How many more surprises can "God's Gift - SGLT2 Inhibitors" surprise humans?

In recent years, the global development process of new drugs, both quantity and quality, is working hard to meet the current unsatiswed clinical needs.
In the field of chronic metabolic diseases, diabetes has been one of the major problems plaguing human beings, in response to this, the development of new drugs around the world is particularly hot, especially SGLT2 to net class drugs, has been listed in a number of varieties.
and even more surprising is that other clinical benefits of net-listed drugs are still emerging! 1, Diabetes Epidemiology and Drug Development Profile 2019, the International Diabetes Alliance (IDF) reported that about 463 million adults worldwide have diabetes, which is expected to reach 700 million by 2045;
current development of new drugs is focused on SGLT2 inhibitors, GLP-1 subjector astrists, DPP-4 inhibitors, AMPK astrists, GCGr antagonists, GK astrists, GPRII9 astrists, 11 beta-HSD1 inhibitors, and so on.
, SGLT2 inhibitors have been a surprise to drug developers and are highly available in the industry!Figure 1.1 International Diabetes Alliance (IDF)/Data Bulletin (Image Source: 2, 1835-SGLT2 inhibitors Discovered In 1835, the physiological properties of the non-selective SGLT inhibitor genotide were found in apple roots, and the physiological properties of SGLT protein re-absorption of glucose in renal tubes were further discovered.
In a normal physiological state, the body's renal sphere filtered about 180g of glucose per day, renal sphere filtered glucose in the near-curve tube is almost completely re-absorbed, of which SGLT2 is involved in the renal sphere filter 90% of glucose re-absorption, the remaining 10% by SGLT1.
SGLT2 inhibitors selectively inhibit the re-absorption of glucose by SGLT2, reduce the renal sugar threshold, increase urinary sugar excretion, its mechanism of action is independent of insulin on blood sugar regulation, not affected by the secretion function of human islet beta cells and the body's insulin resistance.
2.1 SGLT2 regulated glucose re-absorption (Photo: doi: 10.1016/j.ejps.2016.08.025) 3, listed SGLT-2 inhibitor drugs so far, more than one has been listed worldwide SGLT2 inhibitors, respectively, Dagled net, Kagli net, Ingre net, Igli net, Aegle net, Togele net, Rugle net;
Dapagliflozin Dagliflozin, developed by Ariscon and Baccaer, can be used as an auxiliary drug to control blood sugar levels in adults with type 2 diabetes, or as a single patient who is resistant to metformin.
was approved for listing by the EMA in November 2012, and in the U.S., the variety was finally approved by the FDA in January 2014 as the second SGLT-2 inhibitor approved by the FDA after a rejection of the listing and a re-application for additional data. the
study noted that in patients with type 2 diabetes who failed to meet the criteria for primary treatment or with other oral antisaccharins or insulin, the use (plus) daglass was significantly lower than the baseline, and the risk of hypoglycemia did not increase.
common adverse reactions are genitourinary system infection, nasopharyngitis, polyurea, abnormal blood lipids, back pain and so on.
use of PS:SGLT2 inhibitors has certain requirements for kidney function.
Canagliflozin, developed by Janssen Pharmaceuticals, was approved by the FDA in March 2013 as the first FDA-approved SGLT-2 inhibitor;
addition to inhibiting SGLT-2, kaglile net also has inhibitory effect on SGLT-1, which can reduce blood sugar after meals to a certain extent.
sugar reduction has a concentration dependence.
study, Kaglia net can reduce weight by reducing adipose tissue and can slightly lower blood pressure in patients.
adverse reactions are most common urinary tract infections, but also can be seen polyurea, a small number of elderly patients with low blood pressure, dizziness and so on.
Empagliflozin Engliflozin, the development company for Grigg Ingelheim and Lilly, in 2014 EMA and the FDA have approved Englig net listing, regardless of single drug or in association with other sugar-lowering drugs, Engele net can reduce patients' empty stomach blood sugar, after-dinner blood sugar and HbA1c to varying degrees.
, Ingrequin also had a positive effect on the patient's weight and blood pressure.
is less demanding for kidney function than D'Agli.
common adverse reactions are genitourinary tract infections, polyurea, nasopharyngitis and so on.
Ipragliflozin Igliflozin, jointly developed by Astellas, Japan Life Pharmaceuticals and Merca East, was approved by the Japan Pharmaceutical Medical Devices Integrated Agency (PMDA) in January 2014 and is listed for sale in Japan by the three companies mentioned above;
Ertugliflozin, developed by Grigg Ingham and Lilly for the treatment of type 2 diabetes, is a powerful, selective SGLT-2 inhibitor.
the drug was approved by the EMA in March 2014 and can be given separately or in combination with other sugar-lowering drugs.
