Professional guidelines recommend the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) to reduce adverse cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes (T2D) and increased cardiovascular or renal risk. ^, In placebo-controlled trials, SGLT2i reduce atherosclerotic cardiovascular disease (ASCVD), heart failure, and chronic kidney disease (CKD) outcomes, while higher potency GLP-1RA have shown benefit in ASCVD, heart failure with preserved ejection fraction (HFpEF), and CKD. ^,, However, no direct randomized comparison of SGLT2i and GLP-1RA for cardiovascular and kidney outcomes has been performed. Additionally, given the putative complementary benefits of these medication classes, guidelines have increasingly recommended dual therapy with both classes for those not meeting glycemic targets despite a dearth of evidence weighing the benefits, risks, and feasibility of combination therapy. ^,,

We designed the PREVention of CardIovascular and DiabEtic kidNey disease in Type 2 Diabetes (PRECIDENTD) trial to evaluate the comparative effectiveness of SGLT2i, GLP-1RA, or both classes (dual therapy) on cardiac, kidney, mortality, and patient-reported outcomes. Funded by the Patient-Centered Outcomes Research Institute (PCORI) in 2021, the funding mechanism required completion of a feasibility phase before a decision to proceed with the trial, with the potential for the final trial design to be modified by feasibility findings. In collaboration with professional and patient partners and participants, PRECIDENTD implemented an innovative pragmatic trial design in which eligible participants with T2D and ASCVD or high ASCVD risk consented to random assignment to 1 of 3 treatment groups: prescription of SGLT2i, GLP-1RA, or dual therapy. To be generalizable to real-world patient experience where free medications are not provided, participants used their own health insurance coverage to obtain their assigned medication(s).

Herein, we describe the results of the feasibility phase which evaluated whether sites could execute the protocol and whether participants would enroll and could initiate and continue study medications at sufficiently high rates for valid evaluation of the study hypotheses in the full study phase. The trial’s data and safety monitoring board (DSMB) reviewed unblinded data on rates of medication initiation and continuation. The feasibility phase demonstrated that monotherapy initiation was feasible and the trial components comparing SGLT2 to GLP-1 RA monotherapy were approved to continue with certain modifications. However, despite support from central and local site staff, uptake of and adherence to dual therapy was judged to be insufficient to continue this group in the trial.. Here, we report the findings from the feasibility phase that supported these decisions, comparing rates of medication initiation and continuation in the pooled monotherapy to the dual therapy group over a median 10-month treatment period. Data from both monotherapy groups are pooled because a masked, randomized comparison between those groups is ongoing.

Trial design. PRECIDENTD was designed as a pragmatic, parallel, 3-arm randomized controlled trial with 1:1:1 allocation of eligible participants to an SGLT2i, GLP-1RA, or dual therapy with combined SGLT2i and GLP-1RA. The specific medication within each class was selected by the site investigator from a preferred list based on evidence of cardiovascular benefit and the participant’s pharmacy benefit plan coverage. To enroll a sufficiently high-risk population, the protocol aimed to enroll 70% of participants with established ASCVD (secondary prevention cohort) and 30% with indicators of high ASCVD risk (primary prevention cohort), determined by clinical criteria. Patient and professional research partners have participated in trial design since its inception and continue to advise on trial conduct. The initial protocol was approved by the Mass General Brigham (MGB) Institutional Review Board (IRB) and conducted at 8 sites across the U.S. (seven sites affiliated with the National Patient-Centered Clinical Research Network [PCORnet]) during the feasibility phase. This report on the feasibility phase of the trial includes all randomized participants from the first on September 26, 2022, through the last randomization into the 3-arm trial on January 25, 2024, with randomized patients followed until July 1, 2024.

