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I. How does the existing drug lower blood sugar?

Most of the glucose digested and absorbed from food is transported to various tissues of the body along with blood circulation, generating heat for human use, and a small part is converted into glycogen, stored in liver and muscle tissue, and then turned into glucose when the body needs it. use.

If the sugar intake is too much, it can be converted into fat for storage. When the blood sugar supply is insufficient, in addition to immediately mobilizing hepatic glycogen and muscle glycogen into glucose, the liver can also use other raw materials, such as amino acids, lactic acid and fat in the body to synthesize glucose, which uses other substances to synthesize glucose. The process is called gluconeogenesis.

To sum up, there are three ways to source blood sugar: absorption in food, glycogen decomposition and gluconeogenesis; and there are three ways to get blood sugar: the uptake and utilization of human tissue, conversion to glycogen, glycogen storage, and conversion to fat.

Existing hypoglycemic agents exert hypoglycemic effects by affecting the above pathways.

1. Insulin: Insulin mainly lowers blood sugar by two aspects. On the one hand, it increases the utilization of glucose, such as accelerating the utilization of glucose by various tissues and accelerating the synthesis of glycogen; on the other hand, reducing production, such as inhibiting gluconeogenesis And inhibit the decomposition of glycogen.

2. Insulin secretagogues: including sulfonylureas and glinide-type secretagogues, all of which lower blood sugar by promoting insulin secretion.

3. DPP4 inhibitors (statins) and GLP-1 agonists: glucose concentration-dependently stimulates insulin secretion and suppresses appetite to lower blood sugar.

4. Metformin: Reduces blood glucose by increasing the utilization of glucose, inhibiting glycogenolysis, inhibiting gluconeogenesis, and has insulin sensitization, increasing the sensitivity of insulin receptors and increasing the hypoglycemic effect of insulin.

5. Insulin sensitizer: Increases the sensitivity of the insulin receptor and increases the hypoglycemic effect of insulin.

6. Alpha glycosidase inhibitors: lower blood sugar by reducing the absorption of glucose.


II. Kidney regulation of blood sugar also plays an important role

Many people may not know that the kidney is also an important organ regulating blood sugar. The study found that 180g of glucose was filtered from the glomerulus every day, but was completely absorbed by the renal tubules, so there was no sugar in the urine and urine sugar was negative. When the blood glucose concentration exceeds 11 mmol/L, the glucose filtered out from the glomerulus is too much, which exceeds the absorption capacity of the renal tubules, and the sugar is discharged with the urine, and the urine sugar is positive.

The substance responsible for sugar absorption in the renal tubule is called “sodium-glucose cotransporter 2”, abbreviated as SGLT-2. SGLT-2 is mainly distributed in the S1 segment of the proximal convoluted tubule of the kidney. It is a low-affinity, high-transporting transporter whose main physiological function is to complete the reabsorption of 90% glucose in glomerular filtrate. If SGLT-2 is inhibited, it can reduce the absorption of glucose by the renal tubules, and a large amount of sugar is discharged from the urine, thereby achieving the purpose of lowering blood sugar.


III. SGLT-2 inhibitor

SGLT-2 inhibitors selectively inhibit the function of SGLT-2 for hypoglycemic purposes.
There are currently six SGLT-2 inhibitors on the market, namely: dapagliflozin, engliflozin, cangliflozin, igrilide, rugliflozin and togliflozin.

Dagliflozin has a very strong hypoglycemic effect:

A number of studies have shown that dapagliflozin has a significant reduction in fasting blood glucose and glycosylated hemoglobin in patients with type 2 diabetes. One dose of dapagliflozin (10mg) is equivalent to 4 tablets of metformin sustained-release agent (2000mg). The effect of reducing glycosylated hemoglobin is comparable to that of sulfonylurea, and the incidence of hypoglycemia is extremely low.

