 1.316 [-0.4385-3.21], p = 0.067, R2 = 0.40) but not the other enzyme targets, nor for Vd. Conclusion: The findings suggest a clinical relevance of gliptins selectivity for DDP-4 in the development of BP as a result of exposure to these drugs. Future preclinical and clinical studies are needed for a better understanding of this correlation.

Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Outcome and Cardiac Function in Patients With Diabetes and Heart Failure　- Insights From the Ibaraki Cardiac Assessment Study-Heart Failure (ICAS-HF) Registry.

BACKGROUND: Although experimental animal studies report many pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), their prognostic value has not been demonstrated in clinical trials.Methods and Results:Among 838 prospectively enrolled heart failure (HF) patients hospitalized for acute decompensated HF, 79 treated with DPP-4i were compared with 79 propensity score-matched non-DPP-4i diabetes mellitus (DM) patients. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of cardiovascular death and hospitalization. During follow-up (423±260 days), 8 patients (10.1%) in the DPP-4i group and 13 (16.5%) in the non-DPP-4i group died (log-rank, P=0.283). The DPP-4i group did not have a significantly higher rate of all-cause mortality (log-rank, P=0.283), or cardiovascular death or hospitalization (log-rank, P=0.425). In a subgroup analysis of HF with preserved ejection fraction (HFpEF; n=75), the DPP-4i group had a significantly better prognosis than the non-DPP-4i group regarding the primary endpoint (log-rank, P=0.021) and a tendency to have better prognosis regarding the secondary endpoint (log-rank, P=0.119). In patients with HF with reduced EF (n=83), DPP-4i did not result in better prognosis. CONCLUSIONS: DPP-4i did not increase the risk of adverse clinical outcomes in patients with DM and HF. DPP-4i may be beneficial in HFpEF.

Health-related quality-of-life implications of cardiovascular events in individuals with type 2 diabetes mellitus: A subanalysis from the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-TIMI 53 trial.

BACKGROUND: The impact of cardiovascular complications on health-related quality-of-life (HRQoL) in type 2 diabetes mellitus has not been clearly established. Using EQ5D utility data from SAVOR-TIMI 53, a large phase IV trial of saxagliptin versus placebo, we quantified the impact of cardiovascular and other major events on HRQoL. METHODS: EQ5D utilities were recorded annually and following myocardial infarction (MI) or stroke. Utilities among patients experiencing major cardiovascular events were analyzed using linear mixed-effects regression, adjusting for baseline characteristics (including EQ5D utility), and compared to those not experiencing major cardiovascular events. Mean utility decrements with standard errors (SE) were estimated as the difference in utility before and after the event. FINDINGS: The mean EQ5D utility of the sample was 0.776 at all time points, and did not differ by treatment. However, mean baseline and month 12 utilities among those with a major cardiovascular event were 0.751 and 0.714. Mean utilities were 0.691 within 3months of, 0.691 3-6months after, and 0.714 6-12months after, a major cardiovascular event. Cardiovascular event-specific utility decrements were 0.05 (0.007) for major cardiovascular events over the same time periods. Decrements of 0.051 (0.012; myocardial infarction), 0.111 (0.022; stroke), 0.065 (0.014; hospitalization for heart failure) 0.019 (0.024; hospitalization for hypoglycemia) were estimated; all coefficients were statistically significant. INTERPRETATION: Consistent with clinical outcomes reported elsewhere, saxagliptin did not improve HRQoL. Cardiovascular complications were associated with significantly decreased HRQoL, most substantial earlier after the event. FUNDING: BMS/AZ.

Cost-effectiveness of vildagliptin for people with type 2 diabetes mellitus in Brazil; findings and implications.

INTRODUCTION: Vildagliptin is an inhibitor of the enzyme dipeptidyl peptidase 4, indicated for the treatment of type 2 diabetes mellitus, combined or not with metformin. This study aims to evaluate the cost-effectiveness of vildagliptin in the Brazilian context. Areas covered: Using MEDLINE, Cochrane Library, Lilacs and CRD, six studies were selected for the economic models. This study utilised cost data in the Brazilian health system to provide the context. Expert commentary: Type 2 diabetes mellitus is an epidemic disease and represents a challenge for all health care systems. Although guidelines clearly define first-line treatment, there are several other promising treatments. Vildagliptin is one of them, resulting in a mean lifetime increase of 0.31 years compared to metformin alone and 1.19 more life years compared to other metformin combinations. Considering observational data, life years with dual vildagliptin-containing treatments were 0.37 more compared to other dual treatments. However, its high cost versus generic metformin and its unclear safety profile weakens its subsequent cost-effectiveness. Consequently, the incorporation of vildagliptin or its combination with metformin is currently not recommended for the Brazilian Health Care System. This may change as more data becomes available.