Participants. All participants had T2D based on clinical diagnosis, with hemoglobin A1c (HbA1c) ≥6% (42 mmol/mol). Inclusion criteria for the secondary prevention cohort were age 40-80 years and established ASCVD in any vascular bed based on clinical diagnosis or credible participant self-report. Inclusion criteria for the primary prevention cohort were age 60-80 years with at least one of the following additional high-risk features: active smoking, HbA1c ≥8% (64 mmol/mol), or Stage 3a CKD (estimated glomerular filtration rate 45-59 ml/min/1.73m ²) with urinary albumin-to-creatinine ratio of <200 mg/g. Exclusion criteria included a history of diabetic ketoacidosis, active foot ulcer, history of pancreatitis, hospitalization for heart failure within the prior year, known left ventricular ejection fraction <40%, active or recently active cancer, and known inability to afford study medication. Full criteria for the feasibility phase are available in Protocol Version 1.5 (Supplement). Patients currently taking SGLT2i or GLP-1RA (or both) were eligible to enroll if they were willing to accept the randomly assigned treatment allocation. Participants provided written informed consent, including agreement to obtain study medication through their own health insurance. Sites attempted to ascertain whether study medication was accessible to participants by asking probing questions about pharmacy benefits or sending a test prescription.

PRECIDENTD trial leadership was based at 4 study sites: the Clinical Coordinating Center (Mass General Brigham [MGB]), the Data Coordinating Center (MGB), the Engagement Core (Vanderbilt University Medical Center), and the PCORnet Core (Duke Clinical Research Institute [DCRI]). Eight enrolling sites identified potential participants through study-specific electronic health record (EHR) queries developed in partnership with DCRI. The Clinical and Data Coordinating Centers worked closely with the Engagement Core to train sites in outreach and recruitment methods. Recruitment and randomization occurred through both in-person or virtual visits. Study sites partnered with participants’ own usual diabetes care provider and used EHR data to assess medical history and prescribe medication. Data collection and management used Research Electronic Data Capture (REDCap) tools hosted by the MGB Research Applications team. REDCap is a secure, web-based application designed to support data capture for research studies. Study coordinators and investigators completed site data forms using EHR data and participant self-report to confirm diagnoses. Participants used the same web-based system to complete patient-reported outcome measures (PROMs).

Interventions. The study intervention was random assignment to SGLT2i, GLP-1RA, or dual therapy (SGLT2i plus GLP-1RA). For SGLT2i, the protocol specified empagliflozin 10 mg, dapagliflozin 10 mg, or canagliflozin 100 mg. Use of SGLT2i medications that lacked evidence of cardiovascular benefit was discouraged. Preferred GLP-1RA were dulaglutide goal dose 1.5 mg weekly, liraglutide goal dose to 1.8 mg daily, or semaglutide goal dose 0.5 mg weekly. During the feasibility phase, tirzepatide and oral semaglutide were allowed but not preferred given the lack of available cardiovascular outcome data at that time. Study investigators and usual care providers had discretion to further increase medication doses as clinically indicated. Participants assigned to dual therapy who were not already taking 1 class prior to randomization initiated the GLP-1RA first to allow titration, followed by the SGLT2i. In addition to prescribing the medication, sites supported medication initiation through usual care processes such as support for obtaining prior authorization through templates to promote approval, outlining team-based processes and best practices, identifying patient assistance programs, etc. The coordinating center, supported by an interactive text messaging system, reached out to participants to help troubleshoot problems with obtaining assigned medication. Finally, the manual of operations and training webinars promoted knowledge sharing to help sites support medication initiation and adherence. The coordinating center supplied study-specific instructions and materials to educate all participants in the use and adverse effects of their assigned medication (Figure S1). Patient partners reviewed the informed consent form to improve clarity and the consent process, identified early barriers to medication adherence, suggested strategies for troubleshooting these, and contributed to education materials. All participants had a visit 2 months after randomization to promote retention and adherence and to initiate the SGLT2i in the dual therapy arm. Sites followed participants until medication(s) were initiated and reported confirmed initial medication pickup on a REDCap form. Thereafter, participants were transitioned back to usual diabetes care providers, who were asked to try to maintain the participant on the randomly assigned medication(s) while adjusting other diabetes medications as needed. Outcome and adverse event assessments, including current self-reported medication use, occurred at 2, 6 and every subsequent 6 months after randomization. Participant compensation was $100 at randomization and annually in the feasibility phase.

