Glimepiride

The human intestinal tract can secrete a hormone called GLP-1, which is released after humans eat and promotes the secretion of insulin by pancreatic β cells, thus lowering blood sugar. Unfortunately, the half-life of GLP-1 is very short, and it can be easily hydrolyzed by an enzyme called DPP-4, thereby losing its activity.  DPP-4 inhibitors enhance the incretin effect by inhibiting DPP-4. The incretin effect refers to the phenomenon where the stimulation of insulin secretion by orally administered glucose is stronger than that by intravenous injection of glucose. This phenomenon exists because glucose entering the intestines orally can stimulate the intestinal mucosa to produce incretin. Two types of intestinal incretins have been discovered so far: Glucagon-Like Peptide-1 (GLP-1) and Glucose-Dependent Insulinotropic Polypeptide (GIP), both of which enhance insulin secretion stimulated by glucose. GLP-1 and GIP are quickly degraded and inactivated in the body by DPP-4, in which endogenous DPP-4 plays a key role. DPP-4 inhibitors inhibit DPP-4, thereby increasing the level of endogenous active GLP-1 by 2 to 3 times, enhancing the sensitivity of β-cells and α-cells to glucose that increases insulin secretion stimulated by glucose and enhances the inhibitory effect of glucose on glucagon secretion, thereby improving hyperglycemia. DPP-4 inhibitors can lower postprandial blood sugar, as well as fasting blood sugar. DPP-4 inhibitors can be used alone to treat type 2 diabetes, and can also be used in combination with other hypoglycemic drugs to treat type 2 diabetes. The most common hypoglycemic drugs combined with DPP-4 inhibitors are metformin, followed by sulfonylureas, thiazolidinediones, and insulin. DPP-4 inhibitors can also be used in combination with other hypoglycemic drugs for triple therapy. Common triple therapy regimens include DPP-4 inhibitors + metformin + sulfonylureas, DPP-4 inhibitors + metformin + thiazolidinediones, and DPP-4 inhibitors + metformin + insulin. DPP-4 Competitive LandscapeAccording to the data provided by Patsnap Synapse-Global Drug Intelligence Database: the following figure shows that as of 3 Sep 2023, there are a total of 143 DPP-4 drugs worldwide, from 153 organizations, covering 51 indications, and conducting 2227 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. The analysis of the target DPP-4 in the pharmaceutical industry reveals a competitive landscape with several companies actively involved in the development of drugs. Merck & Co., Inc., Takeda Pharmaceutical Co., Ltd., C.H. Boehringer Sohn AG & Co. KG, AstraZeneca PLC, and LG Chem Ltd. are the companies growing fastest under the current target.  The most common indication for drugs targeting DPP-4 is Diabetes Mellitus, Type 2. Small molecule drugs are progressing most rapidly, with biosimilars indicating intense competition. The European Union, Japan, the United States, South Korea, and China are the countries/locations developing fastest under the current target, with China showing significant progress.  Overall, the target DPP-4 presents a competitive landscape with a focus on addressing Diabetes Mellitus, Type 2, and the development of small molecule drugs. The Outstanding Performer in DPP-4 Inhibitors - LinagliptinAs a critical limb of DPP-4 inhibitors, Linagliptin's hypoglycemic efficacy is definitive, accompanied with lesser hypoglycemic events and long-term cardio-renal safety confirmed by numerous studies. A meta-analysis incorporates three parallel, randomized, placebo-controlled Phase III clinical trials that lasted for 24 weeks. The integrated analysis indicates that, after 24 weeks, the baseline of HbA1c in Linagliptin patients dropped by 1.2%, 0.8% lower than the 0.4% drop in the placebo group (P＜0.0001), conclusively proving Linagliptin's hypoglycemic effect. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. In the CAROLINA study, the target for Linagliptin "high-quality standard" was set as HbA1c≤7.0%, no need for glucose-lowering rescue therapy, weight gain of ≤2%, and no occurrence of moderate/severe hypoglycemic events. The results showed that the proportion of Linagliptin "high-quality standard" was significantly higher than that of glimepiride (OR:1.68; 95.47%CI:1.43~1.96; P<0.0001), with more patients achieving high-quality standards with Linagliptin. In addition, the dose of Linagliptin was 5mg/d, no dose adjustment was necessary. For the glimepiride group, the dose was 1-4mg/d, dose adjustments were needed, with an average dose during the study of (2.9±1.1)mg/d, 66% of the patients used the highest dose of 4mg. Besides more patients achieving high-quality standards, the risk of hypoglycemic events in the Linagliptin group was also significantly lower than that of glimepiride. The CAROLINA study (with a median follow-up of more than 6 years) showed that compared with patients treated with glimepiride, the incidence of hypoglycemic events of varying degrees in patients treated with Linagliptin was significantly reduced (Linagliptin 10.6%, glimepiride 37.3%, HR:0.23; 95%CI:0.21~0.26, P<0.0001). Furthermore, only 5% of Linagliptin is excreted through the kidneys, and only 10% is metabolized by the liver, with the metabolites having no pharmacological activity. Therefore, Linagliptin can be used in patients with mild, moderate, and severe hepatic/renal impairment without the need for dose adjustment.

