A traditional Chinese medicine composition for treating diabetic kidney disease in combination with SGLT2 inhibitor, and a preparation method and application thereof

Abstract

This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine composition for the combined treatment of diabetic nephropathy with SGLT2 inhibitors, its preparation method, and its application. The traditional Chinese medicine composition of this invention consists of raw Astragalus membranaceus, raw Rehmannia glutinosa, Paeonia suffruticosa, Salvia miltiorrhiza, Prunus mume, Hedyotis diffusa, Pheretima aspergillum, and Dioscorea nipponica. Raw Astragalus membranaceus invigorates Qi and generates fluids; raw Rehmannia glutinosa and Prunus mume nourish Yin and astringe Yin to generate fluids; Paeonia suffruticosa, Salvia miltiorrhiza, Pheretima aspergillum, and Dioscorea nipponica invigorate blood and unblock collaterals; combined with Hedyotis diffusa to clear heat, invigorate blood, and detoxify, it works synergistically to invigorate Qi and nourish Yin, and invigorate blood and unblock collaterals. This invention takes the basic pathogenesis of diabetic nephropathy as "Qi and Yin deficiency with kidney collateral obstruction" as its starting point, and, referring to pathological research on diabetic nephropathy, proposes a treatment approach based on invigorating Qi and nourishing Yin, and invigorating blood and unblocking collaterals, addressing both the root cause and symptoms, with synergistic effects through mutual reference of mechanisms; simultaneously, it is grounded in "human experience," with clinical practice proving the feasibility, effectiveness, and scientific validity of this invention.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine composition for the treatment of diabetic kidney disease in combination with SGLT2 inhibitors, its preparation method, and its application. Background Technology

[0002] Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. Diabetic kidney disease (DKD) is a common microvascular complication of DM and a major factor leading to chronic renal failure and end-stage renal disease (ESRD). Studies show that approximately 15.6% to 41.3% of DM patients in my country will develop DKD. Although current treatment strategies, such as lowering blood pressure, lowering blood sugar, regulating lipids, and using ACEIs or ARBs, have partially delayed the progression of DKD, the damage to kidney function and proteinuria in patients remain difficult to effectively control, necessitating the exploration of more optimized treatment options.

[0003] Based on its clinical manifestations, DKD can be categorized under "kidney wasting," "asthenia," "edema," and "turbid urine." Some TCM scholars also refer to it directly as "wasting-thirst nephropathy" because it develops from wasting-thirst. Wasting-thirst nephropathy is secondary to wasting-thirst, and its pathogenesis is related to "sugar toxicity." It is also closely related to various factors such as inherent weakness, improper diet, invasion of the six pathogenic factors (wind, cold, dampness, heat, dryness, and fire), mistreatment or delayed treatment, emotional distress, and irregular lifestyle. Modern people experience high work pressure, often stay up late, and crave spicy, stimulating, and rich foods. These factors combined deplete yin and blood, leading to yin and blood deficiency, which manifests as wasting-thirst. Yin deficiency generates internal heat, and excessive heat damages body fluids. Over time, this leads to insufficient yin and blood, or even scorching of yin and blood, resulting in the internal generation of blood stasis, which is called "prolonged illness entering the collaterals." "Blood is the mother of qi." Over time, yin and blood are depleted, unable to carry qi, and qi deficiency weakens the ability to propel blood circulation, leading to even more severe blood stasis. Stagnant blood accumulates and transforms into heat, further depleting yin and blood. Pathological products such as blood stasis lie dormant in the kidney collaterals over time, gradually damaging the kidney's qi transformation function, obstructing the water passages, and ultimately transforming into toxins. These toxins obstruct the membranes and the triple burner, and when the pathogens lie dormant in the membranes, the triple burner's qi transformation is impaired, thus causing systemic diseases.

[0004] In recent years, sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted much attention due to their unique nephroprotective effects. SGLT2 inhibitors lower blood glucose levels by inhibiting glucose reabsorption in the proximal renal tubules and promoting glucose excretion in the urine. Furthermore, SGLT2 inhibitors have nephroprotective effects independent of their hypoglycemic effect, including reducing glomerular pressure, improving hemodynamics, anti-inflammation, anti-oxidative stress, and anti-renal fibrosis. They are recommended as first-line drugs for patients with type 2 diabetes and kidney disease by the Kidney Disease Improvement Organization Globally (KDIGO). However, clinical observations have found that the use of SGLT2 inhibitors may lead to increased serum creatinine (Scr), urinary tract infections, and other adverse reactions. They may also exacerbate symptoms such as dry mouth, fatigue, spontaneous sweating, lower back and knee pain, and frequent urination at night in some patients, thus worsening symptoms of Qi and Yin deficiency. Summary of the Invention

[0005] The purpose of this invention is to provide a traditional Chinese medicine composition for the combined treatment of diabetic kidney disease with SGLT2 inhibitors.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned traditional Chinese medicine composition.

[0007] Another object of the present invention is to provide the application of the above-mentioned traditional Chinese medicine composition.

[0008] According to a specific embodiment of the present invention, a traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors comprises, by weight, 15-25 parts of raw Astragalus membranaceus, 5-15 parts of raw Rehmannia glutinosa, 5-15 parts of Paeonia suffruticosa, 10-20 parts of Salvia miltiorrhiza, 10-20 parts of Prunus mume, 10-20 parts of Hedyotis diffusa, 10-20 parts of Pheretima aspergillum, and 25-35 parts of Dioscorea nipponica.

[0009] According to a specific embodiment of the present invention, a traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors comprises, by weight, 20 parts of raw Astragalus membranaceus, 10 parts of raw Rehmannia glutinosa, 10 parts of Paeonia suffruticosa, 15 parts of Salvia miltiorrhiza, 15 parts of Prunus mume, 15 parts of Hedyotis diffusa, 15 parts of Pheretima aspergillum, and 30 parts of Dioscorea nipponica.

[0010] According to a specific embodiment of the present invention, a traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors comprises, by weight, 15 parts of raw Astragalus membranaceus, 5 parts of raw Rehmannia glutinosa, 5 parts of Paeonia suffruticosa, 10 parts of Salvia miltiorrhiza, 10 parts of Prunus mume, 10 parts of Hedyotis diffusa, 10 parts of Pheretima aspergillum, and 25 parts of Dioscorea nipponica.

