Effects and Safety of Diabetic GUideline Algorithm Implementation Performed by Primary Care Physicians in the Community (GUARD)

Effects and Safety of GUideline Algorithm Based Intervention on CaRdiovascular and Renal Outcomes in Elderly Diabetic Patients With High Cardiovascular Risk in the Community- A Cluster Randomized Controlled Trial (GUARD-Community Study)

The Effects and Safety of Diabetic GUideline Algorithm Implementation in the Community (GUARD-Community) study is a 2-arm, cluster-randomized control trial to evaluate the effect and safety of guideline algorithm intervention performed by primary care physicians on cardiovascular and renal outcomes in elderly patients with high risk in community.

Study Overview

• Status: Recruiting
• Conditions: Diabetic Kidney Disease; Type 2 Diabetes; Cardiovascular Complication
• Intervention / Treatment: Other: Intensive guideline algorithm implementation; Other: Conventional guideline algorithm implementation

Detailed Description

Diabetes is an important public health concern. Elderly diabetic patients are characterized by a long duration and complications, including chronic kidney disease and/or cardiovascular disease. In the past 30 years, the guidelines of CDS, EASD or ADA have been frequently updated. The latest guideline on pharmacological algorithm recommend that patients with cardiovascular, renal disease or very high/high CV risk patients should be treated with anti-diabetic drugs presenting target organ protection, including SGLT2i and GLP1RA. And the guideline recommend comprehensive control of the cardiovascular risk factors, such as hypertension and dyslipidemia.

This GUARD-Community study is a community based cluster-randomized controlled trial and will enroll 5600 or more participants in more than 120 clusters aged ≥ 65 years with T2DM and complicated with high/very high cardiovascular risk factors . The trial will evaluate the the effects and safety of intensive "Guideline" algorithm implementation on CVD and renal outcomes. The primary hypothesis is that guideline algorithm intervention implemented by primary care physicians will significantly reduce the risk of 4-point MACE (comprised of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization of heart failure) rates. In Phase 1 study, the control of blood sugar, blood pressure and lipids will be evaluated at 18 months after intervention. In Phase 2 study, the CVD and renal outcomes will be evaluated at 3 years. The study will last for 4 years.

• Study Type: Interventional
• Enrollment (Estimated): 5600
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xiaomu Li, MD; Phone Number: 13661676591; Email: li.xiaomu@zs-hospital.sh.cn
• Study Contact Backup: Name: Xiaoying Li, MD; Phone Number: 13651913857; Email: li.xiaoying@zs-hospital.sh.cn

Study Locations

• China
  • Jaingsu
    • Suzhou, Jaingsu, China, 215501
      • Recruiting
      • Xiangcheng Second People's Hospital
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • Not yet recruiting
      • Caohu Community Healthcare Center
    • Suzhou, Jiangsu, China, 215131
      • Recruiting
      • Xiangcheng People's Hospital.
      • Contact: Xuefei Xu, Bachelor; Phone Number: 18818211531; Email: pyu15@fudan.edu.cn
    • Suzhou, Jiangsu, China, 215137
      • Recruiting
      • Taiping Community Healthcare Center
      • Contact: Xuejian Ni, Bachelor; Email: 2314831056@qq.com
    • Suzhou, Jiangsu, China, 215138
      • Not yet recruiting
      • Yangchenghu People's Hospital
    • Suzhou, Jiangsu, China, 215141
      • Not yet recruiting
      • Health Center of Xiangcheng Tourism Resort
    • Suzhou, Jiangsu, China, 215131
      • Recruiting
      • Yuanhe Community Healthcare Center
    • Suzhou, Jiangsu, China, 215152
      • Recruiting
      • Dongqiao Community Healthcare Center
    • Suzhou, Jiangsu, China, 215134
      • Recruiting
      • Xiangcheng Third People's Hospital
    • Suzhou, Jiangsu, China, 215155
      • Recruiting
      • Xiangcheng Traditional Chinese Medicine Hospital
      • Contact: Jichao Yu, Bachelor; Email: 344314300@qq.com
    • Suzhou, Jiangsu, China, 215006
      • Recruiting
      • Huangqiao Community Healthcare Center
    • Suzhou, Jiangsu, China, 215144
      • Recruiting
      • Caohu People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ①Males or females aged 65 and above (≥65) receive treatment from the local community health service center;
• ②Diagnosed type 2 diabetes (ADA criteria):
• A. Typical symptoms of diabetes + random blood sugar ≥ 11.1mmol/L;
• B. Fasting blood glucose (FPG) ≥ 7.0mmol/L (fasting blood glucose is defined as no caloric intake within 8 hours);
• C. Oral glucose tolerance test 2h blood glucose (OGTT) ≥ 11.1mmol/L (2h after meal);
• D. have been treated with antidiabetic drugs;
• Each blood sugar test must be repeated to confirm the diagnosis;
• ③Complicated with chronic kidney disease and/or very high/high risk of cardiovascular disease, meet any one of the following:
• A. ASCVD, including coronary heart disease, cerebral infarction, peripheral vascular disease;
• B. Or target organ damage (albuminuria, renal impairment with eGFR ≥ 30 ml/min/1.73m2, left ventricular hypertrophy or retinopathy);
• C. ≥ 3 major risk factors (age ≥ 65 years old, hypertension, dyslipidemia, smoking, obesity );
• D. Diabetes duration ≥ 10 years, with any one traditional cardiovascular risk factor such as advanced age, obesity, smoking, sedentary, family history of cardiovascular disease, hypertension, abnormal lipid metabolism.

