Learn About The Clinical Use Of SGLT-2i in One Article
May 04, 2023
1. What is SGLT-2i?
In 1835, French chemist Petersen. C extracted phlorizin from apple bark and found that it could cause polyuria, urinary sugar excretion, and weight loss. Later, when people studied the reabsorption of glucose by the kidney, they found that the root bark Glycosides can inhibit the reabsorption of glucose by the renal proximal tubule.
Click to cistanche tubulosa capsules for kidney disease
In the late 1980s, scientists discovered the role of sodium-glucose cotransporters (including SGLT-1 and SGLT-2) in urinary glucose reabsorption, and in the late 1990s, they identified the role of sodium-glucose cotransporters in diabetes. association. Further research found that the affinity of phloridzin to sodium-glucose transporter is 1000-3000 times that of glucose, and because of this, phloridzin can prevent the channel function of sodium-glucose transporter in urinary sugar reabsorption, but it was later found that The chemical nature of phlorizin itself determines that it is not suitable for oral hypoglycemic drugs, but inspired by this, scientists have made unremitting efforts to prepare derivatives suitable for oral administration that are similar in structure and activity to phlorizin. It mainly inhibits the activity of SGLT-2, and this derivative is named SGLT-2i.
2. How does SGLT-2i exert its hypoglycemic effect?
Among the many oral hypoglycemic drugs, SGLT-2i is quite special. Its hypoglycemic effect is different from that of most clinical hypoglycemic drugs—directly reducing the blood glucose concentration to achieve the hypoglycemic target through different channels—but in vivo By competing for the affinity of glucose for sodium-glucose transporter (mainly inhibiting the activity of SGLT-2), it can reduce the absorption of urinary sugar and lower blood sugar.
Brief Mechanism
The kidney is an important organ of the human body. Its basic function is to produce urine. In the urine, many metabolites, wastes, and poisons in the body are excreted with the urine. On the other hand, the kidney also has an important "selection" function, It reabsorbs water and other useful substances, such as glucose, amino acids, sodium ions, potassium ions, etc., from the urine back into the blood circulation, which is the reabsorption function of the kidneys.
Glucose is an important energy substance in the human body. When it flows through the kidneys, it is reabsorbed back into the blood circulation. This reabsorption process is mainly completed by sodium-glucose co-transporter (mainly SGLT-2). Normally, glucose is leaked into the urine when the blood glucose concentration exceeds 10mmol/L (renal glucose threshold). The more the blood glucose concentration exceeds the renal glucose threshold, the more glucose is excreted in the urine.
Since the affinity of SGLT-2i and SGLT-2 is much greater than that of glucose and SGLT-2, it blocks the channel for glucose to be reabsorbed into the blood circulation, so that the glucose in urine will be obediently discharged out of the body, and the blood sugar will naturally decrease. decline.
3. What are the types of SGLT-2i?
Worldwide, currently marketed drugs include Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin, Luseogliflozin, 10 types of tofogliflozin, sotagliflozin, Ertugliflozin, and Henagliflozin. In China, the listed products mainly include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and empagliflozin.
4. Six highlights of SGLT-2i
1. Hypoglycemic, efficient, and safe
As a new type of hypoglycemic drug, SGLT-2i has obvious advantages compared with other drugs. Traditional hypoglycemic drugs keep sugar in the human body, but this type of drug directly excretes sugar through the kidneys, and only when the blood sugar exceeds the renal When the sugar threshold is reached, the hypoglycemic effect is only exerted, instead of stimulating insulin secretion to lower blood sugar, so it will not cause the risk of hypoglycemia, to achieve the good effect of rapid and safe hypoglycemia.
2. Protect the kidneys and effectively reduce proteinuria
Since SGLT-2i inhibits the entry of glucose into renal tubular cells, it can protect the renal tubules from the effects of hyperglycemia and has the potential benefit of reducing the glucose toxicity to the kidneys. At the same time, the osmotic diuresis produced by the increase in the concentration of urinary glucose in the renal tubules can Promote the transport of sodium ions to the distal convoluted tubule, reduce the glomerular filtration rate and return to normal, reduce the damage to the glomerulus, and thus play a protective role in the kidneys.
According to research, after treatment with canagliflozin in patients with diabetes mellitus and nephropathy, it can continuously reduce urinary protein, delay the progress of urinary protein, reverse the grading of urinary protein, and significantly reduce renal composite endpoint events (eGFR decreased by 40%, renal replacement therapy or renal death) with a 40% risk.
