PREvention of CardIovascular and DiabEtic KidNey Disease in Type 2 Diabetes

Study Purpose: 2.1. Objective The primary objective of PRECIDENTD is to compare rates of the total number of important cardiovascular, kidney, and death events among two alternative treatments for patients with type 2 diabetes and either established ASCVD or at high risk for ASCVD. To accomplish this objective, we will randomly assign 6,000 patients with established T2D and ASCVD or high-risk for ASCVD in a 1:1 allocation to SGLT2i or GLP-1RA to address the following hypotheses: 2.2. Primary Hypotheses: We propose to test the null hypothesis that allocation to SGLT2i or to GLP-1 RA results in no observed difference in the rate of the total (first and recurrent) number of composite atherosclerotic cardiovascular events (MI, stroke, arterial revascularization), plus hospitalizations for heart failure, development of end-stage kidney disease or kidney transplantation, or all-cause mortality. Study Duration: Participant visits will take place at baseline, two months, 12 months, and then every year thereafter. The two-month visit will serve to evaluate all participants for adherence, safety, and tolerability, troubleshoot, and promote retention. Annual visits will be scheduled at 1, 2, 3, 4, 5, 6, 7 and 8 years after randomization. The visits can be in-person or telemedicine (including telephone only, according to patient and investigator preference). Study Commitment: 1 screening visit (2-3h); 2-month FU (30min) in-person or video conference; once a year 1h visit in-person or video conference; 6-month visit (30 min) after each yearly visit; 30 min questionnaire on-line or over the phone after every annual visit and 6-month call; 8-years in study or less if enrolled later. Age: 40-80 years old Sex: Male and Female Conditions/Eligibility: Inclusion Criteria • Type 2 diabetes based on clinical diagnosis • HbA1c >6% measured within 12 months prior to screening; the most recent value available at the time of screening will be used for screening and to determine eligibility. • Secondary prevention cohort (at least 70% of cohort) Age 40 to 80 years Evidence of established atherosclerotic cardiovascular disease (ASCVD), as defined by one or more of the following: Coronary heart disease defined by at least one of the following: prior myocardial infarction, prior coronary percutaneous coronary intervention, ≥50% stenosis of a coronary artery documented by invasive or non-invasive imaging (including CT coronary angiography), positive stress test, or coronary artery calcium score >400 Agatston units; Cerebrovascular disease defined by at least one of the following: prior ischemic stroke, prior carotid revascularization procedure, carotid stenosis ≥ 50% documented by X-ray angiography, MR angiography, CT angiography, or Doppler ultrasound; Symptomatic peripheral artery disease defined by at least one of the following: leg symptoms with an ABI ≤ 0.9, leg symptoms with imaging evidence of a stenosis ≥50% in a peripheral artery documented by X-ray angiography, MR angiography, CT angiography, or Doppler ultrasound, or prior amputation for atherosclerotic disease. o Presence of these comorbidities will rely on the clinical diagnosis in the EHR. In the absence of clinical documentation in the EHR to support the diagnosis of ASCVD, patient report of disease meeting the above criteria will be considered sufficient. • Primary prevention cohort (capped at 30% of cohort) o Age 60-80 years and at least 1 additional high-risk feature. o Cardiovascular risk factors/high-risk features  Active smoking (combustible tobacco or marijuana) HbA1c ≥ 8% measured within 12 months prior to screening. The most recent value available at the time of screening will be used for screening and to determine eligibility. Stage 3a CKD, eGFR 45-59 ml/min/1.73m2 measured within 12 months prior to screening. The most recent value available at screening will be used for screening and to determine eligibility.  