HbA1c development in combination therapies of sitagliptin as add on to either metformin or pioglitazone. The results of the combination studies on HbA1c development are shown for the week study with metformin left panel from data of Karasik et al and for the study with pioglitazone right panel from data of Rosenstock et al a. The baseline HbA1c in this study was 8.
As in the monotherapy studies, beta-cell function measured by the above parameters improved. The addition of sitagliptin to the ongoing metformin therapy was also weight neutral, the combination therapy was well tolerated and the gastrointestinal side-effects as well as hypoglycemic episodes were not increased Charbonnel et al ; Karasik et al Comparable results were observed in a study with similar design with an add-on combination of sitagliptin to an existing pioglitazone therapy.
As in the metformin combination study, the glycemic parameters HbA1c, and fasting and 2-h postprandial glucose improved. From a baseline HbA1c of 7. Sitagliptin was again weight neutral for the development of the body weight in the patients with pioglitazone treatment. The incidence of side-effects was similar in the combination therapy and pioglitazone monotherapy groups, the incidence of hypoglycemias was not higher with the combination of sitagliptin and pioglitazone Rosenstock et al a , b.
In two studies investigating sitagliptin monotherapy and one study investigating the combination of sitagliptin with metformin, beta-cell function was estimated using a frequent-sampling meal-tolerance test in a subgroup of patients.
In these studies basal and stimulated insulin responses were improved as well as the disposition index. The sensitivity of the beta-cells to glucose was enhanced, whereas the incidence of hypoglycemic episodes remained very low, suggesting a glucose-dependent mechanism for beta-cell responsiveness Xu et al a , b. Sitagliptin was also generally well tolerated and effective in patients with impaired renal function.
Sitagliptin has been shown to be effective, well tolerated, and safe in the treatment of type 2 diabetes in monotherapy or in the combination with metformin or thiazolidinediones. It reduces the glycemic parameters HbA1c, and fasting and postprandial glucose and improves beta-cell function.
The reduction of HbA1c observed in the studies was at least as good as that seen with other oral antihyperglycemic agents. In this respect, it has to be noted, however, that the potency of HbA1c reduction in type 2 diabetes by oral agents is also dependent on the baseline HbA1c; in studies with higher baseline HbA1c values, usually higher reductions of HbA1c are observed. Sitagliptin is weight neutral and does not increase the incidence of hypoglycemic episodes or the occurrence of adverse events.
The studies published so far contain data from up to 24 weeks; longer studies will be published soon. In man, long-term data on immunological effects mediated by CD are unknown yet, but to date, no alterations in immune functions have been detected in clinical studies or long-term animal studies.
Sitagliptin and DPP-4 inhibitors in general address a novel multimodal principle of action in type 2 diabetes. By preserving stimulated circulating plasma levels of incretin hormones, insulin secretion is stimulated under hyperglycemic conditions and glucagon secretion is suppressed. Therefore, not only insulin secretion and insulin resistance are altered, as by the previously used oral antihyperglycemic agents, but also unmet needs of type 2 diabetes therapy are covered by this novel therapeutic principle Ahren ; Gallwitz In case the effects observed on beta-cell function and beta-cell mass in preclinical studies also apply to human studies, sitagliptin could also have the potential to be useful in pre-diabetic stages and early stages of type 2 diabetes to retard or prevent the disease progression Gallwitz National Center for Biotechnology Information , U.
Vasc Health Risk Manag. Baptist Gallwitz. Author information Copyright and License information Disclaimer. Correspondence: Baptist Gallwitz Dept. All rights reserved. This article has been cited by other articles in PMC. Keywords: incretins, type 2 diabetes, diabetes therapy, DPP-4 inhibitors, sitagliptin. Utilizing the therapeutic potential of GLP-1 in type 2 diabetes Since glucagon-like peptide-1 GLP-1 itself is not feasible for type 2 diabetes therapy due to its very short biological half-life, two major strategies have been developed to utilize the beneficial effects of GLP-1 Drucker DPP-4 inhibition in type 2 diabetes The incretin effect is diminished in type 2 diabetes.
Table 1 Hormones and regulatory peptides as substrates for DPP-4 modified according to Mentlein Open in a separate window. The pharmacological profile of sitagliptin Sitagliptin MK , chemically 2R Oxo[3- trifluoromethyl -5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7 8H -yl] 2,4,5-trifluorophenyl butanamine see Figure 1 has a very high selectivity towards DPP-4, with an IC 50 of 18 nM.
