Sitagliptin Therapy Research Articles

997-P: Effect on DPP-4 Inhibitors on Fat Metabolism in Patients with Diabetes and Obesity

Objective: To evaluate the influence of combined therapy of sitagliptin and metformin on fat metabolism in patients with type 2 diabetes mellitus. Methods: The study included 82 patients (age, 55.3±9.1 years) with obesity and lipid metabolism disorders. None of the patients had reached their target glycated haemoglobin levels after metformin and diet therapy. Patients in gr1 (n=42) received 1.5-2-g metformin daily before the study and were switched to a formulation of 100-mg sitagliptin and 2-g metformin once a day. Patients in gr 2 (n=40) were on a diet therapy before inclusion and were started on 2-g metformin/day. The following were evaluated at baseline and after 6 months of therapy: fasting glucose levels, postprandial glucose levels, HbA1c, weight, waist circumference and lipid profile; insulin, proinsulin, leptin and adiponectin levels; HOMA IR and HOMA-β. In addition, magnetic resonance imaging was performed to assess the amount of visceral fat for the total cohort. Results: After 6 months, HbA1c decreased by 18.52% (p <0.001) in gr 1 and by 8.17% (p <0.001) in gr 2. FPGl and PPG levels in gr 1 were reduced by 21% (p <0.001) and 26.35% (p <0.001), respectively; the corresponding reductions in gr 2 were 1.45% (p >0.05) and 5.31% (p <0.05), respectively. HOMA-β increased by 33% in gr1 (p <0.001) and by 11% in gr 2 (p >0.05). Adiponectin levels increased by 27.06% (p <0.001) in gr 1 and by 7.16% in gr 2 (p <0.001). Leptin levels were reduced by 30.47% (p <0.001) in gr 1 and by 5.41% in gr 2 (p <0.001). MRI showed a 7.52% reduction in visceral fat for gr 1 (p <0.001) and a 1.76% reduction for gr2 (p <0.01). The comparison of subcutaneous fat dynamics did not show statistically significant differences between the groups. Conclusion: Compared with metformin monotherapy, sitagliptin and metformin combination therapy had a prominent effect on nonglycaemic parameters, with more marked decreases in visceral fat and leptin and increases in adiponectin levels. Disclosure A. Ametov: None. D. Gusenbekova: None.

OR05-6 The Effect of the GLP1R Variant rs6923761 on Post-Prandial Glucose Levels during Treatment with Sitagliptin

BACKGROUND: Glucagon-like peptide-1 (GLP-1) functions to increase insulin production in a glucose-dependent manner. Endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP4), and GLP-1 receptor agonists and DPP4 inhibitors (DPP4Is) are now used in the treatment of diabetes. The GLP-1 receptor (GLP-1R) is a G-protein coupled receptor that is expressed widely, encoded for by GLP1R. The GLP1R variant rs6923761 (Gly168Ser) has been associated with increased weight loss in response to GLP-1 agonist therapy in some studies. This study tested the hypothesis that this variant would be associated with responsiveness to endogenous GLP-1 during DPP4I therapy. METHODS: Forty-seven subjects with hypertension and type 2 diabetes mellitus were assigned to one-week crossover therapy with placebo and the DPP4I sitagliptin (100 mg/d), and underwent a mixed meal study. Subjects were excluded for type 1 diabetes, poorly controlled diabetes with Hgb A1c ≥8.7%, use of an anti-diabetic medication other than metformin for last 12 months, or presence of secondary hypertension. RESULTS: Post-prandial GLP-1 levels were increased during sitagliptin (AUC 11413, 95% CI [7113, 15712]) as compared with placebo treatment (AUC 5101, 95% CI [2254, 7949], p<0.05), and did not significantly differ by genotype. Peak post-prandial glucose was significantly higher in placebo as compared with sitagliptin treatment (146.6 +/- 35.8 mg/dL versus 133.0 +/- 26.5 mg/dL, respectively; t=90 minutes, p<0.01). Subjects with one or two copies of the wild-type allele (Gly/Gly or Gly/Ser) had increased post-prandial glucose excursion as compared with Ser/Ser subjects, in both the placebo and sitagliptin treatments (plasma glucose at 90 minutes: placebo Gly/- 150.1 +/- 38.0 mg/dL vs Ser/Ser 132.6 +/- 13.7 mg/dL, p<0.05; sitagliptin Gly/- 135.8 +/- 27.3 mg/dL vs Ser/Ser 117.4 +/- 14.7 mg/dL, p<0.05). Post-prandial insulin levels were not different in the placebo versus sitagliptin treatments (AUC 13264, 95% CI [9296,17232] vs 11996, 95% CI [8278, 15714], respectively), but there was a genotype by drug treatment interaction (p<0.05) such that Ser/Ser subjects had higher post-prandial insulin in the placebo treatment as compared with other genotypes. This difference was eliminated with sitagliptin therapy. CONCLUSIONS: Homozygosity for the Ser variant of GLP1R is associated with decreased glucose after a mixed meal without altering the effect of sitagliptin on post prandial GLP-1 concentrations. Further studies are needed to assess whether this variant confers increased sensitivity at the GLP-1R and whether it affects the long-term response to DPP4I.

