Clinical Trial Of Jiedu Tongluo Kaibi Formula On Type 2 Diabetic Lower Extremity Arteriosclerosis Obliterans

ObjectiveTo verify the hypoglycemic,lipid-lowering,anti-inflammatory,and vascular protection effects of Jiedu Tongluo Kaibi Recipe on type 2 diabetes patients with lower extremity arteriosclerosis obliterans(DLASO),evaluate its effectiveness and safety,explain its impact on glucose and lipid metabolism,find its mechanism of action,to expand the clinical application of Jiedu Tongluo Recipe,and provide new methods and new ideas for traditional Chinese medicine to prevent and treat vascular complications of diabetes.Methods1.Systematic evaluation of the efficacy of detoxification and collaterals unblocking traditional Chinese medicine in the treatment of type 2 diabetic lower extremity arteriosclerosis obliteransBy January 25,2023,we searched the clinical randomized controlled research literature published on CNKI,Wanfang,Weipu Journal,PubMed,EMBase,Cochrane Library,and Web of Science databases about the treatment of diabetes lower extremity arteriosclerosis obliterans with detoxification and collaterals unblocking traditional Chinese medicine prescriptions.We evaluated the bias risk of the included literature,and used Revman5.3 software for meta-analysis,Systematically evaluating the efficacy and safety of Jiedu Tongluo herbal compound in the treatment of DLASO.2.Clinical trial on the treatment of type 2 diabetic lower extremity arteriosclerosis obliterans with Jiedu Tongluo Kaibi Formula90 subjects who passed the inclusion and exclusion criteria and signed the informed consent form were randomly divided into the test group and the control group using a random number table and were grouped and hidden by the envelope method.The control group subjects were given basic treatment,including diabetes education,exercise,diet,and conventional hypoglycemic,antihypertensive,lipid-lowering,and antiplatelet drugs.The experimental group received the intervention of Jiedu Tongluo Kaibi Formula based on the control group,and the course of treatment of both groups was 15 weeks.The primary efficacy index was the ankle-brachial index(ABI),and the secondary efficacy index included indexes related to blood glucose,blood lipid,body mass,atherosclerosis,and the total score of TCM syndromes.After 15 weeks of intervention,the main and secondary efficacy indicators were collected using the case report form,the safety indicators were tested and adverse events were evaluated at enrollment,6 weeks,and 15 weeks.SPSS software was used to analyze the difference in the effective rate and various indexes between the two groups after treatment.3.Exploring the mechanism of Jiedu Tongluo Kaibi Formula in type 2 diabetic lower extremity arteriosclerosis obliterans based on metabonomicsCollect serum and urine samples from healthy people and DLASO patients before and after the intervention of Jiedu Tongluo Kaibi Formula and basic treatment.After data inspection and quality control,use LC-MS metabonomics method for multivariate statistical analysis,screen the differential metabolites of the disease and the differential metabolites after the intervention of Jiedu Tongluo Kaibi Formula,analyze the metabolic pathway with KEGG database,and obtain the key functional pathway of Jiedu Tongluo Kaibi Formula.Results1.Systematic evaluation of the efficacy of detoxification and collaterals unblocking traditional Chinese medicine in the treatment of type 2 diabetic lower extremity arteriosclerosis obliteransA total of 26 RCT studies were included,with 2355 DLASO patients(1209 in the experimental group/1146 in the control group).Compared with the control group,the total effective rate of Jiedu Tongluo Chinese herbal compound in treating DLASO was superior to the control group,with a statistically significant difference(OR=3.82,95%CI(2.98,4.90),P<0.00001);The TCM syndrome score is lower,and the difference is statistically significant[MD=-4.60,95%CI(-4.89,-4.31),Z=30.90(P<0.00001)];The overall therapeutic effect on blood sugar,blood lipids,ABI,and inflammatory factors is better,and it has good safety.2.Clinical trial on the treatment of type 2 diabetic lower extremity arteriosclerosis obliterans with Jiedu Tongluo Kaibi FormulaIn terms of the main efficacy indicators,the ABI of both groups of patients increased after treatment,and there was a significant statistical difference(P<0.01)between the experimental group and the control group after treatment;In terms of secondary efficacy indicators,the FBG of experimental group decreased after treatment compared to before intervention(P<0.01),while in the control group did not decrease compared to before intervention(P>0.05);After treatment,the HbAlc of both groups decreased compared to before treatment,and there was no significant statistical difference between the groups(P>0.05);After treatment,the TC and LDL-C of the experimental group patients decreased compared to before