Exclusion Criteria:

• ①Pregnant women or women planning to become pregnant;
• ②eGFR<30 mL/min/1.73m2 (CKD-EPI formula);
• ③Patient cannot be followed up for 36 months (due to health condition or migration);
• ④Unwilling or unable to sign the informed consent;
• ⑤Type 1 diabetes;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensive guideline algorithm implementation; SGLT2i or GLP-1RA recommended in priority in subjects at very high/high CV risk. The targets of intervention will be achieved at HbA1C <7%, blood pressure <130/80mmHg， LDL-c<1.8mmol/L at very high CV risk or <2.6mmol/L at high CV risk patients, antiplatelet as secondary prevention of ASCVD.	Other: Intensive guideline algorithm implementation; Diabetes guideline pharmacological algorithm will be implemented by primary care physicians in community. In brief, SGLT2i or GLP-1RA will be recommended to control blood glucose in priority when subjects at very high/high CV risk and meet the target HbA1C<7%, control blood pressure <130/80mmHg， LDL-c<1.8mmol/L at very high CV risk patients or <2.6mmol/L at high CV risk patients, and antiplatelet as secondary prevention of ASCVD.
Active Comparator: Conventional guideline algorithm implementation; Treatment based on the current approaches implemented by local physicians(primary care physicians). Guideline based education and consults will be conducted to primary care physicians.	Other: Conventional guideline algorithm implementation; The guideline intervention is based the guidance which the local physicians followed through self learning and education. The management of diabetes paitients will be decided by local physicians.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Outcome of Phase 1: Comprehensive management effect of various cardiovascular risk factors in T2D，meeting control targets for a combination of A1c, BP, LDL-C.	The proportion of participants with HbA1C<7.0%, blood pressure< 130/80 mm Hg，LDL-c<1.8mmol/L at very high CV risk or <2.6mmol/L at high CV risk.	18 months since randomization
Primary Outcome of Phase 2: Composite of 3P MACE and hospitalization for heart failure.	Time to occurrence of cardiovascular and cerebrovascular death, non-fatal myocardial infarction, non-fatal Stroke, hospitalization for heart failure.	3 years since randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Outcome of Phase 1: Glycemic control rate	The proportion of participants with tight glucose control, targeting HbA1c <7.0%	18 months since randomization
Secondary Outcome of Phase 1: Mean HbA1C changes	Mean HbA1C changes of participants	18 months since randomization
Secondary Outcome of Phase 1: Mean systolic and diastolic pressure changes	Mean systolic and diastolic pressure changes of participants	18 months since randomization
Secondary Outcome of Phase 1: Mean LDL-c changes	Mean LDL-c changes of participants	18 months since randomization
Secondary Outcome of Phase 1: Adherence to guideline algorithm medication recommendation rate	Use electronic medical recorded prescription and questionnaires to assess the proportion of participants who adhere to guideline recommended medication	18 months since randomization
Secondary Outcome of Phase 2: Incident or worsening nephropathy	Time to composite of incident macroalbuminuria (UACR >300 mg/g), a sustained decline in eGFR (decrease in the eGFR of 30% or more to a value of less than 60 when baseline ≥60ml per minute per 1.73 m2, decrease in the eGFR of 50% or more when baseline <60ml per minute per 1.73 m2)from baseline, or chronic renal replacement therapy, or renal death.	3 years since randomization
Secondary Outcome of Phase 2: Cardiorenal composite endpoint	Time to eGFR (CKD-EPI formula) decrease, renal replacement therapy, renal or cardiovascular death	3 years since randomization
Secondary Outcome of Phase 2: 3P MACE	Time to events occurence: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke	3 years since randomization
Secondary Outcome of Phase 2: New onset of macroalbuminuria.	Time to UACR>300mg/g	3 years since randomization
Secondary Outcome of Phase 2: Changes of myocardial ischemia in electrocardiogram (ECG)	Participants number of ECG ischemia demonstration occurence: ST-T segment depression more than 0.1mv in two adjacent leads of ECG compared with baseline, poor R wave progression.	3 years since randomization
Secondary Outcome of Phase 2: New onset of albuminuria	Time to UACR increase from <30mg/g to ≥30mg/g	3 years since randomization
Secondary Outcome of Phase 2: Albuminuria progression	Time to albuminuria progression: UACR increased by ≥30% and grade progression (ie, from normal to micro or macro, or from micro to macro)	3 years since randomization
Secondary Outcome of Phase 2: Albuminuria regression	Time to albuminuria regression: UACR grade regression(ie, from macro to micro or normal, or from micro to normal), and the UACR value decreases by more than or equal to 30%	3 years since randomization
Secondary Outcome of Phase 2: Changes in the ratio of patients with normal or abnormal urine protein at the end of the study	Rate change of normal or abnormal UACR. Normal means UACR<30mg/g. Abnormal means UACR≥30mg/g	3 years since randomization
Secondary Outcome of Phase 2: Slope of eGFR decline	Decrease of the eGFR over time	3 years since randomization
Secondary Outcome of Phase 2: Retinopathy changes	Occurrence or regression of retinopathy(ETDRS-DRSS)	3 years since randomization
Secondary Outcome of Phase 2: Body weight change	Absolute weight change and the percentage change of body weight	3 years since randomization
Secondary Outcome of Phase 2: Changes of fatty liver prevalence	Rate change of fatty liver.	3 years since randomization
Secondary Outcome of Phase 2: Changes in beta-cell function	Absolute change assessed by HOMA2-%β method	3 years since randomization
Secondary Outcome of Phase 2: Changes in cognitive function	Improvement or progression of cognitive function: The Mini-CogTM scale	3 years since randomization
Secondary Outcome of Phase 2: The FRAIL scale	Changes of the simple frailty questionnaire score	3 years since randomization
Secondary Outcome of Phase 2: All-cause death	Time to the death due to any cause	3 years since randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health Economics Indicators	Cost-effectiveness analysis： quantification of Incremental Cost Ratio Life Cycle (ICER) and Quality Adjusted Years (QALYs)	3 years since randomization
Changes in cardiovascular risk indicators	Framingham score	3 years since randomization
Serology and urine testing	Biomarkers associated with diagnosis or prognosis: using "omics" screening.	3 years since randomization
Genomics testing	Gene polymorphism testing for drug response or prognosis: using genome-wide association study(GWAS) screening.	3 years since randomization
The time rate of glycemic target range	Continous glucose monitor detection	3 years since randomization