[0011] According to a specific embodiment of the present invention, a traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors comprises, by weight, 25 parts of raw Astragalus membranaceus, 15 parts of raw Rehmannia glutinosa, 15 parts of Paeonia suffruticosa, 20 parts of Salvia miltiorrhiza, 20 parts of Prunus mume, 20 parts of Hedyotis diffusa, 20 parts of Pheretima aspergillum, and 35 parts of Dioscorea nipponica.

[0012] This invention proposes that the pathogenesis of diabetic nephropathy lies in the collateral vessels of the kidney, and the pathogenesis is characterized by deficiency of the root and excess of the branch, with a mixture of deficiency and excess. Diabetic nephropathy is based on deficiency of the body's vital energy, which in the early and middle stages mainly refers to insufficient Qi and Yin in the kidneys, and in the late stage it develops into deficiency of both Yin and Yang, with excess of pathogenic factors as the branch. The excess of pathogenic factors is wind, heat, dampness, phlegm and blood stasis, which are latent pathogenic factors that obstruct the kidney collateral vessels, and blood stasis syndrome runs through the entire course of the disease. In the early stages of the disease, the underlying deficiency is often manifested as yin deficiency and dryness-heat, while the superficial manifestation is stagnation of the kidney meridians, accompanied by qi deficiency. Symptoms mainly include intermittent or persistent microalbuminuria, dry mouth and eyes, five-center heat (palms, soles, and chest), lower back and knee pain, and numbness in the hands and feet—all symptoms of yin deficiency and meridian stagnation. In the middle stage, the disease manifests as deficiency of both qi and yin, and stagnation of the kidney meridians, often presenting with overt proteinuria, fatigue, dry throat and thirst, numbness in the hands and feet, five-center heat, spontaneous sweating and night sweats, and numbness and pain in the hands and feet. In the late stage, prolonged yin deficiency extends to yang, resulting in deficiency of qi, blood, yin, and yang, with kidney yang deficiency being particularly pronounced. This is accompanied by masses in the kidney meridians and internal accumulation of turbid toxins, commonly presenting with massive proteinuria, five-center heat accompanied by aversion to cold and cold limbs, and coldness in the lower back and knees. The condition is complex and accompanied by various concurrent symptoms. In summary, deficiency of both qi and yin and stagnation of the kidney meridians is the core TCM syndrome type of DKD.

[0013] This invention takes the basic pathogenesis of diabetic nephropathy as "deficiency of both qi and yin and obstruction of kidney collaterals" as its starting point. Referring to the pathological research of diabetic nephropathy, it proposes to treat diabetic nephropathy by invigorating qi and nourishing yin, and promoting blood circulation and unblocking collaterals. This approach addresses both the symptoms and the root cause, with mutual reference to the mechanisms and synergistic effects. At the same time, it takes "human experience" as its starting point, using clinical practice and basic research to prove the feasibility, effectiveness and scientific nature of this invention.

[0014] This invention further discovered that the use of SGLT2 inhibitors exacerbates symptoms such as dry mouth, fatigue, spontaneous sweating, lower back and knee weakness, and frequent urination at night in some patients, indicating that the symptoms of Qi and Yin deficiency are more severe. Based on this, this invention proposes a formula using Astragalus membranaceus as the principal ingredient to invigorate Qi and generate fluids, Rehmannia glutinosa and Prunus mume as the secondary ingredients to nourish Yin and astringe Yin, and Paeonia suffruticosa, Salvia miltiorrhiza, Pheretima aspergillum, and Dioscorea nipponica as the auxiliary ingredients to invigorate blood and unblock collaterals. It is combined with Hedyotis diffusa to clear heat, invigorate blood, and detoxify, thus achieving the combined effects of invigorating Qi and nourishing Yin, and invigorating blood and unblocking collaterals. Studies have found that this invention can improve symptoms such as fatigue, dry throat, and thirst in patients, and alleviate the symptoms of Qi and Yin deficiency.

[0015] The traditional Chinese medicine composition of the present invention, which combines SGLT2 inhibitors for the treatment of diabetic kidney disease, can protect the renal function of DKD patients, reduce proteinuria, and improve the TCM syndrome of diabetic kidney disease patients on the basis of using SGLT2 inhibitors.

[0016] According to a specific embodiment of the present invention, a traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors comprises, by weight, 20 parts of raw Astragalus membranaceus, 10 parts of raw Rehmannia glutinosa, 10 parts of Paeonia suffruticosa, 15 parts of Salvia miltiorrhiza, 15 parts of Prunus mume, 15 parts of Hedyotis diffusa, 15 parts of Pheretima aspergillum, and 30 parts of Dioscorea nipponica.

[0017] The SGLT2 inhibitors in this invention include dapagliflozin, empagliflozin, canagliflozin, eltoggliflozin, hengagliflozin, or soragliflozin. More preferably, the herbal composition of this invention is used in combination with dapagliflozin to treat diabetic nephropathy.

[0018] A method for preparing a traditional Chinese medicine composition for treating diabetic nephropathy in combination with an SGLT2 inhibitor according to a specific embodiment of the present invention: the method includes the following steps:

[0019] The prepared raw astragalus, raw rehmannia, peony bark, salvia miltiorrhiza, dried plum, oldenlandia diffusa, earthworm, and smilax china are boiled over high heat and then simmered over low heat for 10-15 minutes to obtain the Chinese herbal composition.

[0020] The present invention also provides the application of the above-mentioned traditional Chinese medicine composition in the preparation of a treatment for diabetic kidney disease.

[0021] According to a specific embodiment of the present invention, a medicament for treating diabetic kidney disease in combination with an SGLT2 inhibitor comprises the above-mentioned traditional Chinese medicine composition and pharmaceutically acceptable excipients.

[0022] According to a specific embodiment of the present invention, a drug for treating diabetic kidney disease in combination with an SGLT2 inhibitor is provided, wherein the drug is an oral formulation.

[0023] Preferably, the drug is a decoction, pill, powder, ointment, medicated wine, granule, tablet or capsule.

[0024] Based on long-term clinical experience and research on traditional theories, the inventor believes that the basic pathogenesis of diabetic nephropathy is deficiency of both qi and yin and obstruction of kidney collaterals, and the site of the disease may involve the collaterals of the kidney.