3. SGLT-2i has a weight-reducing effect
It mainly reduces body weight by reducing fat mass, and can also reduce non-fat mass: one is the calorie loss (200-300kcal/d) related to increased excretion of diabetes, and the other is 5-10% body fluid loss caused by osmotic diuresis. Its weight loss effect is very helpful for diabetic patients to control their weight and improve insulin resistance.
Multiple meta-analyses showed that all three SGLT-2i significantly reduced body weight compared with placebo: empagliflozin by 1.84 kg, canagliflozin by 2.81 kg, and dapagliflozin by 2.10 kg. This weight loss peaks at 3-6 months and can be maintained for extended periods.
4. SGLT-2i can protect the heart and significantly reduce major cardiovascular adverse events
The possible mechanisms include three aspects: (1) reduce cardiac preload and post load, reduce oxygen consumption; (2) osmotic diuresis, increase urinary sodium excretion, slightly lower blood pressure, (3) improve cardiac energy metabolism, increase oxygen supply, improve the metabolism of cardiomyocytes, increase ATP energy storage in cardiomyocytes, inhibit myocardial fibrosis, and improve myocardial remodeling.
According to research, Dapagliflozin can effectively reduce the risk of cardiovascular death and heart failure hospitalization by 17% when used in a wide range of early-stage populations. For type 2 diabetic patients with a history of myocardial infarction, the risk of major adverse cardiovascular events can be significantly reduced by 16%, and the risk of re-MI can be significantly reduced by 22%.
5. SGLT-2i can reduce the level of blood uric acid to a certain extent
The possible mechanism includes two aspects: (1) SGLT-2i leads to increased renal blood flow caused by high glucose filtration and is associated with increased excretion of uric acid; (2) hyperuricemia is associated with competitive binding and reabsorption of uric acid in renal tubules The transporter of uric acid reduces the reabsorption and increases excretion of uric acid.
Studies on various SGLT-2i drugs have found that a variety of SGLT-2i (empagliflozin, canagliflozin, and dapagliflozin) can reduce blood uric acid levels to varying degrees, with an average reduction of uric acid by about 37.73 umol/L, of which empagliflozin can be reduced by about 42.07umol/L, canagliflozin can be reduced by about 37.02umol/L, and dapagliflozin can be reduced by about 38.05umol/L. In many evidence-based studies, it has been seen that SGLT-2i has the additional benefit of controlling UA levels in addition to effective blood sugar for T2DM patients with HUA.
6. Mild blood pressure lowering effect
Many kinds of SGLT-2i have a blood pressure-lowering effect, which can reduce 3~4/1~2mmHg on average without increasing the incidence of orthostatic hypotension. In patients with SBP>140mmHg, the blood pressure drop is more significant.
Possible mechanisms include decreased blood volume due to diuresis and natriuresis, decreased body weight and intra-abdominal fat, improved glycemic control and insulin sensitivity, suppression of oxidative stress associated with obesity and hyperglycemia, improved vessel wall inflammation and endothelial function, uric acid lower levels, etc.
5. Which patients are suitable for SGLT-2i?
1. The drug is suitable for adult patients with type 2 diabetes whose blood sugar is still poorly controlled with oral hypoglycemic agents or basal insulin injections alone. Because it can significantly reduce weight and benefit the heart and kidneys, it is especially suitable for patients with type 2 diabetes who are obese, with cardiovascular disease or chronic kidney disease, and also suitable for those who do not have cardiovascular disease but have cardiovascular risk factors Diabetic patients, such as age ≥ 55 years, have hypertension, dyslipidemia, atherosclerosis (carotid artery, lower extremity artery, coronary artery, etc.) and microalbuminuria. In addition, for diabetic patients with confirmed heart failure, SGLT-2i is also a good choice.
2. Because SGLT-2i has a certain degree of renal benefit. In the past, SGLT-2i was more used in patients with diabetic nephropathy, and there was a lack of research on patients with non-diabetic nephropathy.
The newly released research results show that whether there is diabetes or not, SGLT2i can delay the progression of CKD and reduce the risk of death. It can be said that this is a milestone in progress in the treatment of chronic kidney disease.
The global large-scale DAPA-CKD study found that dapagliflozin can significantly improve the prognosis of chronic kidney disease. After the application of dapagliflozin in CKD patients, the risk of eGFR decline, progression to end-stage renal disease, and death due to renal disease or cardiovascular disease was reduced by 39%, and the longer the time, the more obvious the effect. The incidence of cardiovascular death or hospitalization for heart failure fell by 29%, while the overall death rate also fell by 31%.
In general, the application of dapagliflozin in CKD patients can slow down the decline of renal function, progress to end-stage renal disease later, and patients can have a longer survival time. As a result, dapagliflozin has been approved by the European Commission and the United States, respectively, for the treatment of adults with chronic kidney disease (CKD), regardless of type 2 diabetes.