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital
• Investigators: Principal Investigator: Xiaoying Li, MD, Fudan University

Publications and helpful links

General Publications

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
• Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017 Jun 12.
• Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389. Epub 2018 Nov 10.
• Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.
• Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum In: Lancet 1999 Aug 14;354(9178):602.
• Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14.
• Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Juni P, Lettino M, Marx N, Mellbin LG, Ostgren CJ, Rocca B, Roffi M, Sattar N, Seferovic PM, Sousa-Uva M, Valensi P, Wheeler DC; ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 7;41(2):255-323. doi: 10.1093/eurheartj/ehz486. No abstract available. Erratum In: Eur Heart J. 2020 Dec 1;41(45):4317.
• Gu TW, Zhu DL. [Interpretation of treatment part of national guideline for the prevention and control of diabetes in primary care (2018)]. Zhonghua Nei Ke Za Zhi. 2019 Jul 1;58(7):538-540. doi: 10.3760/cma.j.issn.0578-1426.2019.07.011. Chinese.
• Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005 Jan;28(1):164-76. doi: 10.2337/diacare.28.1.164.
• Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021 Jan 14;384(2):117-128. doi: 10.1056/NEJMoa2030183. Epub 2020 Nov 16.
• Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.
• Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Ryden L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-130. doi: 10.1016/S0140-6736(19)31149-3. Epub 2019 Jun 9.
• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsboll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. doi: 10.1056/NEJMoa1607141. Epub 2016 Sep 15.
• American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021 Jan;44(Suppl 1):S111-S124. doi: 10.2337/dc21-S009.
• Mosenzon O, Wiviott SD, Heerspink HJL, Dwyer JP, Cahn A, Goodrich EL, Rozenberg A, Schechter M, Yanuv I, Murphy SA, Zelniker TA, Gause-Nilsson IAM, Langkilde AM, Fredriksson M, Johansson PA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS, Raz I. The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58. Diabetes Care. 2021 Aug;44(8):1805-1815. doi: 10.2337/dc21-0076. Epub 2021 Jul 7.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2022
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: April 16, 2022
• First Submitted That Met QC Criteria: April 22, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 26, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Chronic kidney disease; Diabetes implementation study; Diabetes guideline algorithm
• Additional Relevant MeSH Terms: Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Diabetic Nephropathies
• Other Study ID Numbers: ZSE 20220401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The data will be available from the principle investigator on reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No