Usefulness of antidiabetic alpha-glucosidase inhibitors: a review on the timing of administration and effects on gut hormones.

Elevation of postprandial plasma glucose is correlated with an increase in cardiovascular events, and alpha-glucosidase inhibitors (αGIs) are effective at reducing postprandial glucose levels. In Japan, the αGIs acarbose, voglibose, and miglitol have been available since 1993, 1994, and 2006, respectively. Dipeptidyl peptidase-4 (DPP-4) inhibitors are also effective at reducing postprandial glucose levels, and they have been available in Japan since 2009. A combination therapy of αGI, miglitol, and the DPP-4 inhibitor, sitagliptin, is more effective at decreasing postprandial glucose levels than monotherapy with either miglitol or sitagliptin. Moreover, the combination therapy of miglitol and sitagliptin is more effective at increasing postprandial active glucagon-like peptide-1 (GLP-1) levels than monotherapy. Peptide YY (PYY) has appetite-suppressing and gastric-emptying effects similar to GLP-1. In healthy individuals, miglitol increases the postprandial total PYY; however, combination therapy of miglitol and vildagliptin does not change postprandial total PYY levels. αGIs are typically prescribed to be taken just before a meal, which can result in decreased drug adherence. Different patterns of αGI intake were examined, and the results showed that miglitol or acarbose administration after a meal is effective. The effects of taking miglitol dissolved in water during a meal appeared to be similar to that of taking miglitol as a tablet just before a meal. The long-term effects of taking miglitol dissolved in water should be evaluated in future studies. αGIs may be effective even when they are not taken before a meal, and a more flexible administration may improve drug adherence.

Long-Term Efficacy and Safety of Add-On Therapy of Sitagliptin to a Very Small Dose of Glimepiride Versus a Small Dose of Glimepiride Over Eighteen Months

Long-Term Efficacy and Safety of Add-On Therapy of Sitagliptin to a Very Small Dose of Glimepiride Versus a Small Dose of Glimepiride Over Eighteen Months

Efficacy and Safety of Adding Sitagliptin in Type 2 Diabetes Patients on Insulin: Age-Stratified Comparison at One Year in the ASSIST-K Study.