In vitro assessment of the multifunctional bioactive potential of Alaska pollock skin collagen following simulated gastrointestinal digestion.

BACKGROUND: Dietary mineral deficiency, hypertension and diabetes have become serious human health problems. Dietary approaches are increasingly being investigated to address these issues. Identification of food-derived biological peptides has become an important approach to control such diseases. Peptides generated from aquatic byproducts have been shown to possess biological activities. RESULTS: Significantly higher copper-chelating activity was observed on simulated hydrolysis of intact collagen. The collagen hydrolysate generated in the gastric stage exhibited moderate angiotensin-converting enzyme (ACE)-inhibitory activity with an IC50 value of 2.92 ± 0.22 mg mL(-1), which significantly decreased to 0.49 ± 0.02 mg mL(-1) after intestinal digestion. The dipeptidyl peptidase (DPP) IV-inhibitory potency of the collagen hydrolysate generated directly following simulated gastrointestinal digestion (SGID) (IC50 2.59 ± 0.04 mg mL(-1)) was significantly lower than that of the collagen tryptic hydrolysate (CTH) (IC50 1.53 ± 0.01 mg mL(-1)). The antioxidant activities of collagen and CTH using the ferric-reducing antioxidant power (FRAP) assay were 0.87 ± 0.10 and 1.27 ± 0.03 µmol Trolox equivalent (TE) g(-1) respectively after SGID. CONCLUSION: This study identifies collagen as a good and inexpensive substrate for the generation of biologically active peptides with potential applications as functional ingredients in the management of chronic illness and mineral deficiency problems.

Effects of dipeptidyl peptidase IV inhibition on glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to fat in healthy males.

Fat is the most potent stimulus for glucagon-like peptide-1 (GLP-1) secretion. The aims of this study were to determine whether dipeptidyl peptidase IV (DPP-IV) inhibition would enhance plasma active incretin [glucose-dependent insulinotropic polypeptide (GIP), GLP-1] concentrations and modulate the glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to intraduodenal fat infusion. In a double-blind, randomized, placebo-controlled crossover design, 16 healthy lean males received 50 mg vildagliptin (V), or matched placebo (P), before intraduodenal fat infusion (2 kcal/min, 120 min). Blood glucose, plasma insulin, glucagon, active GLP-1, and GIP and peptide YY (PYY)-(3-36) concentrations; resting energy expenditure; and energy intake at a subsequent buffet meal (time = 120-150 min) were quantified. Data are presented as areas under the curve (0-120 min, means ± SE). Vildagliptin decreased glycemia (P: 598 ± 8 vs. V: 573 ± 9 mmol·l⁻¹·min⁻¹, P < 0.05) during intraduodenal lipid. This was associated with increased insulin (P: 15,964 ± 1,193 vs. V: 18,243 ± 1,257 pmol·l⁻¹·min⁻¹, P < 0.05), reduced glucagon (P: 1,008 ± 52 vs. V: 902 ± 46 pmol·l⁻¹·min⁻¹, P < 0.05), enhanced active GLP-1 (P: 294 ± 40 vs. V: 694 ± 78 pmol·l⁻¹·min⁻¹) and GIP (P: 2,748 ± 77 vs. V: 4,256 ± 157 pmol·l⁻¹·min⁻¹), and reduced PYY-(3-36) (P: 9,527 ± 754 vs. V: 4,469 ± 431 pM/min) concentrations compared with placebo (P < 0.05, for all). Vildagliptin increased resting energy expenditure (P: 1,821 ± 54 vs. V: 1,896 ± 65 kcal/day, P < 0.05) without effecting energy intake. Vildagliptin 1) modulates the effects of intraduodenal fat to enhance active GLP-1 and GIP, stimulate insulin, and suppress glucagon, thereby reducing glycemia and 2) increases energy expenditure. These observations suggest that the fat content of a meal, by enhancing GLP-1 and GIP secretion, may contribute to the response to DPP-IV inhibition.

Bioactive compounds from culinary herbs inhibit a molecular target for type 2 diabetes management, dipeptidyl peptidase IV.