Stage 3b CKD, eGFR 30-44 ml/min/1.73m2 measured within 3 months prior to screening. • (Historical transition criteria for participants enrolled in the combination therapy arm of the pilot and feasibility trial who were eligible at the time of enrollment may be re-randomized into the two-arm trial if they would like to continue in the trial). o These patients may no longer have high-risk eligibility criteria at the time of re-randomization if they have improved since initial enrollment. For patients without ASCVD HbA1c>8, smoking, or CKD 3a at time of pilot trial enrollment will remain qualifying (as prior indicators of high risk), but current HA1c, smoking status, and CKD stage at the time of reenrollment will be collected as the new baseline variables. o If participants have progressed to criteria that are disqualifying for reasons of safety or lack of equipoise, they will not be eligible for randomization. Example: participants with hospitalization for heart failure within the past year or other exclusionary criteria will not be eligible to reenroll.) • Willingness to be randomly assigned to medication class (SGLT2i or GLP-1 RA) and fill prescription through personal pharmacy benefit while having other medications adjusted for safety • Willingness to avoid starting a therapy in the alternative treatment group (e.g., if randomized to GLP-1 RA, avoid starting an SGLT2i) unless strongly recommended by the participant’s usual care provider. • If taking one of the study medication classes, willingness to stop SGLT2i or GLP-1 RA and be randomly assigned to one of the two medication classes • Willingness to consent to data collection using the electronic health record and sign a medical release to obtain future medical records from other health care facilities 4.2. Exclusion Criteria • Known or suspected diabetes of other cause (type 1 diabetes, pancreatogenic diabetes, monogenic diabetes, etc.) • Any background diabetes medication regimen will be allowed in this pragmatic trial with the following provisos: o Patients currently taking an SGLT2i or GLP-1 RA are eligible to enroll if the patient, PRECIDENTD site principal investigator, and/or the usual diabetes care provider believe it is reasonable for participant to stop their current medication and be randomly assigned to either class. o Participants taking basal-bolus, prandial, or multiple daily injection insulin (MDI) regimens (e.g., short-acting in combination with long-acting insulin, called MDI regimens) are eligible only if the research staff attests that there has been communication with the usual diabetes care provider and that the provider has agreed to manage insulin adjustment with initiation of study medications. If such agreement has not been obtained, participants taking MDI regimens are excluded. • History of diabetic ketoacidosis • Active diabetic foot ulcer • History of pancreatitis • Heart failure as a primary reason for hospitalization within the past year • Known left ventricular ejection fraction <40% • Estimated glomerular filtration rate (eGFR) less than 30 ml/min/1.73m2. • Known inability to afford study medication through current insurance coverage. • Pregnancy or actively breastfeeding a child • People of child-bearing potential must use effective birth control throughout the study. • Active treatment for cancer, planned treatment for cancer, or recent active cancer with likelihood of recurrence or progression, which, in the opinion of the site investigator, has a likelihood of recurrence that would interfere with study therapy prior to 2029 o Treated cancer with no evidence of disease, no evidence of disease progression, and no planned change in therapy is allowed. Examples of allowable cancers include:  Breast cancer stable after active treatment, managed with long-term anti-estrogen therapy  Prostate cancer being observed  Stage 0 or 1 tumors status post resection or other definitive treatment  Other similarly stable cancer comorbidities • History of solid organ or bone marrow transplant • Allergy to SGLT2 inhibitor or GLP-1 receptor agonist Study Procedures: bution • Participants will fill the prescribed medication at their preferred pharmacy using their own health insurance coverage. • If preferred agent within a medication class changes, the study team or usual diabetes care provider will prescribe the preferred agent within that class. o Example: at randomization, patient starts semaglutide. The following year, the pharmacy benefit plan prefers dulaglutide. Study team or usual diabetes care provider will prescribe dulaglutide. 