Outcomes . For this report on the feasibility phase of PRECIDENTD, the main outcomes are medication initial fill rates in the pooled monotherapy groups compared to the dual therapy group. We also report medication discontinuation rates among those who started medication, reasons for medication noninitiation and discontinuation; secondary outcomes included adverse events (AEs), global health measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale V1.2 , and a modified version of the Kansas City Cardiomyopathy Questionnaire, 12-item version (mKCCQ).

Medication initiation and adherence were ascertained through several sources. One week after a visit when a protocol-specified treatment was prescribed, the Clinical Coordinating Center contacted the participant to ascertain medication initiation or its barriers, and to assist with access challenges. At scheduled study visits (2, 6, and every subsequent 6 months after randomization), participants provided additional information on timing of initiation, and any treatment interruptions or discontinuations with reasons. Specifically, participants completed the 1-item Summary of Diabetes Self-Care Activities Measure Medication Subscale and Adherence to Refills and Medications Scale for Diabetes.

The feasibility process measure of overall initial medication fill rates was defined as the number of participants who reported ever obtaining the assigned medication(s) during the feasibility phase divided by the total number of participants; we also report this rate by 10 weeks (allowing a 2 week grace period for the 2-month follow up visit) and 4 months after randomization (when all participants should have had time to initiate both medications, allowing for a wide assessment window) after randomization. For the dual therapy group, participants had to start both treatments to qualify as filling initial randomly assigned therapy and were considered to have discontinued dual therapy if they stopped at least one of these 2 treatments (restricted to those who started both treatments).

For the ongoing PRECIDENTD trial, the primary outcome is the total (first and recurrent) number of episodes of myocardial infarction, stroke, arterial revascularization, hospitalization for heart failure, development of end-stage kidney disease, kidney transplantation, and mortality, counting all events from randomization until end of study. The overall trial sample size was based on a power calculation to detect this primary outcome. This outcome will not be reported until the trial is complete.

Secondary endpoints included in this report are: the change in PROMIS V1.2 Physical and Mental Health scores from baseline to 12 months; the slope in mKCCQ-12 Overall Summary Score from baseline to 6 and 12 months; and serious AEs, including targeted AEs (severe hypoglycemic episodes, diabetic ketoacidosis, genital fungal infections, amputation, fractures, worsening diabetic retinopathy, pancreatitis, and gallbladder disease), obtained at 6- and 12-month study visits. The PROMIS Scale V1.2 was administered at baseline and 12 months, and the mKCCQ at baseline, 6, and 12 months. PROMIS is a validated global measure of physical and mental health with scores ranging from 0 to 100 normalized to the US population such that a score of 50 with standard deviation of 10 represents the mean population-level response to a given construct; scores above and below the mean represent greater or lesser degrees of the construct. ^, The KCCQ-12 is a disease-specific measure scaled from 0 to 100, initially designed to capture symptoms of heart failure. However, the instrument broadly assesses quality of life and cardiovascular symptoms common in people with cardiometabolic conditions and has been adapted for use in other cardiometabolic disease conditions, including type 2 diabetes without clinical heart failure. ^, In keeping with this approach, our adaptation for this population replaced 6 instances of the words “heart failure” in the instrument with “your health” or “health.” For example, we changed “Please indicate how much you have been limited by heart failure … over the past 2 weeks” to “Please indicate how much you have been limited by your health … over the past 2 weeks.” In addition, we deleted a prompt in item 1 that describes heart failure. KCCQ score changes of 5, 10, and 20 points represent small, moderate-to-large, and large-to-very-large clinical changes.

Sample size . There was no power calculation for the feasibility phase, as feasibility is determined based on metrics of trial conduct. The recruitment target for the feasibility phase was 400 participants.

Randomization. Eligible and willing participants were randomly assigned in a 1:1:1 ratio using blocks of size 6 to treatment with SGLT2i, GLP-1RA, or dual therapy based on an algorithm programmed into and implemented by the REDCap system. Randomization was stratified by site, primary or secondary prevention, and age <65 or ≥65 years. As a pragmatic trial, neither participants nor local investigators were blinded, though the principal investigators (BME and DJW) and the staff at the MGB Clinical Coordinating Center do not have access to trial data stratified by randomized treatment group.