intervention,while HDL-C increased compared to before intervention.TG showed no significant change compared to before intervention;There were no significant changes in TC,TG,LDL-C,and HDL-C in the control group compared to before intervention;The BMI of the experimental group patients decreased significantly after intervention compared to before(P<0.05),while in the control group patients did not significantly decrease compared to before intervention(P>0.05);After treatment,the HCY,CRP,and CysC of the experimental group patients were significantly reduced compared to before intervention,while UA and Fbg were not significantly reduced compared to before intervention;The control group showed no significant decrease in HCY,CRP,UA,CysC,and Fbg compared to before intervention;After treatment,the diameters of the bilateral common femoral artery,popliteal artery,and dorsalis pedis artery in the experimental group decreased compared to before intervention,while there was no significant change in the diameters of the bilateral anterior tibial artery compared to before intervention(P>0.05);After treatment,the diameter of bilateral common femoral arteries in the control group decreased compared to before intervention(P<0.05),while there was no significant change in the diameter of bilateral popliteal arteries,anterior tibial arteries,and dorsal pedis arteries compared to before intervention(P>0.05).There was a statistically significant difference in the diameter of bilateral common femoral arteries between the two groups after treatment(P<0.05);After treatment,both groups had a decrease in the total score of traditional Chinese medicine syndromes,and the decrease in the experimental group was greater than that in the control group(P<0.01).After 15 weeks of treatment,the total clinical effective rate in the experimental group was 85.71%,while in the control group was 61.90%.The overall safety of two groups was good,with a safety rating of Level 2.3.Exploring the mechanism of Jiedu Tongluo Kaibi Formula in type 2 diabetic lower extremity arteriosclerosis obliterans based on metabonomicsCompared with the healthy control group,DLASO patients had significantly up-regulated L-fucose,L-rhamnose,trehalose,2-deoxyglucose,D-glucose and other carbohydrate substances,and significantly down-regulated heptanose and galactose;Oleie acid β-Glycerophosphate and other fatty acids were significantly up-regulated,while myristic acid,O-acetylcarnitine,galactosylglycerol and other fatty acids and their products were significantly down-regulated;Taurine,serine phosphate,(L-proline)adenosine,2-ketobutyric acid,2-ketoglutaric acid and other amino acids and their upstream and downstream substances were significantly up-regulated,y-Amino acids such as glutamyl cysteine,creatinine,L-arginine,isoxanthopterin and their metabolites were significantly down-regulated.The effects of DLASO on metabolites include ABC transporters,cholesterol metabolism,galactose metabolism,tyrosine metabolism and so on.After the intervention of Jiedu Tongluo Kaibi Formula,the sorbitol of DLASO patients was significantly increased,and 1-deoxy-D-ethylfructose was significantly decreased;7-dehydro-chain sterol was significantly down-regulated;Threonine,dimethylglycine and(5-L-glutamyl)-L-glutamic acid in blood were significantly decreased;Threonine,phenylacetylglycine and glutamic acid in urine were significantly up-regulated.It can also up-regulate substances such as betaine,dolicholine and protoporphyrin,and down-regulate oxidized styrene,(E)-3-(4-hydroxyphenyl)2-acrolein and hypoxanthine.Jiedu Tongluo Kaibi Formula may affect the glucose metabolism,lipid metabolism and amino acid metabolism of human body by regulating FoxO,HIF-1,MAPK,Rap1,insulin,glucagon signal pathway and other pathways,among which FoxO signal pathway is the most core pathway.Conclusion1.The combination of Jiedu Tongluo traditional Chinese medicine and basic treatment has good effectiveness and safety for DLASO,but it still needs to be verified by higher level evidence-based medical evidence.2.Jiedu Tongluo Kaibi Formula combined with basic treatment has a good clinical effect on DLASO of qi deficiency,blood stasis and toxin blocking type.It can reduce the fasting blood glucose and glycosylated hemoglobin of patients,reduce weight,control homocysteine,C-reactive protein and cystatin C related to atherosclerosis,slow down the process of atherosclerosis and chronic inflammatory reaction,and expand the inner diameter of lower limb arteries,Alleviate plaque and vascular stenosis,and relieve clinical symptoms of patients,with good safety.3.Jiedu Tongluo Kaibi Formula can regulate glucose metabolism,lipid metabolism and amino acid metabolism of DLASO patients,and has potential liver protection and detoxification effects.Its mechanism may related to regulating FoxO,HIF-1,MAPK,Rap 1,insulin signal pathway,glucagon signal pathway,etc.,among which FoxO signal pathway is the most core pathway.