Intraclass differences in the risk of hospitalization for heart failure among patients with type 2 diabetes initiating a dipeptidyl peptidase-4 inhibitor or a sulphonylurea: Results from the OsMed Health-DB registry.

AIMS: To re-analyse data from a previous retrospective study on 127 555 patients, in which we showed that dipeptidyl peptidase-4 (DPP-4) inhibitor therapy was associated with a lower risk of hospitalization for HF (HHF) than sulphonylurea (SU) therapy, in order to evaluate intraclass differences among DPP-4 inhibitors and SUs. METHODS: We included patients with type 2 diabetes (T2D) initiating DPP-4 inhibitor or SU therapy, alone or in combination with metformin. Patients undergoing intraclass switch, those with a previous HHF, those receiving insulin treatment, and those with <6 months observation were excluded. We calculated the incidence of first and total HHF events/1000 person-years. Cox proportional hazard and Poisson multiple regression models, as well as propensity-score matching, were used to account for baseline confounders. RESULTS: The analysis included 17 615 DPP-4 inhibitor users (60.1% sitagliptin; 27.0% vildagliptin; 12.9% saxagliptin) and 86 734 SU users (37.5% glibenclamide; 34.6% glimepiride; 27.9% gliclazide). No intraclass difference in the incidence rate of first and total HHF events was noted among the 3 DPP-4 inhibitors or among the 3 SUs. Multivariable adjustments for baseline confounders or propensity-score matching did not change the results. In addition, no intraclass difference in HHF risk was observed in patients at high compared with low cardiovascular risk. CONCLUSIONS: In a cohort of patients with T2D taken from approximately one-third of the Italian population, no intraclass difference was noted for DPP-4 inhibitor and SU therapy with regard to HHF risk.

In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis.

Recent epidemiological studies show conflicting data for the first-line anti-diabetic sulphonylureas drugs in treating cancer progression in type II diabetes patients. How sulphonylureas promote or diminish tumor growth is not fully understood. Here, we report that seven sulphonylureas exhibit different in vitro inhibition towards AKR1Cs (AKR1C1, AKR1C2, AKR1C3), which are critical steroid hormone metabolism enzymes that are related to prostate cancer, breast cancer and endometrial diseases. Interactions of the sulphonylureas and AKR1Cs were analyzed by X-ray crystallography.

No differences in mortality between users of pancreatic-specific and non-pancreatic-specific sulphonylureas: a cohort analysis.

To assess whether users of pancreatic-specific sulphonylureas are at reduced risk of mortality and cardiovascular mortality compared with users of non-specific sulphonylureas, we conducted a cohort study in the population of Tayside, Scotland. We identified 3331 patients with type 2 diabetes who were newly treated with sulphonylureas between 1994 and 2001 and categorized them into those treated with only pancreatic-specific sulphonylureas and those treated with only non-specific sulphonylureas. The risks of mortality and cardiovascular mortality were compared in a survival analysis. There were 2914 patients treated with pancreatic-specific sulphonylureas only, of which 683 (23.4%) died. Of 186 patients treated with non-specific drugs only, 40 (21.5%) died. After adjusting for confounding factors, the adjusted risk ratios (with 95% CI) for mortality and cardiovascular mortality were 0.84 (0.61 to 1.17) and 0.81 (0.59 to 1.11) among the non-specific users compared with the pancreatic-specific users. This provides no evidence that there are differences between the two sulphonylureas types.

Rapid increase in the use of oral antidiabetic drugs in the United States, 1990-2001.

OBJECTIVE: To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. RESEARCH DESIGN AND METHODS: Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. RESULTS: In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for approximately 77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured approximately 33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for approximately 17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. CONCLUSIONS: Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.

Treatment strategies and new therapeutic advances for type 2 diabetes.

Because type 2 diabetes is caused by two defects, impaired insulin secretion and insulin resistance, logical management of diabetes will include combination therapies to treat this dual condition. Initial combination therapy should include an insulin secretagogue and an insulin sensitizer, with the addition of insulin in the evening if the HbA1c remains greater than 8%. Treatment to target should be clearly defined to achieve HbA1c < 7% unless there are specific individual considerations that make higher HbA1c levels acceptable or desirable. Patients are now treated earlier, when fasting blood glucose levels are in the 126 to 140 mg/dL range; and drugs with less chances of hypoglycemia are preferred at this stage. However, low-dose combination therapy as an early initial treatment, if HbA1c remains > 7%, is an emerging aggressive strategy that requires further consideration and further studies to prove its long-term efficacy and safety.

Sulfonilureas: estado actual de los conocimientos sobre su mecanismo de acción y su uso clínico / Sulfonylureas: present state of the knowledge on its mechanism of action and its clinic use

Las llamadas sulfonilureas de segunda generación comenzaron a emplearse extensamente en terapéutica durante la década de los setenta e incluyendo la glibenclamida, la gliclazida y la glipizida que se ha agregado recientemente la glimepirida. De una manera general, se encuentra que estas drogas actúan directamente sobre los islotes pancreáticos, aumentando la secreción de insulina por interacción entre la sulfoniluria y un receptor específico localizado en la membrana de las células beta. Se han descrito además efectos extrapancreáticos que consisten fundamentalmente en una potenciación de la acción metabólica que la insulina produce sobre los distintos tejidos efectores (hígado, tejido adiposo y muscular) y sobre la regulación de la producción hepática de glucosa. Las investigaciones acerca del mecanismo de estos efectos extrapancreáticos sugieren que ellos se deben a la estimulación de vías metabólicas situadas a nivel post-receptor. Teniendo en cuenta la fisiología de la diabetes no insulino-dependiente, la administración de sulfonilureas sigue siendo el método farmacológico dominante en el manejo de estos pacientes porque practicamente todos ellos son relativamente insulino-deficientes cuando la enfermedad se hace clínicamente manifiesta, y estas drogas mejoran tanto la secreción de insulina como su acción periférica

Oral hypoglycemic agents in the treatment of type II diabetes.

The cornerstones of therapy for non-insulin-dependent diabetes mellitus are patient education, dietary modification with weight loss, and regular exercise. If diet and exercise fail to control hyperglycemia, pharmacologic intervention is warranted. The sulfonylureas are the only hypoglycemic agents approved for use in the United States. Their hypoglycemic effect is achieved through stimulation of insulin secretion and reduction of insulin resistance in the peripheral tissues. Two classes of sulfonylureas are available. First-generation drugs, such as tolbutamide and tolazamide, are less expensive and less powerful than second-generation drugs, such as glipizide and glyburide.