[0025] The principles and methods of treatment in this invention: In clinical practice, the treatment of diabetic nephropathy should focus on the basic pathogenesis of "deficiency of both qi and yin and obstruction of kidney collaterals". The first priority should be to replenish qi and yin, and blood-activating and collateral-dredging should be integrated throughout the entire treatment process.

[0026] The formula composition and explanation of this invention: (1) Composition: Astragalus membranaceus, Rehmannia glutinosa, Paeonia suffruticosa, Salvia miltiorrhiza, Prunus mume, Hedyotis diffusa, Pheretima aspergillum, Dioscorea nipponica.

[0027] (2) Explanation: Astragalus membranaceus is the chief ingredient for replenishing qi and generating fluids, Rehmannia glutinosa and Prunus mume are the assistant ingredients for nourishing yin, astringing yin and generating fluids, and Paeonia suffruticosa, Salvia miltiorrhiza, Pheretima aspergillum and Dioscorea nipponica are the adjuvant ingredients for promoting blood circulation and unblocking collaterals. It is combined with Hedyotis diffusa to clear heat, promote blood circulation and detoxify, so as to replenish qi and nourish yin, promote blood circulation and unblock collaterals.

[0028] (3) Pharmacological effects Raw astragalus root is sweet and warm in nature, entering the lung and spleen meridians. It invigorates qi and raises yang, promotes fluid production and diuresis, and is considered a holy medicine for replenishing qi. The *Tangye Bencao* states that it "replenishes the original qi of the kidneys," and it can be used to treat patients with qi deficiency, fatigue, edema, and internal heat and thirst. Astragalus contains various chemical components such as saponins and polysaccharides. Studies have found that astragaloside A has anti-inflammatory and antioxidant effects. It can upregulate the expression of antioxidant enzymes by regulating the PI3K / Akt-ERK-dependent Nrf2 / ARE pathway, inhibiting the increase of ROS / NF-κB-induced inflammatory cytokines, fibrosis biomarkers, and cell proliferation, thereby protecting against HG-induced GMC damage. It can also regulate the IRE-1α signaling pathway, reduce endoplasmic reticulum oxidative stress, and improve DKD podocyte damage. Astragalus polysaccharides can protect microvessels and improve renal vascular endothelial damage. Studies have found that Astragalus membranaceus and its active ingredients can regulate metabolism, regulate glucose and lipid metabolism disorders and mitochondrial dysfunction, inhibit cell apoptosis, autophagy and endoplasmic reticulum stress, reduce proteinuria; and have multiple effects such as anti-oxidative stress, anti-inflammation and inhibition of EMT, and anti-renal fibrosis, thereby delaying the progression of renal function.

[0029] Rehmannia glutinosa has a sweet taste and cold nature. It can nourish yin and clear heat, cool the blood and promote blood circulation, and has both tonifying and clearing effects. The "Shennong's Classic of Materia Medica" states that it "treats internal injuries, expels blood stasis, and replenishes bone marrow." The effective components of Rehmannia glutinosa include rehmannia oligosaccharides, rehmannia glycosides, etc., which can lower blood sugar and lipids, improve insulin resistance; have anti-inflammatory and antioxidant effects; protect podocytes; improve microcirculation and inhibit renal fibrosis. Studies have found that Rehmannia glutinosa oligosaccharides can rebuild the endocrine regulatory network, improve insulin resistance and glucose and lipid metabolism, and maintain blood glucose homeostasis; Rehmannia glutinosa targets and inhibits the NF-κB and TGF-β1 / Smads pathways, reducing inflammatory factors such as IL-6, Hs-CRP, and TNF-α; Rehmannia glutinosa upregulates Nrf2 and ERα / ERβ expression, enhances SOD activity, and reduces lipid peroxidation; In addition, Rehmannia glutinosa activates the SIRT1 signaling pathway, inhibits mTOR activity and promotes TFEB nuclear translocation, enhances podocyte autophagy, stabilizes the cytoskeleton, and reduces proteinuria; By downregulating the RAGE / p38 MAPK / NF-κB and RAGE / NOX4 / NF-κB pathways, it reduces BAX / Caspase-3 expression and inhibits podocyte apoptosis; It reduces whole blood viscosity and fibrinogen content in the blood stasis syndrome model, improves blood rheology, and improves microcirculation; Rehmannia glutinosa extract can inhibit the progression of renal fibrosis by regulating the miR-122-5p / PKM axis.

[0030] Ume (dried plum) has a sour and astringent taste, is neutral in nature, and enters the liver, spleen, lung, and large intestine meridians. It can promote the production of body fluids and quench thirst, relieve steaming heat and irritability, and is used for thirst due to deficiency heat. The *Shennong Bencao Jing* states that ume "mainly lowers qi, relieves heat and irritability, calms the mind… and alleviates hemiplegia and numbness." The *Bielu* records that ume "stops excessive salivation and dry mouth." The *Ben Cao Jing Shu* states that ume's sour taste can astringe and reduce superficial heat, clear deficiency fire, and promote the production of body fluids, treating excessive salivation and dry mouth. Modern research has found that ume has anti-inflammatory, antioxidant, immunomodulatory, and apoptosis-inhibiting effects. Ume and its formulations can promote the recovery of pancreatic β-cell function, stimulate insulin secretion, improve insulin resistance, activate AMPK expression in tissues, upregulate GLP-1, reduce NF-κB p65, and regulate glucose and lipid metabolism.