Figure 1. Animal studies with sitagliptin Animal studies have been performed to investigate the effect of sitagliptin on beta- and alpha-cells in the pancreatic islets. Figure 2. Abbreviations : STZ, streptozotocin-induced. Figure 3. Sitagliptin in clinical studies in type 2 diabetes Sitagliptin improved the glycemic parameters HbA1c, fasting glucose, and postprandial glucose in clinical studies in patients with type 2 diabetes in monotherapy in doses of mg and mg given once daily in a week study.
Figure 4. Figure 5. Abbreviations : Pbo, placebo. Figure 6. It is used in addition to diet and exercise in the following ways:. Januvia is taken at a dose of mg once a day.
If Januvia is taken with a sulphonylurea or insulin, the dose of the sulphonylurea or insulin may need to be lowered to reduce the risk of hypoglycaemia low blood sugar levels. In patients with moderately or severely reduced kidney function the dose of Januvia should be reduced. Type-2 diabetes is a disease in which the pancreas does not make enough insulin to control the level of glucose in the blood or when the body is unable to use insulin effectively. The active substance in Januvia, sitagliptin, is a dipeptidyl-peptidase-4 DPP-4 inhibitor.
These hormones are released after a meal and stimulate the pancreas to produce insulin. By increasing levels of incretin hormones in the blood, sitagliptin stimulates the pancreas to produce more insulin when blood glucose levels are high. Sitagliptin does not work when the blood glucose is low. Sitagliptin also reduces the amount of glucose made by the liver, by increasing insulin levels and decreasing the levels of the hormone glucagon.
Together, these processes reduce blood glucose levels and help to control type-2 diabetes. Januvia was studied in nine studies involving almost 6, patients with type-2 diabetes whose blood glucose levels were not adequately controlled:.
In all of the studies, the main measure of effectiveness was the change in the level of a substance in the blood called glycosylated haemoglobin HbA1c , which gives an indication of how well the blood glucose is controlled. Januvia was more effective than placebo when it was taken alone or in combination with other antidiabetes medicines. In patients taking Januvia on its own, HbA1c levels fell from around 8. In contrast, they rose by 0. Adding Januvia to metformin reduced HbA1c levels by 0.
When added to pioglitazone, Januvia reduced HbA1c levels by 0. In the studies comparing Januvia with other medicines, the effectiveness of adding Januvia to metformin was similar to that of adding glipizide.
When taken on their own, Januvia and metformin produced similar reductions in HbA1c levels, but the effectiveness of Januvia seemed to be slightly lower than that of metformin. In the additional studies, adding Januvia to glimepiride with or without metformin led to a reduction in HbA1c levels of 0. HbA1c levels were reduced by 1.
Finally, they were reduced by 0. Subjects already on metformin at a dose of at least mg per day were randomized after completing a 2-week single-blind placebo run-in period.
Subjects on metformin and another antihyperglycemic agent and subjects not on any antihyperglycemic agents off therapy for at least 8 weeks were randomized after a run-in period of approximately 10 weeks on metformin at a dose of at least mg per day in monotherapy.
Subjects were randomized to the addition of either mg of Januvia or placebo, administered once daily. The second randomized, double-blind, placebo-controlled trial enrolled subjects.
It was designed to evaluate Januvia in combination with pioglitazone as treatment for 24 weeks. Patients on any oral antihyperglycemic agent in monotherapy or on a PPAR agent in combination therapy or not on an antihyperglycemic agent off therapy for at least 8 weeks were switched to monotherapy with pioglitazone at a dose of mg per day , and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients were randomized to the addition of either mg of Januvia or placebo, administered once daily.
This combination therapy demonstrated significant improvements in A1C and FPG compared to placebo with pioglitazone. Adverse events associated with the use of Januvia may include, but are not limited to, the following:.
Januvia is an an orally-active inhibitor of the dipeptidyl peptidase-4 DPP-4 enzyme. Januvia slows the inactivation of incretin hormones and thus increases and prolongs their action. Current medical research and opinion Oct;22 10 Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus.
Diabetologia Nov;49 11 Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers.
0コメント