In a large clinical trial that directly compared four drugs commonly used to treat type 2 diabetes, researchers found that insulin glargine and liraglutide performed the best of four medications approved by the U.S. Food and Drug Administration to maintain blood glucose levels in the recommended range. Blood glucose management is a key component of keeping people with type 2 diabetes healthy. All four medications evaluated were added to treatment with metformin, which is the first-line drug to treat type 2 diabetes. In a large clinical trial that directly compared four drugs commonly used to treat type 2 diabetes, researchers found that insulin glargine and liraglutide performed the best of four medications approved by the U.S. Food and Drug Administration to maintain blood glucose levels in the recommended range. Blood glucose management is a key component of keeping people with type 2 diabetes healthy. All four medications evaluated were added to treatment with metformin, which is the first-line drug to treat type 2 diabetes. The trial was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. More than 37 million Americans have diabetes, and approximately 90 to 95% of them have type 2 diabetes. People with diabetes who keep their blood glucose levels in the near-normal range generally have a much lower risk of developing diabetes complications such as nerve, kidney, and eye diseases. Most people with type 2 diabetes require more than one medication to control blood sugar levels over time. While there is general agreement among health care professionals that metformin combined with diet and exercise is the best early approach in diabetes care, there is no consensus on what to do next to best keep high blood glucose in check. Launched in 2013, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study was conducted at 36 U.S. study centers. It was designed to compare four major medications approved by the FDA at the time GRADE started to treat diabetes in combination with metformin. Major results were published in a pair of papers in The New England Journal of Medicine. "This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes," said Dr. Henry Burch, NIDDK's project scientist for GRADE. "This is an integral step toward precision medicine for diabetes care, as these results can now be used in the decision-making process for each individual patient in light of their levels of glucose control, how well the medications are tolerated, and the person's other health considerations." The study enrolled 5,047 people with type 2 diabetes from diverse racial and ethnic groups who were already taking metformin. Participants were randomly placed into one of four treatment groups. Three groups took metformin plus a medicine that increased insulin levels, sitagliptin, liraglutide, or glimepiride. The fourth group took metformin and insulin glargine U-100, a long-acting insulin. After an average of four years of follow-up, the study found that participants taking metformin plus liraglutide or insulin glargine achieved and maintained their target blood levels for the longest time compared to sitagliptin or glimepiride. This translated into approximately six months more time with blood glucose levels in the target range compared with sitagliptin, which was the least effective in maintaining target levels. Treatment effects did not differ based on age, sex, race, or ethnicity. However, none of the combinations overwhelmingly outperformed the others. Although average blood sugar levels decreased during the study, nearly three quarters of all participants were unable to maintain the blood glucose target over four years, underscoring the difficulty in maintaining recommended targets in many patients with type 2 diabetes. "GRADE effectively shows which drugs worked best at achieving and maintaining blood glucose targets over time, but we need to establish even more effective strategies for the long-term maintenance of acceptable glucose levels," said GRADE Study Chair Dr. David M. Nathan, director of the Massachusetts General Hospital Diabetes Center, Boston. "We still have more work to do, such as evaluating other interventions and treatment combinations to help people with type 2 diabetes achieve long-term glucose control." The study also looked at the treatments' effects on developing diabetes-related cardiovascular disease. Researchers found that participants in the liraglutide group were least likely to experience any cardiovascular disease overall compared to the other groups. The study also examined side effects of the drugs, finding: In addition, on average, participants in all treatment groups lost weight. Over four years, people in the liraglutide and sitagliptin arms lost more weight (an average of 7 and 4 pounds, respectively) than the glargine and glimepiride arms (less than 2 pounds). "With many treatment options available for type 2 diabetes, health care providers and patients can find it difficult to know which drug is best for which person," said NIDDK Director Dr. Griffin P. Rodgers. "NIDDK stands uniquely poised to support comparative effectiveness trials like GRADE to help providers make evidence-based recommendations that lead to better health for their patients, and for all people living with type 2 diabetes." A now-available type of diabetes drug called SGLT2 inhibitors was not approved by the FDA at the launch of GRADE recruitment and was not included in the study. The GRADE Study was supported by a grant from NIDDK (U01DK098246). Additional support was provided by the National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Center for Advancing Translational Sciences; the Centers for Disease Control and Prevention; and the American Diabetes Association. The Department of Veterans Affairs provided resources and facilities. Material support in the form of donated medications and supplies has been provided by Becton, Dickinson and Company, Bristol-Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics, and Sanofi.