BackgroundSitagliptin, the first dipeptidyl peptidase-4 inhibitor, has demonstrated efficacy and safety as monotherapy and as add-on therapy to oral antidiabetic agents or insulin. However, there have been few reports about sitagliptin in elderly patients. The ASSIST-K observational study was performed in patients with type 2 diabetes mellitus (T2DM) receiving sitagliptin as add-on therapy to insulin. Changes of hemoglobin A1c (HbA1c), body weight, and the estimated glomerular filtration rate (eGFR), as well as adverse events, were investigated over 12 months in age-stratified groups.MethodsAmong outpatients with T2DM treated at member institutions of Kanagawa Physicians Association, those starting sitagliptin as add-on therapy to insulin were followed for 12 months. HbA1c (National Glycohemoglobin Standardization Program), body weight, and eGFR were the efficacy endpoints, while adverse events were investigated to assess safety. Patients were stratified into three age groups (≤ 64 years, 65 - 74 years, and ≥ 75 years) for comparison of the endpoints.ResultsAmong 937 patients on insulin before starting sitagliptin, 821 patients were analyzed after excluding those without HbA1c data at baseline and 12 months. The two groups of elderly patients (65 - 74 years and ≥75 years) had more complications and their HbA1c was lower at initiation of sitagliptin therapy. The dose of sitagliptin, daily number of insulin injections, and number of concomitant oral antidiabetic agents were all lower in the elderly patients. HbA1c showed a significant decrease after initiation of sitagliptin in all age groups, and there were no significant intergroup differences in the change of HbA1c at 12 months. Body weight did not change significantly in any group. eGFR decreased significantly in all groups, with no significant intergroup differences at 12 months. Regarding adverse events, there were no significant intergroup differences in the incidence of severe hypoglycemia, gastrointestinal symptoms, or constipation.ConclusionsDespite baseline differences in demographic factors and medications, sitagliptin showed good efficacy and safety in all age groups of patients receiving it as add-on therapy to insulin during routine management of T2DM. Adding sitagliptin to insulin achieves similar efficacy and safety outcomes at 12 months in both elderly and non-elderly T2DM patients.

Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus: A focus on hypoglycemia.

Aims/IntroductionTo investigate the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus, with a focus on hypoglycemia.Materials and MethodsType 2 diabetes mellitus patients who started sitagliptin therapy and were followed for 52 weeks were enrolled in the Impact of Sitagliptin on Diabetes Mellitus in Japanese Elderly Patients study. The frequency of hypoglycemia and knowledge of hypoglycemia were analyzed using a questionnaire.ResultsIn total, 5,130 patients (aged 73.8 ± 6.1 years) were analyzed. A significant reduction in glycated hemoglobin (−0.7 ± 1.1%, P < 0.001) and glycoalbumin levels (−2.2 ± 3.8%, P < 0.001) was observed at week 52. The percentage of patients with hypoglycemia did not increase from the baseline (3.3%) to week 52 (2.8%) of sitagliptin administration. Hypoglycemia incidence was significantly higher for combination therapy with insulin (odds ratio 17.75, P < 0.001) or sulfonylurea (odds ratio 2.22, P < 0.001). The increase in sitagliptin dose for combination therapy with antidiabetic drug(s) increased the percentage of patients with hypoglycemia (5.6% in sitagliptin increased subgroup, 2.4% in sitagliptin maintained subgroup, P < 0.01). The awareness of hypoglycemia symptoms and attitude to carry glucose as a countermeasure to prevent hypoglycemia increased during the study.ConclusionsSitagliptin did not increase the percentage of patients with hypoglycemia among elderly patients with type 2 diabetes mellitus. However, hypoglycemia occurred more frequently in add‐on therapy to sulfonylurea or when the sitagliptin dose was increased in combination therapy, showing that sitagliptin should be used with caution.

Efficacy and Safety of Sitagliptin in Hispanic/Latino Patients with Type 2 Diabetes: A Pooled Analysis from Ten Randomized, Placebo-Controlled Phase 3 Clinical Trials.

IntroductionTo assess the efficacy and safety profile of the dipeptidyl-peptidase-4 inhibitor sitagliptin in a population of self-identified Hispanic/Latino patients with type 2 diabetes.MethodsData were pooled from ten randomized, double-blind studies in which subjects were treated with sitagliptin 100 mg/day (as mono- or combination therapy) or placebo, and used to evaluate the glycemic efficacy, safety, and tolerability of sitagliptin compared with placebo after 24 weeks of treatment.ResultsA total of 804 Hispanic/Latino patients were included in the analysis. Baseline characteristics in the treatment groups were similar (mean baseline HbA1c of approximately 8.5%). The LS mean HbA1c changes from baseline were − 0.94% with sitagliptin and − 0.32% with placebo, and the between-group difference was − 0.62%, p < 0.001. After 24 weeks of treatment, 35% and 18% of subjects were at the HbA1c goal of < 7% in the sitagliptin and placebo groups, respectively. Body weight increased slightly in both treatment groups. Incidences of adverse events of hypoglycemia were similar and low (1.9% and 1.4% for sitagliptin and placebo, respectively) in both groups in studies in which insulin or sulfonylurea were not used and were similar (9% and 11% for sitagliptin and placebo, respectively) when all studies were included. Overall safety and tolerability of treatment with sitagliptin and placebo were similar. No clinically meaningful differences between the safety profile of sitagliptin in the Hispanic/Latino population analyzed here and broader populations previously evaluated were observed.ConclusionIn this pooled analysis of sitagliptin therapy vs placebo in Hispanic/Latino patients, sitagliptin provided significant improvement in glycemic control and was generally well tolerated.FundingMerck & Co., Inc., Kenilworth, NJ, USA.