[0031] Moutan bark has a bitter and pungent taste, is slightly cold in nature, and enters the heart, liver, and kidney meridians. It can clear heat and cool the blood, promote blood circulation and remove blood stasis. The *Shennong Bencao Jing* states that it "treats chills and fever, stroke, convulsions, spasms, epilepsy, and evil qi; removes hard masses and stagnant blood in the intestines and stomach; and soothes the five internal organs." Moutan bark can clear heat and promote blood circulation, thus cooling the blood and dispersing blood stasis, clearing heat from the blood, and treating latent fire in the kidney meridians and stagnant masses. Moutan bark not only clears excess heat in the blood, but also treats yin deficiency fever. Combined with Rehmannia glutinosa, it can nourish the kidneys and purge fire, treating deficiency heat. The effective components of Moutan bark include moutan bark polysaccharides, terpenoid glycosides, paeonol, and phenolic compounds. Paeonia suffruticosa polysaccharides can block the AGEs-RAGE signaling pathway, reduce glomerular mesangial cell proliferation and basement membrane thickening, and upregulate superoxide dismutase (SOD) activity and downregulate NF-κB pathway, as well as inflammatory factors such as TNF-α and IL-6, by activating the Nrf2 / ARE pathway. It can also reduce circulating endotoxin levels and alleviate kidney damage by regulating gut microbiota. Terpenoid glycosides significantly inhibit AGEs formation, target endoplasmic reticulum stress-related inflammatory responses, inhibit the IRE1α / XBP1 pathway, reduce inflammatory infiltration in renal tissue, and reduce oxidative stress and the release of inflammatory factors. Paeonol inhibits ROS generation, protects renal tubular epithelial cells from high glucose-induced apoptosis, inhibits cyclooxygenase (COX) activity, reduces thromboxane A2 (TXA2) production, and lowers the hypercoagulable state. The traditional heat-clearing, blood-cooling, blood-activating, and stasis-removing effects of Paeonia suffruticosa correspond to its synergistic effects of anti-AGEs, anti-inflammatory, antioxidant, and microcirculation-improving properties, making it particularly suitable for diabetic kidney disease (DKD) complicated by chronic inflammation and hypercoagulability. When combined with Rehmannia glutinosa, it can enhance the effects of regulating glucose and lipid metabolism and inhibiting renal fibrosis.

[0032] Danshen (Salvia miltiorrhiza) is bitter and slightly cold in nature, and enters the heart and liver meridians. It can remove blood stasis, relieve pain, invigorate blood circulation, and regulate menstruation. The *Shennong Bencao Jing* states that Danshen treats evil qi in the heart and abdomen… breaks up masses and eliminates lumps, relieves vexation and fullness, and benefits qi. Combined with Astragalus membranaceus, it can replenish qi and blood, invigorate blood circulation, and remove blood stasis. Danshen contains various effective components such as tanshinone, salvianolic acid, and tanshinone. Studies have found that Danshen can regulate glucose and lipid metabolism, improve insulin resistance, has anti-inflammatory and anti-oxidative stress effects, improves microcirculation, and resists renal fibrosis. Salvia miltiorrhiza A can improve mitochondrial function and lower fasting blood glucose through the AMPK signaling pathway; enhance antioxidant capacity by activating the Nrf2 / ARE pathway; and reduce inflammatory damage to the kidneys by inhibiting the activation of the TLR4 / NF-κB signaling pathway. Danshen B reduces insulin resistance through the PI3K / Akt pathway; downregulates inflammatory factors such as IL-6 and TNF-α, and inhibits the inflammatory cascade by blocking p-NF-κB p65 phosphorylation; it also delays EMT and inhibits renal fibrosis by targeting signaling pathways such as TGF-β / Smad, Wnt / β-catenin, and HPSE / SDC-1. Danshen injection can relieve microvascular spasm, reduce platelet viscosity, lower fibrinogen levels, and improve microcirculation.

[0033] Earthworms are salty and cold in nature, entering the liver, spleen, and bladder meridians. They can clear heat and promote diuresis, unblock meridians and collaterals, and clear heat and calm wind. The core active components of earthworms include lumbrokinase, protein, and hypoxanthine. Modern research has found that earthworms can regulate glucose and lipid metabolism, significantly reduce triglyceride, total cholesterol, and fasting blood glucose levels, and reduce urinary protein excretion; inhibit inflammatory responses, downregulate the levels of inflammatory factors such as TGF-β1, IL-6, and TNF-α, and block the activation of the NF-κB pathway, reducing glomerular mesangial cell proliferation and extracellular matrix deposition; improve oxidative stress, enhance SOD activity, and repair HG-induced vascular endothelial damage; improve microcirculation perfusion, reduce whole blood viscosity and fibrinogen content, and inhibit platelet activation; antagonize renal fibrosis by reducing collagen deposition and delaying glomerular sclerosis through regulation of the TGF-β / Smad pathway.

[0034] Dioscorea nipponica has a sweet and bitter taste, is warm in nature, and enters the liver, kidney, and lung meridians. It has the effects of dispelling wind and dampness, promoting blood circulation and unblocking collaterals, relaxing muscles and tendons, and clearing the kidney collaterals. Master of Traditional Chinese Medicine Zhu Liangchun frequently used Dioscorea nipponica to treat rheumatic immune diseases such as lupus and Sjögren's syndrome, as well as kidney diseases such as chronic nephritis, believing that it can be used for both cold and hot, deficiency and excess conditions. The main effective components of Dioscorea nipponica include steroidal saponins such as diosgenin and fine saponins, as well as flavonoids and other compounds. Modern research has found that Dioscorea nipponica has multiple effects such as lowering blood sugar, lowering blood lipids, anti-inflammation, regulating immunity, anti-oxidative stress, improving microcirculation, and inhibiting renal fibrosis. It can reduce blood urea nitrogen and serum creatinine (Scr) in CKD patients and reduce proteinuria. Diosgenin can resist oxidative stress and protect against LPS-induced inflammatory kidney injury. This anti-inflammatory effect may be achieved by regulating the microRNA let-7i / TLR4 / MyD88 signaling pathway; inhibiting NF-κB nuclear translocation; inhibiting PI3K and Akt phosphorylation; increasing SOD2 levels; decreasing the mRNA levels of IL-1β, IL-6, MIP-1α, Fas, and FasL; and regulating the Keapl-Nrf2 pathway to resist oxidative stress. Total saponins can inhibit renal fibrosis by inhibiting the TGF-β1 / Smads and PI3K / Akt / mTOR signaling pathways.