Agrigliflozin has shown good efficacy and safety in clinical trials, and two Phase 3 clinical trial data have been published showing that ertugliflozin significantly reduces patients' levels of HbA1c, whether in association with metformin or with Januvia.
Tofogliflozin, a Chinese and foreign pharmaceutical company for the treatment of type 2 diabetes, was approved for sale in Japan in May 2014, and the advantage of this new SGLT2 inhibitor is that the drug is more selective and can be used alone to treat type 2 diabetes or in a joint application with other antidiabetic drugs.
Luseogliflozin, a development company for Novarlor, was approved for listing in Japan in May 2014.
Clinical results showed that in terms of sugar-lowering efficacy, the incidence of type 2 diabetes in rugle net group was less statistically significant than that of patients with type 2 diabetes in rugle net group, 2h blood sugar after meals, and weight control was better than placebo( P.lt;0.05);
Figure 3.1 has been listed SGLT2/ column net class drugs to structural modification site (Picture source: doi: ) 4, other effects of SGLT2 inhibitors Although the sugar reduction effect of SGLT2 inhibitors is significant, but the more hope is derived from other clinical benefits of such drugs, the greatest attention is "heart failure", "weight loss", "kidney decay".
heart failure - for many years no new drugs on the market! Why is there so much attention paid to heart failure? Remember the roglitone variety? Because the sugar-lowering drug can increase the risk of heart failure or cardiovascular death and de-market in the U.S. market, the FDA has also launched a mandatory new sugar-lowering drug for cardiovascular research, known as CVOTs.
While SGLT2 inhibitors have achieved very good clinical performance in terms of cardiovascular benefits, such as Dagle Net, Kaglig net, Engli Net, clinical studies of heart failure adaptation are in Clinical Phase III;
heart failure adaptation, has not been on the market for many years! Weight loss - the same need for new drugs on the market! Since the first SGLT2 inhibitor, Dagledge, was introduced in 2012, a meta-analysis of the weight-loss effects of these drugs has been published one after another: 26 weeks of clinical trials such as Kagle net (300mg specification) can lose nearly 2.5 kg, and 52 weeks is more obvious.
, however, the therapeutic effect of stable weight loss needs to be further evaluated, whether dose dependence is also not clear results.
kidney protection.
Through a large number of clinical randomized controlled studies, SGLT2 inhibitors showed significant kidney protection, and through a variety of ways to play long-term kidney protection, the current widely recognized mechanisms and hypothreasures include: through the role of sugar reduction to protect the kidneys, improve hemodynamics, lower blood pressure, lower uric acid, improve kidney hypoxia, improve blood lipid abnormalities, inhibit the exchange of sodium and hydrogen protein in the kidneys, and so on.
Figure 4.1 SGLT2 inhibitors on the more aspects of the benefits (Image Source: ) 5, domestic SGLT2 inhibitors of the new drug development statistics for the development of SGLT2 inhibitors, there are also a number of varieties into the clinical, and the highest stage has phase III varieties of Jiangsu Hengrui Henggli net, Shandong Xuanzhu Medicine's Gagle net, Guangdong Dongsian's Ronggli net.
a.m., Hengrui announced Hengle net 20th clinical trial program, has 3 different drug treatment programs into the clinical; The second sugar-lowering drug developed by Xuanzhu Pharmaceuticals, and Rongglie Net of Dongsian, also recently announced its Phase IIIa clinical trial, which aims to evaluate the efficacy of Junglig net in patients with type 2 diabetes who are treated solely with diet and exercise and have poor blood sugar control.
addition to the above-mentioned Phase III varieties, the domestic pharmaceutical companies developed SGLT2 inhibitors are also in the clinical Phase II teglile net, Phase I Wangli net, and so on.
Reference 1. Madaan, Tushar, Akhtar, Mohd. Najmi, Abul Kalam, Sglucose CoTransporter 2 (SGLT2) resedors: Current status and perspective, (2016), doi:10.1016/j.ejps.2016.08.025 2. A new class ofdrugs for heart failure: SGLT2 resedors reduces the overactivity. Journal of Cardiology 71 (2018) 471-476.doi.org/10.1016/j.jjcc.2017.12.004 3. Synthetic strategyyand SAR studies of C-glucoside heteroaryls as SGLT2 reedor: A review, European Journal of Medicinal Chemistry (2019), doi: 4. Mechanisms of CardioVascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Addors.5. 6. The structure in the figure is derived from: 7. New England Magazine 8. Cnki.