Greek oregano (Origanum vulgare), marjoram (Origanum majorana), rosemary (Rosmarinus officinalis), and Mexican oregano (Lippia graveolens) are concentrated sources of bioactive compounds. The aims were to characterize and examine extracts from greenhouse-grown or commercially purchased herbs for their ability to inhibit dipeptidyl peptidase IV (DPP-IV) and protein tyrosine phosphatase 1B (PTP1B), enzymes that play a role in insulin secretion and insulin signaling, respectively. Greenhouse herbs contained more polyphenols (302.7-430.1 µg of gallic acid equivalents/mg of dry weight of extract (DWE)) and flavonoids (370.1-661.4 µg of rutin equivalents/mg of DWE) compared to the equivalent commercial herbs. Greenhouse rosemary, Mexican oregano, and marjoram extracts were the best inhibitors of DPP-IV (IC50=16, 29, and 59 µM, respectively). Commercial rosemary, Mexican oregano, and marjoram were the best inhibitors of PTP1B (32.4-40.9% at 500 µM). The phytochemicals eriodictyol, naringenin, hispidulin, cirsimaritin, and carnosol were identified by LC-ESI-MS as being present in greenhouse-grown Mexican oregano and rosemary. Computational modeling indicated that hispidulin, carnosol, and eriodictyol would have the best binding affinities for DPP-IV. Biochemically, the best inhibitors of DPP-IV were cirsimaritin (IC50=0.43±0.07 µM), hispidulin (IC50=0.49±0.06 µM), and naringenin (IC50=2.5±0.29 µM). Overall, herbs contain several flavonoids that inhibit DPP-IV and should be investigated further regarding their potential in diabetes management.

The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice.

Dipeptidyl peptidase-4 (DPP-4)-deficient mice exhibit prevention of obesity with increased energy expenditure, whereas currently available DPP-4 inhibitors do not induce similar changes. We investigated the impact of the novel DPP-4 inhibitor teneligliptin on body weight, energy expenditure, and obesity-related manifestations in diet-induced obese mice. Six-weeks-old C57BL/6N mice were fed a high-fat diet (60%kcal fat) ad libitum and administered teneligliptin (30 or 60mg/kg) via drinking water for 10 weeks. Mice fed a high-fat diet showed accelerated body weight gain. In contrast, compared with the vehicle group, the administration of teneligliptin reduced body weight to 88% and 71% at dose of 30mg/kg/day and 60mg/kg/day, respectively. Although there was no change in locomotor activity, indirect calorimetry studies showed that teneligliptin (60mg/kg) increased oxygen consumption by 22%. Adipocyte hypertrophy and hepatic steatosis induced by a high-fat diet were suppressed by teneligliptin. The mean adipocyte size in the 60-mg/kg treatment group was 44% and hepatic triglyceride levels were 34% of the levels in the vehicle group. Furthermore, treatment with teneligliptin (60mg/kg) reduced plasma levels of insulin to 40% and increased the glucose infusion rate to 39%, as measured in the euglycemic clamp study, indicating its beneficial effect on insulin resistance. We showed for the first time that the DPP-4 inhibitor prevents obesity and obesity-related manifestations with increased energy expenditure. Our findings suggest the potential utility of teneligliptin for the treatment of a broad spectrum of metabolic disorders related to obesity beyond glycemic control.

Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: first new anti-diabetic drug in the history of Korean pharmaceutical industry.

Gemigliptin, a potent, selective and long-acting DPP 4 inhibitor was developed by LG Life Sciences and approved for use in patients with type 2 diabetes mellitus by the Korean Food and Drug Administration in June 2012 under the trade name Zemiglo(®). Clinical pharmacokinetic and pharmacodynamic data suggest the efficacy and once daily dosing of gemigliptin. In clinical phase III studies, gemigliptin was efficacious as either monotherapy or combination therapy (add-on to metformin) and well tolerated in patients with type 2 diabetes. Further development of combination therapy is on-going.

Comparative safety and effectiveness of sitagliptin in patients with type 2 diabetes: retrospective population based cohort study.