[0035] Hedyotis diffusa has a sweet and bland taste, and is cool in nature. It enters the stomach, large intestine, and small intestine meridians. It has the functions of clearing heat and detoxifying, promoting diuresis and reducing swelling, and activating blood circulation and relieving pain. It can treat symptoms such as urinary tract infections, difficulty urinating, and sore throat. Professor Gao Yanbin often uses Hedyotis diffusa to treat patients with mid-to-late stage DKD with symptoms of yin deficiency and heat transformation, and blood stasis and heat toxicity. It can reduce proteinuria in patients, and the usual dosage can be up to 30g. Hedyotis diffusa contains a variety of effective components such as flavonoids, polysaccharides, and anthraquinones, which have anti-inflammatory, antioxidant, and immunomodulatory effects. The main anti-inflammatory active components of Hedyotis diffusa, such as total flavonoids, can reduce the levels of inflammatory factors such as IL-6, IL-1β, and TNF-α by inhibiting the MAPK pathway. The polysaccharides and flavonoids in Hedyotis diffusa can scavenge ROS, reduce lipid peroxidation products (such as MDA), and upregulate the activity of SOD and glutathione peroxidase (GSH-Px), thus playing an antioxidant role. The polysaccharides in Hedyotis diffusa can significantly promote NK cell activity and splenic lymphocyte proliferation, regulate the Th1 / Th2 balance, and inhibit excessive immune response-induced kidney tissue damage. Anthraquinone components may reduce autoantibody-mediated glomerular damage by regulating the TLR4 / NF-κB pathway and downregulating the PI3K / Akt / mTOR pathway. In summary, Hedyotis diffusa, through its synergistic anti-inflammatory, antioxidant, and immunomodulatory effects, targets key pathological aspects of kidney disease (DKD)—chronic inflammation, oxidative stress, and immune dysregulation—providing multidimensional protection for the kidneys.

[0036] This invention also provides the application of the above-mentioned traditional Chinese medicine composition in combination with SGLT2 inhibitors in the preparation of combination drugs for diabetic nephropathy. According to the weight parts, the traditional Chinese medicine composition includes 15-25 parts of raw Astragalus membranaceus, 5-15 parts of raw Rehmannia glutinosa, 5-15 parts of Paeonia suffruticosa, 10-20 parts of Salvia miltiorrhiza, 10-20 parts of Prunus mume, 10-20 parts of Hedyotis diffusa, 10-20 parts of Pheretima aspergillum, and 25-35 parts of Dioscorea nipponica; the SGLT2 inhibitor includes one or more of dapagliflozin, empagliflozin, canagliflozin, eltoggliflozin, hengagliflozin, or soagliflozin.

[0037] Preferably, the SGLT2 inhibitor is dapagliflozin.

[0038] The beneficial effects of this invention are: The herbal composition of this invention consists of eight herbs: raw Astragalus membranaceus, raw Rehmannia glutinosa, Paeonia suffruticosa, Salvia miltiorrhiza, Prunus mume, Hedyotis diffusa, Pheretima aspergillum, and Dioscorea nipponica. Raw Astragalus membranaceus invigorates Qi and generates fluids; raw Rehmannia glutinosa and Prunus mume nourish Yin, astringe Yin, and generate fluids; Paeonia suffruticosa, Salvia miltiorrhiza, Pheretima aspergillum, and Dioscorea nipponica invigorate blood and unblock collaterals; and Hedyotis diffusa clears heat, invigorates blood, and detoxifies. Together, they invigorate Qi, nourish Yin, invigorate blood, and unblock collaterals.

[0039] The herbal composition of this invention is made from pure Chinese herbs and has fewer toxic side effects.

[0040] The combination of traditional Chinese medicine and SGLT2 inhibitors has a synergistic effect in the treatment of diabetic nephropathy. It is significantly superior to SGLT2 inhibitors alone in improving renal function (eGFR, Scr), reducing proteinuria (UACR, 24hUTP), and improving TCM syndrome scores. It is particularly outstanding in two indicators: eGFR (glomerular filtration rate) and improvement of TCM syndromes (dry mouth, fatigue, spontaneous sweating, soreness of the waist and knees, and frequent urination at night). This shows that the combination therapy may enhance the efficacy through a multi-target mechanism. Attached Figure Description

[0041] Figure 1 Changes in serum creatinine levels in patients after treatment with the composition of Example 1 of this invention. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0043] Example 1 The traditional Chinese medicine composition of the present invention for the combined treatment of diabetic kidney disease with SGLT2 inhibitors comprises, by weight (one part by weight is equivalent to 1g), 20 parts of raw Astragalus membranaceus, 10 parts of raw Rehmannia glutinosa, 10 parts of Paeonia suffruticosa, 15 parts of Salvia miltiorrhiza, 15 parts of Prunus mume, 15 parts of Hedyotis diffusa, 15 parts of Pheretima aspergillum, and 30 parts of Dioscorea nipponica.

[0044] Preparation method of the traditional Chinese medicine composition of the present invention: First, soak raw Astragalus membranaceus, raw Rehmannia glutinosa, Paeonia suffruticosa, Salvia miltiorrhiza, Prunus mume, Hedyotis diffusa, Pheretima aspergillum, and Dioscorea nipponica in 500mL of purified water for 30 minutes. Bring to a boil over high heat, then simmer over low heat to obtain approximately 300mL of the medicinal liquid.

[0045] Example 2 The traditional Chinese medicine composition of the present invention for the combined treatment of diabetic nephropathy with SGLT2 inhibitors comprises, by weight (one part by weight equals 1g): 15 parts Astragalus membranaceus, 5 parts Rehmannia glutinosa, 5 parts Paeonia suffruticosa, 10 parts Salvia miltiorrhiza, 10 parts Prunus mume, 10 parts Hedyotis diffusa, 10 parts Pheretima aspergillum, and 25 parts Dioscorea nipponica. The preparation method is the same as in Example 1.

[0046] Example 3 The traditional Chinese medicine composition of the present invention for the combined treatment of diabetic nephropathy with SGLT2 inhibitors comprises, by weight (one part by weight equals 1g): 25 parts Astragalus membranaceus, 15 parts Rehmannia glutinosa, 15 parts Paeonia suffruticosa, 20 parts Salvia miltiorrhiza, 20 parts Prunus mume, 20 parts Hedyotis diffusa, 20 parts Pheretima aspergillum, and 35 parts Dioscorea nipponica. The preparation method is the same as in Example 1.

[0047] Example 4 The traditional Chinese medicine composition of the present invention, in combination with SGLT2 inhibitors for the treatment of diabetic nephropathy, comprises, by weight (one part by weight equals 1g): 15g Astragalus membranaceus, 15g Rehmannia glutinosa, 10g Paeonia suffruticosa, 20g Salvia miltiorrhiza, 12g Prunus mume, 15g Hedyotis diffusa, 15g Pheretima aspergillum, and 30g Dioscorea nipponica. The preparation method is the same as in Example 1.

