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SGLT2 Inhibitors: Star Hypoglycemic Agents
EP39011
Poster Title: SGLT2 Inhibitors: Star Hypoglycemic Agents
Submitted on 07 Jul 2022
Author(s): Sally Zou
Affiliations: Hunan Huateng Pharmaceutical Co. Ltd.
Poster Views: 73
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Poster Information
Abstract: On May 14, Henagliflozin, a SGLT2 inhibitor independently developed by Hengrui Pharma was officially launched. This is the first independently developed SGLT2 inhibitor in China. SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Now, the SGLT2 inhibitor has once again been shown to the public, which makes us wonder what the charm of this magical target that constantly bringing "blockbusters"?

SGLT2 inhibitors --- the statins of the 21st century
In 1835, French chemist C. Petersen isolated Phlorizin (originally used in malaria treatment) from the root bark of apple trees. Later, studies confirmed that injection of phloridzin can reduce blood sugar concentration in diabetic animals.

But it wasn't until 1996 that researchers at Kyoto University and Tanuba Seiygyu developed the first chemically synthesized SGLT2 inhibitor.

In 2012, the European EMA approved the first SGLT2 inhibitor, Dapagliflozin for marketing.

Subsequent studies have proved that SGLT2 inhibitorsare not only a hypoglycemic drug, but also effective in the treatment of type 2 diabetes, heart failure with or without type 2 diabetes and diabetic nephropathy. Eugene Braunwald once called SGLT2 inhibitors "statins of the 21st century" in his review article.

Mechanism of action of SGLT2 inhibitors.jpg

Figure 1 Mechanism of action of SGLT2 inhibitors

(Image source: Reference 2)

SGLT2, full name is Sodium-glucose Cotransporter-2, which is distributed in the renal tubules and plays the role of reabsorbing the glucose in the original urine back into the blood. When SGLT2 is inhibited, the reabsorption of glucose by the renal tubules will be inhibited, and the urine sugar will increase, thereby reducing blood sugar.

Notably, SGLT2 inhibitors are safe because their hypoglycemic effect is independent of insulin and fasting increases compensatory hepatic endogenous glucose production.

In addition to hypoglycemic effects, SGLT2 inhibitors have these effects:

1. Cardiovascular protection
A number of studies have shown that SGLT2 inhibitors have cardioprotective effects and can be used in the treatment of heart failure. They can not only improve the prognosis of patients, but also reduce the hospitalization rate and mortality rate, and have certain effects on heart failure with or without diabetes. In addition, it can improve atherosclerosis, myocardial energy metabolism and anti-fibrosis.

2. Antihypertensive effect
Clinical data show that SGLT2 inhibitors can reduce systolic blood pressure to varying degrees, and the reduction is significantly dose-dependent. For example, in the clinical trial of canagliflozin, systolic blood pressure decreased between 2.6-5.7mmHg at the 100mg dose and 3.5-7.9mmHg at the 300mg dose compared to the placebo group.

The mechanism of action is on the one hand to reduce blood pressure through urinary sodium excretion, and on the other hand to improve vascular cell function and reduce arteriosclerosis by reducing inflammatory response and oxidative stress. Surprisingly, SGLT2 inhibitors can reduce blood pressure without causing hyponatremia.

3. Weight loss
SGLT2 inhibitors reduce energy through the action of urine sugar, and at the same time induce browning of white adipose tissue. Since there are two main types of fat in humans, namely white fat and brown fat, the former stores energy and the latter produces heat and consumes energy, thus increase the quantity of brown fat, can increase energy consumption, improve metabolism, achieve the effect of weight loss.

4. Decreased uric acid
SGLT2 inhibitors can lead to increased excretion of uric acid and decrease uric acid in the body. However, compared with classical uric acid lowering drugs, the effect is relatively weak, so it is more promising to be applied to patients with asymptomatic hyperuricemia or diabetes complicated with hyperuricemia.

5. Liver protection
SGLT2 inhibitors can protect the liver by altering the glucose-fatty acid cycle, increasing the utilization and oxidation of fatty acids in skeletal muscle, adipose tissue and the liver, thereby reducing the accumulation of fatty acids in the liver. Clinical data show that SGLT2 inhibitors can prevent and treat nonalcoholic fatty liver disease to a certain extent.
Summary: SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Now, the SGLT2 inhibitor has once again been shown to the public, which makes us wonder what the charm of this magical target that constantly bringing "blockbusters"?References: [1]. SGLT2 inhibitors: the statins of the 21st century
[2]. Characteristics and molecular mechanisms through which SGLT2 inhibitors improve metabolic diseases: A mechanism review
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