Modeling Long-Term Cost-Effectiveness of Sitagliptin and SGLT2i Combination Therapy for the Treatment of Type 2 Diabetes

Clinical benefits of dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) combination therapy have been demonstrated through clinical trials; however, there is limited understanding of economic benefits of sequential use of these therapies. This study evaluated the long-term cost-effectiveness of a treatment strategy involving intensification with SGLT2is (pathway 1) compared to NPH insulin (pathway 2) in type 2 diabetes (T2D) patients not at goal on metformin and sitagliptin therapy in the UK. The QuintilesIMS CORE Diabetes Model was used to perform cost-effectiveness analysis over a patient’s lifetime. Treatment effect data were obtained from randomized clinical trials, and economic data were obtained from multiple published sources. Several scenario analyses were performed to assess the robustness of base case results. Pathway 1 increased total life years (13.49 vs. 13.37, respectively) and quality-adjusted life years (QALY) (9.40 and 9.22, respectively) compared to pathway 2. Although drug costs in pathway 1 were higher than pathway 2, they were offset by decreases in diabetes-related complications and body mass index, leading to lower total direct medical costs for pathway 1 (£25,747 vs. £26,095). Thus, pathway 1 dominates pathway 2, as it is both more effective and less costly. Results from scenario analyses assessing changes in treatment effect, hypoglycemia rate, body mass index, cardiovascular protective effect of SGLT2i consistently showed that pathway 1 was either dominant (incremental cost effectiveness ratio (ICER) &amp;lt;$0/QALY) or cost-effective [(ICER &amp;lt; £3,000/QALY for patients with lower baseline HbA1c (7%) or older age (65+years)]. Among patients not at goal on metformin and sitagliptin therapy, treatment intensification with SGLT2i is likely to be cost effective compared to intensification with NPH insulin as 3rd line therapy in T2D in the UK. Disclosure M. Pawaskar: Employee; Self; Merck &amp; Co., Inc. S. Bilir: Consultant; Self; Merck &amp; Co., Inc.. A. Graber-Naidich: None. C.D. Gonzalez: Employee; Self; Merck &amp; Co., Inc. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc. G.M. Davies: Employee; Self; Merck &amp; Co., Inc..

Impact of Early Intensification with Sitagliptin on Glycemic Goal Attainment among Patients with Metformin Monotherapy Failure

Background: Delay in the intensification of type 2 diabetes (T2DM) treatment after metformin monotherapy failure, or clinical inertia, is often observed among patients with poor glycemic control. Sitagliptin is used frequently as an add-on to metformin monotherapy among patients with T2DM. The objective of the study is to evaluate the association between early treatment intensification with sitagliptin and glycemic goal attainment among patients failing metformin monotherapy. Methods: This retrospective database study of adult T2DM patients was conducted using the Quintiles Electronic Medical Record (EMR) database. The study population consisted of patients diagnosed with T2DM who failed to achieve A1c level of &amp;lt;7% on metformin monotherapy between January 20and June 2015. The study included two groups (1) those who did not receive treatment intensification within 3 months after metformin failure (non-early group), but were intensified with any oral anti-hyperglycemic agent between 4 and 12 months and (2) those who were intensified with sitagliptin within 3 months (early sitagliptin group). A Cox regression analysis was conducted to evaluate the association between sitagliptin use and A1c goal attainment within 12 months. Results: We identified 2,852 patients aged ≥18 years with T2DM who failed metformin monotherapy, of which 362 patients were intensified with sitagliptin within 3 months and 2,490 patients were included in the non-early group. A multivariate Cox regression model adjusted for age, gender, BMI, smoking status, baseline A1c, comorbidities, and other nondiabetic medications showed that early sitagliptin therapy resulted in doubling the likelihood of achieving A1c goal attainment (HR 2.12; 95% CI 1.80-2.50) within 12 months compared to non-early group. Conclusion: Early intensification with sitagliptin results in higher goal achievement levels among patients failing metformin monotherapy failure. Disclosure F. Ejzykowicz: Employee; Self; Merck Sharp &amp; Dohme Corp. J. Liu: Employee; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; Anthem, Inc.. Employee; Self; Janssen Scientific Affairs, LLC. S.S. Engel: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc..