[0048] Example 5 Typical Case 1 Patient Wang, male, 59 years old. First visit on December 4, 2023. Present illness: In 2019, the patient's physical examination showed SCr 78 umol / L, and urinalysis: PRO 2+, BLD+, which was not taken seriously. In 2021, a physical examination showed SCr 141 umol / L, BUN 11 mmol / L, UA 500 umol / L, and urinalysis: PRO-, BLD-. The patient sought treatment at Guang'anmen Hospital and received traditional Chinese medicine treatment. On November 3, 2023, a follow-up examination showed SCr 127 umol / L, UA 316 umol / L, urinalysis: PRO-, 24hUTP 128.7 mg, UACR 48.3. Fundus examination suggested diabetic retinopathy. Current symptoms: The patient experiences lower back pain and fatigue, dry mouth, normal appetite, poor sleep, foamy urine, formed stools, once a day. Red tongue with thin white coating, and a wiry and thready pulse. Past medical history: Diabetes for over 10 years, currently taking dapagliflozin 10mg once daily and linagliptin 5mg once daily. Glycated hemoglobin is 5.7%, fasting blood glucose is controlled at 5-6 mmol / L, and postprandial blood glucose is controlled at 9-10 mmol / L. History of hypertension, currently taking losartan potassium 100mg twice daily, with blood pressure currently controlled at 110-120 / 70-80 mmHg. History of hyperlipidemia, currently taking atorvastatin 10mg once daily.

[0049] Based on the patient's medical history, symptoms, signs, tongue appearance, and pulse, the TCM diagnosis is "Xiao Ke Shen Bing" (Western medicine diagnosis is "diabetic nephropathy"). The basic pathogenesis is Qi and Yin deficiency with blood stasis in the kidney meridians. Treatment is based on understanding the underlying mechanism, with the main approach being "tonifying Qi and Yin, and promoting blood circulation and unblocking the meridians." The specific medications are as follows: Raw Astragalus 15g, Raw Rehmannia 15g, Moutan Cortex 10g, Salvia Miltiorrhiza 20g, Mume 12g, Oldenlandia diffusa 15g, Earthworm 15g, Dioscorea nipponica 30g.

[0050] After 14 days of treatment, the patient's lower back pain and weakness lessened, dry mouth improved, and symptoms such as sleep disturbances and foamy urine were relieved. The tongue and pulse remained largely unchanged. The treatment was continued for nearly two months without alteration.

[0051] The results are as follows Figure 1 As shown, a follow-up Scr test on January 5, 2024, showed a level of 123 umol / L and proteinuria. A follow-up SCr test on February 26, 2024, showed a level of 112 umol / L, with no abnormalities found in the urinalysis. The patient is in good spirits, has no particular discomfort, and is living a normal life, and is still undergoing treatment.

[0052] Typical Case 2 Ms. Sun, female, 44 years old. First visit on July 9, 2021. Chief complaint: Elevated blood sugar for over 20 years, proteinuria for 2 years. Present illness: The patient was diagnosed with type 2 diabetes mellitus (D2) over 10 years ago and was treated with subcutaneous insulin injections to control her blood sugar. However, she did not continue regular blood sugar control treatment or blood sugar monitoring. Two years ago, due to poor blood sugar control, she visited a local hospital. A fundus examination revealed diabetic retinopathy and positive urine protein (details unknown). DKD was suspected, and she was treated with oral metformin, glimepiride, and dapagliflozin to lower her blood sugar. Fasting blood glucose was controlled at 6-9 mmol / L, and postprandial blood glucose was controlled at 9-11 mmol / L. On June 7, a urinalysis at our hospital showed protein PRO3+ > 3.0 g / L. Current symptoms: The patient experiences fatigue, dry mouth, bitter taste, hot flashes in the palms, soles, and chest, occasional dizziness and headache, poor appetite, normal sleep, slightly dry stools (once a day), normal urine volume with a small amount of foam, and nocturia 2-3 times. The tongue is red with little coating, the sublingual veins are tortuous, and the pulse is thin and weak.

[0053] Auxiliary examinations: serum creatinine (SCr) 99 μmol / L, urinalysis: PRO3+, urine renal function: MALB / CR 269.22 mg / g, 24-hour urine protein quantification 380 mg / 24h.

[0054] Traditional Chinese Medicine Diagnosis: Diabetes mellitus, Qi and Yin deficiency syndrome, Kidney meridian obstruction syndrome.

[0055] Western medicine diagnosis: Type 2 diabetes, type 2 diabetic nephropathy, type 2 diabetic retinopathy, grade 2 hypertension (very high risk).

[0056] The treatment principle is to replenish qi and nourish yin, and to invigorate blood and unblock collaterals. The formula of this invention is modified as follows: Astragalus membranaceus 30g, Rehmannia glutinosa 15g, Paeonia suffruticosa 10g, Salvia miltiorrhiza 20g, Prunus mume 12g, Hedyotis diffusa 15g, Pheretima aspergillum 15g, Dioscorea nipponica 30g, Artemisia capillaris 15g, Euonymus alatus 15g, Ligustrum lucidum 20g, Glycyrrhiza uralensis (processed) 6g. A total of 14 doses are prescribed, one dose per day, decocted in water and taken warm in 200ml twice daily.

[0057] On July 23, 2021, the patient had a second consultation. She reported that her fatigue and dry mouth had improved compared to before, but she still experienced irritability, sweating, occasional dizziness, poor appetite, small amounts of foamy urine, and nocturia twice. Her tongue was red with a thin, white coating, and her pulse was thready and weak. The initial prescription was modified by adding 10g of stir-fried gardenia and 30g of poria cocos, and the prescription was copied from a local pharmacy.

[0058] On November 20, 2021, the patient had their third consultation. They reported occasional irritability, but no other significant discomfort. Their tongue was dark red with a white coating, and their pulse was deep and thready. A repeat SCr test showed 61 μmol / L, 24-hour urine protein quantification was 227.5 mg, and urinalysis was positive (PRO). The prescription from the second consultation was modified by adding 15g of Ophiopogon japonicus and 15g of Pheretima aspergillum. The patient's condition stabilized, and this modified prescription was continued. They were advised to regulate their diet, maintain emotional well-being, and be mindful of their daily routine.