OBJECTIVE: To determine if the use of sitagliptin in newly treated patients with type 2 diabetes is associated with any changes in clinical outcomes. DESIGN: Retrospective population based cohort study. SETTING: Large national commercially insured US claims and integrated laboratory database. PARTICIPANTS: Inception cohort of new users of oral antidiabetic drugs between 2004 and 2009 followed until death, termination of medical insurance, or December 31 2010. MAIN OUTCOME MEASURE: Composite endpoint of all cause hospital admission and all cause mortality, assessed with time varying Cox proportional hazards regression after adjustment for demographics, clinical and laboratory data, pharmacy claims data, healthcare use, and time varying propensity scores. RESULTS: The cohort included 72,738 new users of oral antidiabetic drugs (8032 (11%) used sitagliptin; 7293 (91%) were taking it in combination with other agents) followed for a total of 182,409 patient years. The mean age was 52 (SD 9) years, 54% (39,573) were men, 11% (8111) had ischemic heart disease, and 9% (6378) had diabetes related complications at the time their first antidiabetic drug was prescribed. 14,215 (20%) patients met the combined endpoint. Sitagliptin users showed similar rates of all cause hospital admission or mortality to patients not using sitagliptin (adjusted hazard ratio 0.98, 95% confidence interval 0.91 to 1.06), including patients with a history of ischemic heart disease (adjusted hazard ratio 1.10, 0.94 to 1.28) and those with estimated glomerular filtration rate below 60 mL/min (1.11, 0.88 to 1.41). CONCLUSIONS: Sitagliptin use was not associated with an excess risk of all cause hospital admission or death compared with other glucose lowering agents among newly treated patients with type 2 diabetes. Most patients prescribed sitagliptin in this cohort were concordant with clinical practice guidelines, in that it was used as add-on treatment.

Acute assessment of an aspalathin-enriched green rooibos (Aspalathus linearis) extract with hypoglycemic potential.

Rooibos, an endemic South African plant, known for its use as herbal tea, has potential as an antidiabetic herbal product, following recent demonstration of the glucose lowering effect of its major flavonoid, the dihydrochalcone C-glucoside aspalathin. The purpose of this study was to confirm antidiabetic activity for rooibos extract high in aspalathin content. An extract (SB1) was selected after screening for high aspalathin content and α-glucosidase inhibition activity. On-line HPLC-biochemical detection confirmed α-glucosidase inhibitory activity for aspalathin. In vitro the extract induced a dose response increase in glucose uptake (5 × 10⁻5 to 5 µg/ml) on C2C12 myotubules. Aspalathin was effective at 1, 10 and 100 µM, while rutin was effective at 100 µM. In the Chang cells only the extract was effective. In vivo the extract sustained a glucose lowering effect comparable to metformin over a 6h period after administration (25mg/kg body weight (BW)) to STZ-induced diabetic rats. In an oral glucose tolerance test the extract (30 mg/kg BW) was more effective than vildagliptin (10mg/kg BW), a dipeptidyl peptidase-4 inhibitor. An aspalathin-rutin mixture (1:1; m/m) dosed at 1.4 mg/kg BW, but not the single compounds separately, reduced blood glucose concentrations of STZ-induced diabetic rats over a 6h monitoring period. The improved hypoglycemic activity of the aspalathin-rutin mixture and the extract illustrated synergistic interactions of polyphenols in complex mixtures.

Linagliptin: the newest dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are some of the newest medications in our armamentarium for the management of type 2 diabetes mellitus. Through inhibition of the DPP-4 enzyme, these agents increase the amount of circulating incretin hormones, leading to an increase in insulin release and a suppression of glucagon secretion. Linagliptin is the third DPP-4 inhibitor approved by the Food and Drug Administration in the United States. It has been studied as monotherapy and as an adjunctive therapy to other oral agents in a dual or triple combination regimen. Linagliptin lowers glycosylated hemoglobin by about 0.4% when used as monotherapy and by about 0.5% to 1.1% when used in combination with other oral antihyperglycemic agents. Since linagliptin is mostly eliminated via the enterohepatic system (80%) and not to a significant extent through renal excretion, dosage adjustment is not necessary in patients with renal impairment. Linagliptin also has a favorable safety profile; nasopharyngitis is one of the more common observed side effects. Given its encouraging safety and efficacy profile, linagliptin is a good alternative to the other 2 agents in this class, especially for patients with renal impairment. This article provides a review of the pharmacologic and pharmacokinetic properties of linagliptin. The differences among the 3 available DPP-4 inhibitors will also be examined.

Comparison of costs among patients with type 2 diabetes treated with exenatide or sitagliptin therapy.