Sitagliptin on carotid intima-media thickness in type 2 diabetes patients receiving primary or secondary prevention of cardiovascular disease: A subgroup analysis of the PROLOGUE study

BackgroundWhether a dipeptidyl peptidase-4 (DPP-4) inhibitor can attenuate atherosclerosis is still controversial. Some clinical trials reported that DPP-4 inhibitors in diabetes patients without a previous history of cardiovascular (CV) events could reduce carotid intima-media thickness (IMT). However, in the PROLOGUE study, which enrolled diabetes patients both with and without previous CV events, sitagliptin failed to slow the progression of carotid IMT relative to conventional therapy. Aim and methodsWe hypothesized that the effect of DPP-4 inhibitors on carotid atherosclerosis might be different between the primary and secondary prevention groups. We performed a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in carotid IMT in subgroups with or without previous CV events. ResultsNo significant difference in the IMT changes between the treatment groups was found in the secondary prevention subgroup (sitagliptin, N = 102; conventional, 111). However, in the primary prevention subgroup (sitagliptin, 120; conventional, 109), we found significant inhibitory effects of sitagliptin on mean and max internal carotid artery IMT [estimated group difference: −0.096 mm (95% CI −0.175 to −0.018, p = 0.017) and −0.162 mm (95% CI −0.272 to −0.052, p = 0.004), respectively], although there was no significant difference in the common carotid artery IMT. ConclusionsOur data suggest that there is a favorable effect of DPP-4 inhibitor treatment on carotid atherosclerosis in diabetes patients without previous CV events.

Efficacy and safety of nateglinide plus sitagliptin combination therapy in type 2 diabetes patients inadequately controlled by sitagliptin monotherapy: a phase 3, multicenter, open-label, long-term study.

Combination therapies of drugs with distinct mechanisms of action are emerging as ways to achieve strict glycemic control, thus preventing the onset and progression of diabetic complications in type 2 diabetes patients. A rapid-acting insulin secretagog, nateglinide, and a potent dipeptidyl peptidase-4 inhibitor, sitagliptin, meet such criteria. A total of 121 patients inadequately controlled with sitagliptin monotherapy received 52-week combination therapy (nateglinide+sitagliptin). The primary endpoint was the safety of the therapy, and its efficacy was also evaluated. A meal tolerance test was performed 4weeks before the start of combination therapy (week -4) and at week 24 and week 52 after the start of combination therapy. HbA1c levels were lower at week 52 than at week 0 [-0.42% (95% confidence interval -0.53, -0.31)]. Fasting plasma glucose levels tended to decrease from baseline (week 0) to week 52 [-4.8mg/dl (-9.4, -0.2)]. In the meal tolerance test, postprandial plasma glucose levels and area under the curve of glucose from before to 2h after the meal load were lower at week 24 and week 52 than at week -4. In addition, the levels of insulin and active glucagon-like peptide-1 were higher at week 52 than at week -4. Furthermore, the incidence of adverse events in combination therapy with sitagliptin was similar to those previously shown in nateglinide monotherapy. Compared with sitagliptin monotherapy, the combination therapy of nateglinide plus sitagliptin was more effective in type 2 diabetes patients at improving glycemic control while showing similar safety.

Increased Risk of Severe Hypoglycemic Events Before and After Cardiovascular Outcomes in TECOS Suggests an At-Risk Type 2 Diabetes Frail Patient Phenotype.

Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk. Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years. SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust. These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype.

Add-On Sitagliptin Therapy for Insulin-Treated Type 2 Diabetes: An Analysis of Hemoglobin A1c and Other Variables Using ASSIST-K Follow-Up Data

Background: Sitagliptin was the first dipeptidyl peptidase-4 (DPP-4) inhibitor approved in Japan. Its efficacy and safety have been demonstrated, both as monotherapy and in combination with oral antidiabetic agents or insulin. However, reduction of hemoglobin A1c (HbA1c) by sitagliptin is insufficient in some patients. Therefore, data from an observational study of sitagliptin as add-on therapy to insulin in patients with type 2 diabetes (ASSIST-K) were used to conduct factor analysis of the 12-month changes in HbA1c, body weight, estimated glomerular filtration rate (eGFR), and adverse events (AEs). Methods: At member institutions of Kanagawa Physicians Association specializing in diabetes, outpatients with type 2 diabetes receiving insulin were followed for 12 months after addition of sitagliptin. The HbA1c (National Glycohemoglobin Standardization Program), blood glucose (fasting/postprandial), body weight, eGFR, and AEs were evaluated at each specified time. Multivariate analysis was performed by using sex and age as explanatory variables and the following response variables: the change in HbA1c, body weight, or eGFR after 12 months of sitagliptin treatment, and occurrence of AEs. Results: Of 1,168 patients registered in the ASSIST-K study, 412 patients were included in this analysis, excluding those not receiving insulin before sitagliptin, those in whom the 12-month change in HbA1c could not be calculated, and those with missing data on explanatory variables. There was a significant decrease in HbA1c and eGFR, but no significant change in body weight. AEs observed in > 10 patients were severe hypoglycemia (14 patients, 3.4%) and constipation (13 patients, 3.2%). Factor analysis revealed the following points: 1) Concurrent dyslipidemia and baseline HbA1c influenced the 12-month change in HbA1c; 2) Baseline body mass index and HbA1c influenced the 12-month change in body weight; and 3) Concurrent dyslipidemia, baseline sulfonylurea treatment, baseline body mass index, and baseline eGFR influenced the 12-month change in eGFR. In addition, the risk of severe hypoglycemia or constipation was significantly influenced by baseline HbA1c. Conclusions: Patients with type 2 diabetes showing higher HbA1c levels after add-on sitagliptin therapy had concurrent dyslipidemia and a lower baseline HbA1c. Severe hypoglycemia or constipation was more likely to occur in patients with a low baseline HbA1c. J Endocrinol Metab. 2018;8(6):126-138 doi: https://doi.org/10.14740/jem540

Comment on Lovshin et al. Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1α1-67 in Patients With Type 2 Diabetes. Diabetes Care 2017;40:1073–1081

We read with interest the study by Lovshin et al. (1) investigating the natriuretic effect of the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes (T2D). The authors report that 1 month of sitagliptin therapy increases creatinine-based fractional sodium excretion (FENa) compared with placebo, which is in line with our previous observation (2). As lithium clearance and (intra)renal hemodynamics were not affected, the authors suggest that sitagliptin inhibits tubular sodium reabsorption at a level that is likely downstream of the macula densa. In parallel with enhanced FENa, DPP-4 inhibition increased intact stromal cell–derived factor (SDF)-1α1–67 levels, suggesting a relevant natriuretic role for this DPP-4 substrate. We agree with the authors that their mechanistic findings are of potential clinical relevance, particularly when hypothesizing about the added natriuretic effect of combined pharmacological DPP-4/sodium–glucose cotransporter …

Combined Oral Administration of GABA and DPP-4 Inhibitor Prevents Beta Cell Damage and Promotes Beta Cell Regeneration in Mice.