[0059] Typical Case 3 Mr. Han, male, 69 years old, first visit on June 20, 2024, chief complaint: elevated serum creatinine for over 2 years. Present illness: Over 2 years ago, the patient was diagnosed with elevated serum creatinine (SCr 120 umol / L) at Peking University First Hospital. Relevant examinations were completed, but the report is unavailable and details are unknown. Diabetic nephropathy was suspected, and a renal biopsy was recommended for definitive diagnosis, which the patient refused. On May 28, the patient's SCr was 124 umol / L, eGFR 50.8, BUN 7.97 mmol / L, and UACR 82.51 mg / g. Current symptoms: foamy urine, no urinary frequency, urgency, or dysuria, no bilateral lower extremity edema, no blurred vision, good appetite, poor sleep with frequent awakenings, bowel movements 1-2 times daily, normal consistency. Dark red tongue with little coating, deep and thready pulse. Past medical history: Type 2 diabetes for over 4 years, currently taking metformin and dapagliflozin orally, and subcutaneously injecting Humalog 50R 36-20 IU to lower blood sugar; HbA1c is controlled at 6.3-6.8%. Hypertension for over 2 years, currently taking valsartan orally; blood pressure is well controlled. Hyperlipidemia, currently taking atorvastatin orally.

[0060] Traditional Chinese Medicine Diagnosis: Diabetes mellitus, Qi and Yin deficiency syndrome, Kidney meridian obstruction syndrome.

[0061] Western medical diagnosis: Diabetic nephropathy, diabetes, chronic kidney disease, stage 3.

[0062] The treatment principle is to replenish qi and nourish yin, and promote blood circulation and unblock the meridians. The prescription of this invention is modified as follows: Astragalus membranaceus 30g, Rehmannia glutinosa 15g, Paeonia suffruticosa 10g, Salvia miltiorrhiza 20g, Prunus mume 15g, Hedyotis diffusa 15g, Pheretima aspergillum 15g, Dioscorea nipponica 30g, Ligustrum lucidum 15g, Lycium barbarum 15g. A total of 14 doses are prescribed. One dose is decocted in water and taken warm in 200ml twice a day.

[0063] On August 24th, a follow-up blood test showed: SCr 107 umol / L, urinalysis: PRO-, UACR 64.45 mg / g. The patient is in good spirits, has no particular discomfort, and is living a normal life, and is still undergoing treatment.

[0064] Example 6 Clinical Trial A randomized controlled, open-label trial was conducted, selecting 54 patients diagnosed with DKD and diagnosed with Qi and Yin deficiency and kidney meridian obstruction syndrome who visited the outpatient or inpatient department of Beijing Hospital of Traditional Chinese Medicine between December 2023 and December 2024. These patients were randomly divided into an experimental group (n=29) and a control group (n=25).

[0065] The control group received basic treatment combined with SGLT2 inhibitor therapy, while the experimental group received the same treatment regimen as the control group plus the composition of this invention. Treatment lasted 12 weeks. Patient information, underlying diseases, and medication use were recorded. Biochemical indicators were recorded before and after enrollment. Changes in estimated glomerular filtration rate (eGFR), serum creatinine (Scr), urine albumin / creatinine ratio (UACR), 24-hour urine protein (24hUTP), TCM syndrome score, and symptom score were observed and statistically analyzed.

[0066] result: Regarding efficacy indicators: (1) Comparison of the experimental group before and after treatment: After 12 weeks of treatment, the levels of eGFR and HgB in the kidney-preserving and yin-nourishing formula group were significantly higher than before treatment (P < 0.05); Scr, UACR, 24hUTP, GLU, HbAlc, and UA were significantly lower than before treatment (P < 0.05).

[0067] (2) Comparison of the control group before and after treatment: After treatment, the UACR, 24hUTP, HbAlc and UA in the control group were significantly lower than before treatment (P < 0.05).

[0068] (3) Comparison between the experimental group and the control group: After treatment, the eGFR level of the kidney-preserving and yin-nourishing formula group was significantly higher than that of the control group (P < 0.05), while the Scr and HbAlc levels were significantly lower than those of the control group (P < 0.05). Compared with the control group, the difference in UACR and 24hUTP in the kidney-preserving and yin-nourishing formula group after treatment was statistically significant (P < 0.05).

[0069]

[0070] Clinical efficacy evaluation: After 12 weeks of treatment, 20 cases in the experimental group showed significant improvement, 6 cases showed improvement, and 3 cases showed no improvement, with a total effective rate of 89.66%; 7 cases in the control group showed significant improvement, 12 cases showed improvement, and 6 cases showed no improvement, with a total effective rate of 76%. The experimental group was superior to the control group, and there was a statistically significant difference in the effective rate between the two groups (P < 0.05).

[0071] Criteria for evaluating therapeutic efficacy: Significant effect: A reduction of ≥ 50% in the main clinical symptom score, a reduction of ≥ 50% in UACR or 24h-UTP, or a return to normal; an increase of ≥ 10% in eGFR or a decrease of ≥ 10% in Scr within 3 months. Any one of these is required for determination.

[0072] Effective: The main clinical symptom score is reduced by ≥ 30% but < 50%; UACR or 24h-UTP is ≥ 30% but < 50%; eGFR is stable or increases by < 10% within 3 months; or Scr is stable or decreases by < 10%. Any one of these criteria is sufficient for determination.

[0073] Invalid: Those that do not meet the above valid standards.

[0074]

[0075] Comparing the TCM symptom scores before and after treatment in the experimental and control groups, and referring to the "Expert Consensus on the Prevention and Treatment of Diabetic Kidney Disease with Integrated Traditional Chinese and Western Medicine (2023 Edition)," scoring criteria were developed based on common symptoms of the TCM syndrome differentiation of DKD with Qi and Yin deficiency and kidney meridian obstruction. 0 points indicated no symptoms; 2 points indicated mild symptoms; 4 points indicated moderate symptoms; and 6 points indicated severe symptoms, with higher scores indicating more severe symptoms. The TCM syndrome scale was completed, as detailed in Table 2.