In addition, dapagliflozin has the effect of reducing sugar:

1. Weight loss: Daggliflozin mainly reduces body weight by reducing fat mass and diuretic drainage. Studies have confirmed that the average body weight decreased by 2.1 kg after dagliflozin monotherapy, and the maximum weight loss reached 4.54 in combination with metformin for 102 weeks. Kg. The weight loss effect peaks 3 to 6 months after administration and can be maintained for a long time.

2. Mild blood pressure: Daglipidum mainly through diuretic, weight loss to reduce blood pressure. Studies have confirmed that daclilevin alone reduces the blood pressure by 3~4/1~2mmHg on average, and the blood pressure drop is more significant when systolic blood pressure is >140mmHg; dapagliflozin and ACEI (Puli class of antihypertensive drugs) or ARB ( A combination of sartan antihypertensive drugs can reduce the systolic blood pressure by 4.3 mmHg.

3. Kidney protection: Daggliflozin has a role in reducing urine protein and stable glomerular filtration, regardless of whether there is chronic kidney disease before treatment. Other studies have confirmed that dapagliflozin can also reduce the incidence of kidney disease.

4. Uric acid reduction: A number of studies have confirmed that dapagliflozin can reduce blood uric acid levels by 10% to 15%. The absorption mechanism and location of glucose and uric acid in the renal tubules are very similar. Daggliflozin inhibits the absorption of urine glucose and also inhibits the absorption of uric acid. The uric acid-lowering mechanism of dapagliflozin may be involved in its cardiovascular and renal protective effects.

5. Cardiovascular benefits

In December 2016, the FDA officially approved a new indication for englitavir: a reduction in cardiovascular death in patients with type 2 diabetes mellitus with cardiovascular disease, and ng Liege is the first to be recognized by the FDA to reduce cardiovascular death. The sugar medicine makes metformin unattainable. These cardiovascular benefits are the class effect of this class of drugs or are unique to Engleet, and it is not clear.


IV. Adverse reactions and potential risks of SGLT-2 inhibitors

1. Genitourinary system infection: Daglipide net to increase the concentration of urine sugar, bacteria easily in the urine, so prone to genitourinary tract infection. The risk of genitourinary infection is a clear adverse reaction of SGLT-2 inhibitors. This risk of infection must be considered when applied to elderly or debilitated patients.

2. Fracture and lower extremity amputation risk: the US FDA has issued a warning that may increase the risk of fracture and lower extremity amputation, it is not clear whether this happens by chance or is unique to Cangliet. No increase in fracture risk was found in the study of dagliflozin and engliflozin.


V. Clinical practice evidence

Clinical studies have shown that 10 mg of dapagliflozin can significantly reduce glycated hemoglobin by 1.16% at 24 weeks of treatment, and this effect is better in patients with hyperglycemia (glycated hemoglobin ≥ 9.0%), a decrease of 1.84%.

In addition, the application of dapagliflozin 10 mg decreased body weight by 2.33 kg, the weight loss was >5%, and the waist circumference decreased by a large margin; dapagliflozin 10 mg reduced systolic and diastolic blood pressure by 1.9 mmHg, respectively. And 1.1mmHg.

In terms of safety, reproductive infections and urinary tract infections in Dalglipo were slightly higher than those in the control group, but there were no serious events. No death or renal failure, pyelonephritis, adverse events caused by insufficient blood volume, good safety, rare hypoglycemia, no severe hypoglycemia events or discontinuation of treatment.

Studies have shown that for patients with type 2 diabetes who are still under poorly controlled by diet and exercise intervention, dapagliflozin brings significant benefits of weight loss and blood pressure while providing significant hypoglycemic, and is safe.

SGLT-2 inhibitors have been on the market for four years and have been recommended as first-line/second-line treatments for type 2 diabetes by the American and European Diabetes Association, the American Society of Clinical Endocrinologists, and the International Diabetes Union guidelines for the treatment of elderly patients with diabetes. The overall evaluation is that the hypoglycemic effect is remarkable, the hypoglycemia is rare, and there is an additional harvest of weight loss and blood pressure reduction, and the safety is good.

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