γ-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin. Oral drug administration was initiated 1 week before STZ injection and maintained for 6 weeks. GABA or sitagliptin administration decreased ambient blood glucose levels and improved the glucose excursion rate. This was associated with elevated plasma insulin and reduced plasma glucagon levels. Importantly, combined use of GABA and sitagliptin significantly enhanced these effects as compared with each of the monotherapies. An additive effect on reducing water consumption was also observed. Immunohistochemical analyses revealed that combined GABA and sitagliptin therapy was superior in increasing beta cell mass, associated with increased small-size islet numbers, Ki67+ and PDX-1+ beta cell counts; and reduced Tunel+ beta cell counts. Thus, beta cell proliferation was increased, whereas apoptosis was reduced. We also noticed a suppressive effect of GABA or sitagliptin on alpha cell mass, which was not significantly altered by combining the two agents. Although either GABA or sitagliptin administration delays the onset of MDSD, our study indicates that combined use of them produces superior therapeutic outcomes. This is likely due to an amelioration of beta cell proliferation and a decrease of beta cell apoptosis.

Chitosan oligosaccharide improves the therapeutic efficacy of sitagliptin for the therapy of Chinese elderly patients with type 2 diabetes mellitus.

Sitagliptin improves glycemic control in type 2 diabetes mellitus (T2DM) patients but its side effects are undesirable. Chitosan oligosaccharide (COS) is expected to improve the therapeutic result as a natural product. A total of 200 elderly T2DM patients were evenly assigned into four groups: sitagliptin group (SG), receiving sitagliptin 100 mg/day; COS group (CG), receiving COS 100 mg/day; combination therapy of sitagliptin and COS group (SCG), receiving both sitagliptin and COS 100 mg/day; and placebo group (PG), receiving placebo 100 mg/day. After 42-week therapy, biochemical indices and clinical parameters for the alterations from start points were analyzed. The related molecular mechanism was tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot at cell level. Lower risk of hypoglycemia was found in the SCG group when compared with SG and other groups (P<0.05). More patients from the SCG group than other groups attained hemoglobin A1c (HbA1c) reduction >2.5% (P<0.05). Weight reduction of 1.2±0.9, 2.6±0.8, 4.7±1.3, and 0.9±0.6 kg was observed in the patients from SG, CG, SCG, and PG groups, respectively (P<0.05). The combined treatment of COS and sitagliptin presented better therapeutic results by improving insulin sensitivity, lipid profile, adiponectin levels, and glucagon-like peptide 1 and reducing side effects, insulin resistance, HbA1c, body mass index, resistin, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) (P<0.05). qRT-PCR and Western blot analysis also showed that COS treatment reduced the levels of resistin, TNF-α, and CRP, and increased the level of adiponectin. The combination of COS and sitagliptin provided better glycemic control with fewer side effects and with more weight reduction in the elderly participants with T2DM.

Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy.

NCT01859793.

Additive effects of atorvastatin combined with sitagliptin on rats with myocardial infarction: a pilot study.

IntroductionAtorvastatin and sitagliptin are able to exert cardio-protective effects. However, whether atorvastatin plus sitagliptin could confer additive benefits for rats with myocardial infarction (MI) is unknown.Material and methodsForty rats with MI were produced and 37 surviving rats were randomly divided into atorvastatin (10 mg/kg daily, n = 9), sitagliptin (10 mg/kg daily, n = 9), combined (10 mg/kg daily atorvastatin plus 10 mg/kg daily sitagliptin, n = 9), and control groups (3 ml normal saline daily, n = 10). Fourteen days later, cardiac function was detected and fasting venous blood was sampled for lipid profiles and glucose evaluation. Cardiac tissues were used for hematoxylin-eosin staining, for interleukin-6 (IL-6) and tumor necrotic factor-α (TNF-α) evaluation, and for rho-associated kinase 2 (ROCK2) assessment.ResultsFourteen days after MI, the inflammatory reaction regarding the degree of leukocyte infiltration and IL-6 and TNF-α expression in cardiac tissues was ameliorated in atorvastatin and sitagliptin groups compared to the control group (p < 0.05). In addition, ROCK2 was attenuated by either atorvastatin or sitagliptin (p < 0.05). Echocardiography showed that cardiac function was significantly improved with atorvastatin and sitagliptin therapy (p < 0.05). Overall, all these benefits were further enhanced by combined therapy, suggesting that atorvastatin combined with sitagliptin therapy has additive effects on reducing cardiac inflammation and improving cardiac function. No significant changes in lipid profiles or glucose were observed, suggesting that the benefits derived from atorvastatin and sitagliptin therapy might not depend on cholesterol and glucose modulation.ConclusionsIn rats with MI, atorvastatin plus sitagliptin therapy provides additive effects for cardio-protection, and mechanisms operating in these processes may be due to ROCK2 diminishment.