INTRODUCTION: Exenatide (Byetta, Amylin Pharmaceuticals Inc., CA, USA) and sitagliptin (Januvia, Merck & Co, NJ, USA) are two antidiabetic agents recently approved by the US Food and Drug Administration. The purpose of this analysis was to compare costs among patients with type 2 diabetes (T2D) treated with either of these agents. METHODS: Data with dates of service from September 1, 2005 through August 31, 2007, were obtained from a large US retrospective claims database. Intent-to-treat cohorts of adults diagnosed with T2D who began taking either exenatide (n=1885) or sitagliptin (n=2482) and did not use the alternate medication in the 6-month follow-up period were created. Six-month total medical costs were estimated using stepwise multivariate regressions. Six-month total diabetes-related medical costs, a component of total medical costs, were also estimated using stepwise multivariate regressions. In addition, other cost components were examined using either stepwise multivariate regressions or a two-part model that controlled for the probability of using the medical service. Smearing estimates were used to transform estimated log costs into costs. The analysis controlled for the potential impact of patient demographics, general health, prior resource use, comorbidities, and timing of treatment initiation. RESULTS: Exenatide was associated with lower total 6-month direct medical costs ($9340 vs. $9995; P<0.0001), despite some component costs being slightly higher with exenatide: diabetes-related drug costs ($1765 vs. $1743; P=0.0062), diabetes-related medical costs ($4142 vs. $4002; P<0.0001), and emergency room costs ($43 vs. $29; P=0.0388). Exenatide was associated with lower outpatient costs ($4498 vs. $5942; P<0.0001). CONCLUSIONS: Compared with the use of sitagliptin, exenatide was associated with lower total medical costs (difference of $655) despite higher total diabetes-related costs (difference of $140). As a result, there appears to be overall cost savings associated with the use of exenatide relative to sitagliptin.

Managed care perspective on three new agents for type 2 diabetes.

BACKGROUND: Despite effective monotherapy for diabetes, approximately 50% of patients require additional medications after 3 years to achieve target glycosylated hemoglobin (A1C) < 7%. Three new agents, each the first in its therapeutic class with a unique mechanism of action, have been approved for the treatment of type 2 diabetes by the U.S. Food and Drug Administration: pramlintide in March 2005, exenatide in April 2005, and sitagliptin in October 2006. OBJECTIVE: To review the efficacy and safety of 3 new agents for type 2 diabetes (exenatide and pramlintide by subcutaneous injection and sitagliptin by oral administration) and to define their place in therapy given their relatively high cost and unknown long-term safety and efficacy. METHODS: A MEDLINE search (1950 to June 2007) for English-language articles of studies in human subjects was conducted using these search terms: type 2 diabetes, exenatide, pramlintide, and sitagliptin. This database was supplemented by systematic reviews and meta-analyses through December 2007 and reference citations from the articles identified in the MEDLINE search. RESULTS: Exenatide, pramlintide, and sitagliptin have all been shown to have a modest effect on reducing A1C. In several relatively short-term trials (generally 15-30 weeks in duration), exenatide injection has been shown to be safe and effective for patients with type 2 diabetes who are either at the maximum doses of or cannot tolerate metformin, sulfonylurea, and/or thiazolidinedione therapy and need to further decrease A1C by at least 0.5% to 1%. While weight loss of 1.5 kg to 2.5 kg associated with exenatide is modest, this effect is of obvious value in many patients with type 2 diabetes. Nausea is the most notable side effect with exenatide, occurring in up to 50% of patients within the first 8 weeks of therapy but decreasing to 5% to 10% by week 24. In addition, the risk for hypoglycemia increases 4- to 5-fold when used in combination with sulfonylureas. Like exenatide, pramlintide injection reduces A1C by approximately 0.5% to 1%, carries the advantage of modest weight loss (1.5 kg over 1 year), and has a high incidence of nausea. Pramlintide can also result in severe hypoglycemia because of its ability to enhance the effects of insulin, a concern given that it is only indicated for use in combination with insulin. Sitagliptin is an oral agent that can be used alone or in combination with other oral hypoglycemic agents and has been shown to reduce A1C by 0.5% to 0.7%. It has only been studied in short-term studies, to date, so the long-term safety and efficacy are unknown. There is potential for severe allergic and dermatologic reactions with sitagliptin. CONCLUSIONS: The 3 new agents for the management of type 2 diabetes have been shown to reduce A1C by no more than 1.0%, modest by comparison with insulin and the older oral agents. The 3 newer agents have either modest positive effects on body weight or are weight neutral. The longterm safety and efficacy of the 3 newer agents are unknown, and their cost is considerably higher than the first-line agents, metformin and sufonylureas, which are available by generic name. The newer agents offer treatment options in select patients, although their use should be reserved for patients who are not adequately managed by agents with known longterm efficacy and safety, which are often available at a lower cost.