3. Since SGLT-2i can reduce the level of blood uric acid to a certain extent, it is especially suitable for diabetic patients with increased uric acid.
6. Safe medication: SGLT-2i side effects and treatment measures
1. Genitourinary tract infection
SGLT-2i prevents the reabsorption of glucose in the kidney, which causes the concentration of glucose in the urinary system to be too high, and glucose is a good medium for bacteria. When the body's resistance decreases, it may cause urinary tract infections. It is not recommended for patients with recurrent genitourinary infections within half a year.
The study showed that with preventive measures, the risk of urinary tract infection associated with SGLT2i was similar to that of a placebo, and the risk of reproductive tract infection was slightly increased.
medication advice
It is recommended that patients who use this type of drug pay attention to personal genital hygiene, drink water in moderation, and keep urinating unobstructed, to prevent and reduce the occurrence of infection. During use, if infection occurs, suspend the medication and carry out the anti-infection treatment.
2. Diabetic ketoacidosis
Clinical studies have found cases of diabetic ketoacidosis and ketosis when using this class of drugs, but they are very rare.
Special attention should be paid to the following patients
(1) Type 1 diabetes, surgery, excessive exercise, myocardial infarction, stroke, severe infection, and other stress states;
(2) Prolonged fasting or very low carbohydrate intake;
(3) Excessive reduction of insulin when insulin is used in combination quickly.
Precautions
The characteristics of ketosis during taking this type of drug are different. The blood sugar usually does not exceed 13.9 mmol/L. It is called "DKA with low blood sugar", so it is easy to miss the diagnosis. To prevent missed diagnosis of diabetic ketoacidosis, if patients taking this drug develop related symptoms such as abdominal pain, nausea, vomiting, fatigue, dyspnea, etc., they should consider testing blood ketones as soon as possible.
3. Adverse skin reactions
SGLT-2i may cause adverse skin reactions, and skin symptoms (such as pruritus, rash, and erythema) mostly occur within 2 weeks after administration. Symptoms are not severe in most patients.
If a patient develops a rash while using SGLT-2i, it is recommended to choose a non-SGLT-2i drug.
4. Other
The risk of fracture and lower limb amputation, abnormal bladder function, and risk of bladder cancer related to SGLT-2i are not very clear and need to be further tested. Nonetheless, it should be used with caution in those at high risk of fracture, such as postmenopausal women or patients with osteoporosis.
The mechanism of Cistanche extract treating kidney disease
Cistanche extract is a traditional Chinese medicine used for the treatment of various diseases, including kidney disease. The mechanism of action of Cistanche extract in treating kidney disease involves several factors.
1. Anti-inflammatory properties: Cistanche extract contains natural compounds that have anti-inflammatory properties. These compounds help to reduce inflammation in the kidneys, which can reduce the damage caused by kidney disease.
2. Antioxidant properties: Cistanche extract also contains antioxidants that help to protect the kidneys from oxidative stress. Oxidative stress occurs when there is an imbalance between free radicals and antioxidants in the body. This can damage the kidneys and contribute to the development of kidney disease.
3. Renal function improvement: Cistanche extract has been found to improve renal function in animal studies. It can help to reduce proteinuria, which is a common symptom of kidney disease, and also reduce the levels of serum creatinine and blood urea nitrogen (BUN), which are markers of kidney function.
4. Immune system modulation: Cistanche extract can help to modulate the immune system, which can reduce the progression of kidney disease. In particular, it can help to regulate T cell activity, which can reduce inflammation in the kidneys and improve renal function.
Overall, the use of Cistanche extract in the treatment of kidney disease is promising.
References:
[1] Diabetes Society of Chinese Medical Association. Guidelines for Prevention and Treatment of Type 2 Diabetes in China (2020 Edition) [J]. Chinese Journal of Endocrinology and Metabolism, 2021, 04:311-398.
[2] Zhou Pei, Tang Xiangyu, Deng Yunxia, Zhang Yiwei, Deng Hao. SGLT-2 Inhibitor-Epagliflozin's Cardiovascular Protection and Mechanism Research Progress [J]. China Medicine Guide, 2021, 23(11 ):823-827.
[3] Expert consensus on the clinical application of hypoglycemic drugs in Chinese adults with type 2 diabetes complicated with heart and kidney disease [J]. Chinese Journal of Diabetes, 2020, 06:369-381.
[4] Ji Linong, Guo Lixin, Guo Xiaohui, etc. Suggestions from Chinese experts on the clinical rational application of sodium-glucose cotransporter 2 (SGLT2) inhibitors [J]. Chinese Journal of Diabetes, 2016,10:865-870.