6.2. Study drug titration 6.2.a. Initiation of each medication class Medications will be prescribed and titrated according to their labeling. The following guidance is provided to site investigators, but study providers should all be clinicians experienced in the management of these medications who will be expected to apply their clinical judgment to individual participant scenarios. SGLT2 inhibitors: Dose: • Usual study dose o Empagliflozin 10 mg daily in the morning o Dapagliflozin 10 mg daily in the morning o Canagliflozin 100 mg daily in the morning • For patients with eGFR >60 ml/min/1.73m2 and HbA1c above individualized target who are tolerating SGLT2i at follow up, the study or usual care diabetes provider may increase doses of SGLT2i if clinically indicated. Ertugliflozin, baxagliflozin, and other SGLT2 inhibitors use will be discouraged in the absence of their demonstrated benefit for atherosclerotic cardiovascular outcomes; however, they will be allowed if other options are not covered by insurance.27 If other drugs in this class demonstrate cardiovascular benefit, they may be added as preferred options to the three SGLT2i drugs listed above. All participants will receive education and written materials reviewing the use and therapeutic and adverse effects of SGLT2 inhibitors. The handout will cover: 1. Importance of maintaining hydration; 2. Importance of genital hygiene; 3. Importance of foot care and instructions to stop if a foot ulcer develops; 4. Advice to stop the medication with illness, poor oral intake, and 4 days prior to procedures including colonoscopy. The handout will contain contact information for the study team along with instructions regarding when to call. In routine clinical care, suggested safety monitoring for SGLT2i should include blood pressure, kidney function, and targeted symptoms screening as detailed in the MOP. GLP-1 receptor agonists: Each medication will be used according to its product label and titrated to the therapeutic dose as tolerated. Study (or usual care) providers may elect to increase the dose at follow up as clinically indicated by HbA1c, weight, or symptoms. All patients should be without nausea, vomiting, or diarrhea before dose is increased. If gastrointestinal symptoms are not tolerated as dose is advanced, the medication should be reduced to the previously tolerated dose for 30 days. One attempt at rechallenge at the next dosing increment is recommended if the patient is willing to try to increase. Dosing guidance described here follows the package labeling for each approved agent (semaglutide, dulaglutide, or liraglutide). Major cardiovascular outcomes trials of exenatide and lixisenatide failed to show cardiovascular benefit. For this reason, these drugs should not be prescribed as members of the GLP-1 RA class in the trial. They will be allowed if they are the only option covered by insurance. • Dulaglutide injection (brand name: Trulicity) o Start 0.75 mg SC weekly x 4 weeks, then increase to 1.5 mg weekly. o Study or usual care physician may elect to increase to 3.0 mg weekly after another 4 weeks and then 4.5 mg weekly after another 4 weeks based on participant HbA1c, weight, and symptoms. • Liraglutide (brand name: Victoza) o Start 0.6 mg SC daily for 1 week, then increase to 1.2 mg daily. o If minimal to no GI symptoms on 1.2 mg daily for at least one week, increase to target therapeutic dose of 1.8 mg daily. • Semaglutide injection (brand name: Ozempic) o Start 0.25 mg SC weekly x 4 weeks, then increase to 0.5 mg weekly x 4 weeks. o The therapeutic target should be to prescribe up to the maximum dose per package labeling guidelines based on participant HbA1c, weight, and symptoms. o Study or usual care physician may increase to 1 mg weekly after 4 weeks if 0.5 mg dose is tolerated and 2 mg weekly after 4 weeks if 1 mg dose is tolerated at the discretion of the usual care or study physician. • Semaglutide tablets (brand name: Rybelsus) are not preferred but may be used. Tablets must be taken at least 30 minutes before first food, beverage, or other medication of the day with no more than 4 ounces of water. o Start 3 mg daily x 30 days, then 7 mg daily x 30 days, then 14 mg daily. Tirzepatide (brand name: Mounjaro), a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist does not yet have cardiovascular outcomes data. Therefore, use of tirzepatide in the trial will be discouraged but allowed. All participants will receive an educational handout to be reviewed with the study team member reviewing the therapeutic and adverse effects of GLP-1 receptor agonists. The handout will cover: 1. Titration instructions. 2. Management of GI symptoms. 3. Instructions to stop for severe epigastric pain. 4. Instructions to stop weekly GLP-1 receptor agonists at least one week prior and daily formulations at least one day prior to elective surgery. The handout will contain contact information for the study team along with instructions regarding when to call. There is no routine safety monitoring for GLP-1 receptor agonists alone other than assessing tolerability and adjusting the dose accordingly. For both medication classes, participants taking sulfonylurea or insulin will be queried regarding signs and symptoms of hypoglycemia. The study team may review self-monitored blood glucose levels, if available, and make dose adjustments of insulin or sulfonylurea for safety in anticipation of the participant’s transition back to the usual diabetes care provider, as outlined in section 6.4. 