A Randomized Controlled Trial of Vildagliptin Versus Alogliptin: Effective Switch From Sitagliptin in Patients With Type 2 Diabetes.

BackgroundWe investigated the effects of vildagliptin or alogliptin on blood glucose and hemoglobin A1c (HbA1c) in patients with type 2 diabetes inadequately controlled by sitagliptin.MethodsIn a single-center open-label trial, 35 patients with inadequate glycemic control on sitagliptin therapy (50 mg once daily) were randomly switched to treatment with vildagliptin (50 mg twice daily) or alogliptin (25 mg once daily). After 12 weeks, patients who failed to achieve the target HbA1c level of < 7.0% with vildagliptin or alogliptin treatment were switched to high-dose sitagliptin (100 mg once daily) and the effect on glycemic control was assessed.ResultsVildagliptin did not significantly alter the mean plasma glucose level (175.5 ± 54.4 mg/dL vs. 179.1 ± 73.4 mg/dL) or HbA1c (8.01% vs. 8.02%) after 12 weeks. With alogliptin, mean plasma glucose increased from 175.4 ± 50.9 mg/dL to 195.3 ± 55.0 mg/dL after 12 weeks and HbA1c increased significantly from 8.0% to 8.3% (P < 0.05). At 12 weeks after switching from vildagliptin to high-dose sitagliptin (100 mg daily), HbA1c was increased to 8.3%, but it was significantly (P < 0.05) reduced to the baseline level of 8.0% after switching from alogliptin. The reduction of HbA1c was significantly greater in the vildagliptin group than the alogliptin group (P = 0.008), but the response rate (achieving the target HbA1c < 7.0%) did not differ significantly between the two groups.ConclusionThe glucose-lowering effects of these three dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, and sitagliptin) were different, and the effects of vildagliptin and sitagliptin were stronger than that of alogliptin.

Primary Care-Based Investigation of the Effect of Sitagliptin on Blood Pressure in Hypertensive Patients With Type 2 Diabetes.

BackgroundThe influence of long-term sitagliptin therapy on office blood pressure (BP) and home BP has been unclear.MethodsIn a retrospective cohort study of 454 patients with type 2 diabetes, the following variables were analyzed before and at 3, 6, 9, and 12 months after initiation of sitagliptin therapy: office systolic blood pressure (SBP), office diastolic blood pressure (DBP), office pulse rate, morning home SBP, morning home DBP, morning home pulse rate, evening home SBP, evening home DBP, evening home pulse rate, hemoglobin A1c (HbA1c), plasma glucose, lipid profile, and renal function parameters.ResultsThe office SBP showed a significant decrease after 6 and 12 months of sitagliptin therapy (P < 0.01 and P < 0.01, respectively), while office DBP was decreased significantly at all time points of evaluation (3, 6, 9, and 12 months: P < 0.05, P < 0.001, P < 0.001, and P < 0.05, respectively). Analysis of covariance revealed a significant decrease in office SBP after 6 and 12 months, as well as significant reduction of office DBP after 6 and 9 months. Morning home SBP and DBP were significantly reduced after 6 months, as was evening home DBP after 6 and 12 months, but there was no significant decrease in evening home SBP. HbA1c and plasma glucose levels were significantly reduced at all time points of evaluation. Examination of the lipid profile revealed that total cholesterol, low-density lipoprotein cholesterol, and triglycerides were also decreased at all time points of evaluation, while high-density lipoprotein cholesterol was significantly reduced after 3, 9, and 12 months. Significant reduction of the estimated glomerular filtration rate was observed after 6, 9, and 12 months, and the urinary albumin/creatinine ratio was significantly lower at 9 and 12 months. Serum creatinine was increased significantly at all time points of evaluation.ConclusionsBP was slightly but significantly reduced from 6 months after initiation of sitagliptin therapy, indicating that this antidiabetic drug has pleiotropic effects, including an antihypertensive effect.