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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The chemical structures of dapagliflozin 230, canagliflozin 231, empagliflozin 232 and ipragliflozin 233 present a C-glycosidic linkage between the glucose moiety and the aglycon; luseogliflozin 235 also possess the C-glycosidic bond, but now between the aglycon and the corresponding 5-thio-D-glucopiranose. Remogliflozin etabonate 236 is the only member of the family possessing the classical O-linkage, while tofogliflozin 234 is a spiranic compound, so that C- and O-linkages are simultaneously present.
Anti-Diabetic Drugs
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Another most recent addition to the list of oral anti-diabetic medicines is a class of drugs known as sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors or the ‘gliflozin’ drug class). These drugs inhibit a member SGLT-2 from a class of cell surface receptors found in the gastrointestinal tract and kidneys. This receptor is responsible for the passive transport of glucose and other monosaccharides. SGLT-2 receptors are primarily found in proximal renal tubules and are highly responsible for renal glucose reabsorption. It was also reported that the expression of SGLT-2 is significantly increased in diabetic patients. Thus, inhibiting these receptors would enhance renal glucose clearance by blocking glucose reabsorption, which raises the plasma glucose concentration. Canagliflozin (Invokana) was the first SGLT-2 inhibitor approved for use [1,4]. It is also the only drug in this class that inhibits SGLT-1 receptors primarily present in the small intestine. Other drugs in this class include dapagliflozin (Forxiga), tofogliflozin (Deberza), empagliflozin (Jardiance), ipragliflozin (Suglat), luseogliflozin (Lusefi) and ertugliflozin (Steglatro). Invokana exists as a 300 mg tablet taken once daily; Forxiga exists as 5 mg and 10 mg tablets and the recommended dose is no more than 10 mg taken once daily; Jardiance comes as 10 mg and 25 mg pills taken once daily; Suglat comes in 25 mg and 50 mg tablets with the maximum dose not exceeding 100 mg per day; Lucefi exists in 2.5 mg and 5 mg pill formulations taken once daily; Steglatro, the latest addition to the class, is available in 5 mg and 15 mg formulations [25–31]. Regarding safety concerns and adverse events, SGLT-2 inhibitors have been shown to be associated with an increased risk of leg and foot amputation, diabetic ketoacidosis, urinary tract yeast infection, vaginal and penile yeast infection, bone fracture (by decreasing bone mineral density) and renal impairment [25–37]. These medications, therefore, should be very cautiously prescribed, taking into account the risk-to-benefit ratio. In a recently published large phase 3 multicentric trial (at 133 centres) evaluating the safety and efficacy of a new oral SGLT-2 inhibitor Sotagliflozin in combination with insulin in T1DM subjects, it was found that patients who received insulin along with Sotagliflozin had better reduction of HbA1c (below 7% recommended baseline value) as compared to the group taking insulin with a placebo. But the rate of ketoacidosis and hypoglycaemia was much higher in the treatment group than the placebo group. Thus, the concomitant use of SGLT-2 inhibitors with insulin should be prescribed with caution and proper monitoring [38].
An update of SGLT1 and SGLT2 inhibitors in early phase diabetes-type 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2019
Ernest Adeghate, Sahar Mohsin, Faisal Adi, Fares Ahmed, Ali Yahya, Huba Kalász, Kornelia Tekes, Ernest A. Adeghate
Tofogliflozin is a product of Chugai Pharmaceutical Company, Japan. It was developed in conjunction with Sanofi-Aventis and Kowa Pharmaceuticals and approved for the treatment of T2DM in 2014 in Japan. In a large post-marketing open study involving more than 6,897 patients, tofogliflozin was reported to markedly reduce HbA1c and body weight. In addition to the beneficial effects of tofogliflozin, polyuria, increased risk infections of the urinary and genital tracts were also observed [51]. The FDA has not yet approved tofogliflozin, and it is therefore still considered an investigational drug in the USA. The recommended dose of tofogliflozin is 20 mg per os, once in a day. Figure 2, Table 2.
An evaluation of the efficacy and safety of Tofogliflozin for the treatment of type II diabetes
Published in Expert Opinion on Pharmacotherapy, 2019
Genya Aharon-Hananel, Itamar Raz
Two pivotal studies were published in 2014 and are primarily responsible for the approval of Tofogliflozin by the Japanese authorities. The first was a multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 Japanese patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy [57]. This study tested Tofogliflozin as a monotherapy in different doses of 10, 20, or 40 mg. The primary efficacy endpoint was the change from baseline HbA1c at week 24. The findings showed that the mean change in HbA1c was −0.028% in the placebo group whereas Tofogliflozin (10, 20 and 40 mg) reduced the HbA1c by −0.797%, −1.017% and −0.870% respectively. Tofogliflozin also significantly reduced fasting blood glucose and 2-hours post prandial blood glucose. Along with the improvement in glycemic control, patients on Tofogliflozin also significantly reduced their body weight compared to the placebo group by −1.87, −2.50, and −2.61 kg for Tofogliflozin 10, 20, and 40 mg, respectively. Of the Tofogliflozin groups, the 20 mg group showed the greatest decrease in fasting blood glucose, and the Tofogliflozin 40 mg group showed the greatest decrease in body weight. Other important parameters were ameliorated in the Tofogliflozin group: systolic and diastolic blood pressures decreased significantly in the 40mg Tofogliflozin group compared to the placebo (−9.4 (11.1) systolic reduction and −4.1 (8.3) diastolic reduction). High-density lipoprotein cholesterol (HDL) levels were also improved in all Tofogliflozin treatment groups. Nevertheless, a significant increase in LDL cholesterol was observed in the 40 mg Tofogliflozin subgroup but not in the other Tofogliflozin subgroups compared to the placebo [57].
Sodium-glucose transporter (SGLT2) inhibition: A potential target for treatment of type-2 Diabetes Mellitus with Natural and Synthetic compounds
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Shubham Batra, Prabhjeet Kaur Bamrah, Manjusha Choudhary
Tofogliflozin and its main phenylacetic acid metabolite M1 made up 42 and 52% of the total amount of drug-related material in circulation, respectively. M1 was also the main substance eliminated in urine and feces and was estimated to make up more than half of the dose [36]. Tofogliflozin can be given in combination with other antidiabetic drugs, such as dipeptidylpeptidase-4 inhibitors, metformin, and sulfonylureas [35]. Overall, tofogliflozin is proving to be an extremely effective oral hypoglycemic medication.