[0076] Traditional Chinese Medicine Syndrome Score The TCM syndrome score was calculated before and after treatment, with 0, 2, 4, and 6 points assigned to mild, moderate, and severe symptoms, respectively. The score for the primary symptom was doubled, and the scores for the primary and secondary symptoms were added together to obtain the syndrome score. The mean ± standard deviation of the syndrome scores from both groups was used for TCM syndrome score evaluation. Referring to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs (Trial Implementation)," the TCM syndrome efficacy evaluation calculation method was: [(Pre-treatment score - Post-treatment score) ÷ Pre-treatment score] × 100%.

[0077] Table 3 Comparison of symptom improvement between the two groups

[0078] Note: Compared with before treatment, # P < 0.05, ## P < 0.01; compared with the control group, P < 0.05, P <0.01. Traditional Chinese Medicine symptom scores are expressed as mean ± standard deviation ( ). ± s) represents.

[0079] Improvement in TCM symptoms and syndrome scores: After 12 weeks of treatment, the TCM syndrome scores in the experimental group were significantly lower than before treatment (P < 0.05). In the control group, the symptoms of dry throat and thirst worsened after treatment with SGLT2 inhibitors alone (P < 0.05), while in the experimental group, these symptoms were alleviated after treatment (P < 0.05), showing a statistically significant effective rate (P < 0.05). After treatment with the TCM composition of this invention, the symptom scores of subjects with symptoms such as fatigue, spontaneous sweating, lower back and knee weakness, and frequent urination at night improved significantly compared to before treatment (P < 0.05). Compared with the control group, the experimental group showed significant improvement in symptoms of Qi deficiency and Yin deficiency, such as dry throat and thirst, fatigue, spontaneous sweating, constipation, lower back and knee weakness, and frequent urination at night (P < 0.05). There were no statistically significant differences in symptoms such as five-center heat, night sweats, itchy skin, rough skin, and numbness and pain in the limbs before and after treatment (P > 0.05).

[0080] The experimental group of this invention, after combining the traditional Chinese medicine composition with the SGLT2 inhibitor, showed significant superiority over the control group (SGLT2 inhibitor) in the following aspects: increased glomerular filtration rate (eGFR), reduced serum creatinine clearance, decreased proteinuria, and significant improvement in traditional Chinese medicine symptoms (dry throat and thirst, fatigue, spontaneous sweating, constipation, soreness and weakness of the waist and knees, and frequent urination at night).

[0081] All of the above differences are statistically or clinically significant, indicating that the combination of traditional Chinese medicine composition and SGLT2 inhibitor has a clear synergistic effect.

[0082] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A traditional Chinese medicine composition for treating diabetic nephropathy in combination with an SGLT2 inhibitor, characterized in that, The traditional Chinese medicine composition comprises, by weight, 15-25 parts of raw Astragalus membranaceus, 5-15 parts of raw Rehmannia glutinosa, 5-15 parts of Paeonia suffruticosa, 10-20 parts of Salvia miltiorrhiza, 10-20 parts of Prunus mume, 10-20 parts of Hedyotis diffusa, 10-20 parts of Pheretima aspergillum, and 25-35 parts of Dioscorea nipponica.

2. The traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors according to claim 1, characterized in that, The traditional Chinese medicine composition comprises, by weight, 20 parts of raw Astragalus membranaceus, 10 parts of raw Rehmannia glutinosa, 10 parts of Paeonia suffruticosa, 15 parts of Salvia miltiorrhiza, 15 parts of Prunus mume, 15 parts of Hedyotis diffusa, 15 parts of Pheretima aspergillum, and 30 parts of Dioscorea nipponica.

3. The traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors according to claim 1, characterized in that, The traditional Chinese medicine composition comprises, by weight, 15 parts of raw Astragalus membranaceus, 5 parts of raw Rehmannia glutinosa, 5 parts of Paeonia suffruticosa, 10 parts of Salvia miltiorrhiza, 10 parts of Prunus mume, 10 parts of Hedyotis diffusa, 10 parts of Pheretima aspergillum, and 25 parts of Dioscorea nipponica.

4. The traditional Chinese medicine composition for treating diabetic nephropathy in combination with SGLT2 inhibitors according to claim 1, characterized in that, The traditional Chinese medicine composition comprises, by weight, 25 parts of raw Astragalus membranaceus, 15 parts of raw Rehmannia glutinosa, 15 parts of Paeonia suffruticosa, 20 parts of Salvia miltiorrhiza, 20 parts of Prunus mume, 20 parts of Hedyotis diffusa, 20 parts of Pheretima aspergillum, and 35 parts of Dioscorea nipponica.

5. The method for preparing the traditional Chinese medicine composition according to any one of claims 1-4, characterized in that, The method includes the following steps: The prepared raw astragalus, raw rehmannia, peony bark, salvia miltiorrhiza, dried plum, oldenlandia diffusa, earthworm, and dioscorea nipponica are boiled over high heat and then simmered over low heat to obtain the Chinese herbal composition.

6. The preparation method according to claim 5, characterized in that, Simmer over low heat for 15-20 minutes.

7. A drug for treating diabetic kidney disease in combination with an SGLT2 inhibitor, characterized in that, The drug comprises the traditional Chinese medicine composition according to any one of claims 1-4 and pharmaceutically acceptable excipients.

8. A medicament for treating diabetic nephropathy in combination with an SGLT2 inhibitor according to claim 7, characterized in that, The drug is an oral preparation.

9. A medicament for treating diabetic nephropathy in combination with an SGLT2 inhibitor according to claim 8, characterized in that, The medicine is in the form of decoction, pill, powder, ointment, medicated wine, granule, tablet or capsule.

10. The application of a traditional Chinese medicine composition combined with an SGLT2 inhibitor in the preparation of a combination drug for diabetic nephropathy, characterized in that, The traditional Chinese medicine composition comprises, by weight, 15-25 parts of raw Astragalus membranaceus, 5-15 parts of raw Rehmannia glutinosa, 5-15 parts of Paeonia suffruticosa, 10-20 parts of Salvia miltiorrhiza, 10-20 parts of Prunus mume, 10-20 parts of Hedyotis diffusa, 10-20 parts of Pheretima aspergillum, and 25-35 parts of Dioscorea nipponica.

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