6.2. Concomitant anti-hyperglycemic drug titration Please see the attached Tables in the MOP for suggested titration and approaches to adjusting the doses of concomitant antihyperglycemic therapy. Usual diabetes care providers will be requested and allowed to adjust concomitant antihyperglycemic therapy per usual care. 6.3. Patient Follow Up and Visits Participant visits will take place at baseline, two months, 12 months, and then every year thereafter. The two-month visit will serve to evaluate all participants for adherence, safety, and tolerability, troubleshoot, and promote retention. Annual visits will be scheduled at 1, 2, 3, 4, 5, 6, 7 and 8 years after randomization. The visits can be in-person or telemedicine (including telephone only, according to patient and investigator preference). After the randomization visit, the participant’s routine diabetes care will be transitioned to the usual diabetes care provider. The usual care provider will be informed which medication the patient was prescribed (within SGLT2i or GLP-1 RA class) as part of the study. Information about the medication and its effects and adverse effects will be provided, along with the request that the usual care provider incorporate the study medication into the diabetes care plan and assume overall diabetes management, including addition or discontinuation of other diabetes and blood pressure medications, as clinically indicated. Participants will then have annual in-person study visits for safety, retention, and medication prescription, with safety and retention calls conducted by a central call center 6 months after each annual in-person visit. Data (Table 1) will be collected at study visits, through in-person or virtual visit, participant report using electronic data capture, call center outreach, electronic health record/common data model at PCORnet sites, and Medicare claims data. In-person data (e.g. weight) will be allowed to be missing if the patient does not have in-person visits as part of study participation. As a pragmatic trial, data elements such as laboratory data will be collected from those obtained in usual care, processed through usual clinical laboratory assays, and recorded in the EHR. • HbA1c measurement date should be within 12 months of screening • Creatinine (eGFR) and lipid panel measurement date should be within 12 months of screening. • Potential participants with eGFR 30-44 ml/min/1.73m2 must have eGFR within 3 months prior to screening to confirm eligibility in order to be randomized. Sites will be asked to enter these results and date of measurement into the electronic data capture form to ensure that they are captured. Study providers may update laboratory measurements for study eligibility and to comport with general recommendations in the management of patients with type 2 diabetes (e.g., HbA1c every 3 months; creatinine, urinary albumin-to-creatinine, and lipid measurements annually). Since these assessments will be billed to participants’ insurance as part of usual care, study providers should obtain participant assent before ordering laboratory tests or should recommend tests to the participant’s usual care providers. 6.4. Study drug adherence monitoring Medication adherence will be assessed through self-report using standardized instruments and through responses to the MEMOTEXT interactive text messaging application. Participants will be asked whether they are taking the study medication and will be able to give a limited number of responses explaining why (e.g. cost, other barriers); they will also be given a phone number to call for help and will be able to request a call for assistance via the MEMOTEXT application. Co-pay and/or acquisition cost will be recorded, as well as any barriers to obtaining the medication. For participants who fill the medication, the 1-item Summary of Diabetes Self-Care Activities Medication Subscale (SDSCA)1 will be administered. Compensation: Participants will be remunerated with approximately $500 via a debit card (vendor: ADVARRA) sent from the BWH CCC through U.S. mail, after randomization and after completing each annual visit.