Statistical methods . Primary analyses used Chi-squared tests to compare rates of treatment uptake, overall and by 10 weeks and 4 months after randomization between the pooled monotherapy groups and the dual therapy group, as well as rates of discontinuation among initiators. Since some participants entered the study on 1 or both study medications, we perfomed sensitivity analyses examining the following subgroups: not on either medication class at baseline (de novo monotherapy or dual therapy), assigned to the same single medication class (concordant monotherapy), assigned to switch to the alternate medication class (discordant monotherapy), or on 1 class at baseline and assigned to dual therapy (adding another class dual therapy), to determine whether rates of medication initiation and continuation differed meaningfully among these groups. P values are not reported for these subgroups given small sample sizes. Comparisons between monotherapy groups are not shown to maintain blinding of the ongoing study. Comparisons of time trends between monotherapy and dual therapy groups in PROMIS and mKCCQ scores at baseline, 6 months (for mKCCQ only) and 12 months after randomization used all available measures, assuming missing values were missing at random. Linear mixed effects models included a random participant effect and fixed effects of time, treatment, and a treatment by time interaction. Analyses used the R version 4.4.2, and the R package for the mixed models was nlme version 3.1-166. ^,

This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Phased Large Award for Comparative Effectiveness (PLACER-2020C3-21005). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Between September 1, 2022 and January 23, 2024, 602 people were formally screened for PRECIDENTD. Of those, 28% ( n = 166) were ineligible and 44% ( n = 262) declined. Among screened patients providing reasons, the most common reasons for declining were unwillingness to be randomly assigned to a medication (21%) or concern that the study would be too burdensome (11%). Median (IQR) time from screening to randomization was 4 (1, 11) days. The last feasibility phase randomization occurred on January 25, 2024. Of the 173 enrolled in the feasibility phase, 113 (65%) were randomly assigned to monotherapy and 60 (35%) to dual therapy ( Figure 1 : CONSORT).

CONSORT diagram for the feasibility phase of the trial. Patients were randomized in the 3-arm feasibility phase of PRECIDENTD between September 1, 2022 and January 23, 2024. *Approached patients were broadly defined as those identified through electronic health record queries or common data model queries as potentially eligible for the study and sent electronic or paper invitation messages.

Median (IQR) duration of follow up was 305 (197, 374 [min-max 1-603]) days, or 10 months. Median (IQR) age was 67 (62, 72), 46% were female, 65% reported White and 25% reported Black race, and 67% had established ASCVD at baseline ( Table 1 ). Twenty-five percent had history of myocardial infarction and 14% had history of heart failure hospitalization >12 months prior to enrollment. HbA1c and body mass index medians (IQR) were 7.3% (6.7, 8.3) and 32 kg/m ² (28, 37), respectively. Thirty-one percent were treated with GLP-1RA and 20% were treated with SGLT2i prior to enrollment ( Table 1 ). All but 1 participant had health insurance: 59% Medicare, 31% employer-based, 14% personally purchased, and 13% Medicaid.

Table 1

Baseline characteristics of the study population in pooled monotherapy and dual therapy groups

	Monotherapy ( N = 113)	Dual therapy ( N = 60)	Total ( N = 173)
Demographics
Cohort
Primary	37 (32.7%)	21 (35.0%)	58 (33.5%)
Secondary	76 (67.3%)	39 (65.0%)	115 (66.5%)
Age group
<65 years	46 (40.7%)	23 (38.3%)	69 (39.9%)
≥65 years	67 (59.3%)	37 (61.7%)	104 (60.1%)
Age at screening (years)	66 (62, 72)	68 (62, 74.2)	67 (62, 72)
Weight (lbs)	205 (179, 236)	200.5 (173.2, 240)	204 (175, 237)
BMI (kg/m^2)	32.1 (27.6, 36.5)	32.4 (27.9, 38.1)	32.3 (27.7, 36.8)
Male	64 (56.6%)	29 (48.3%)	93 (53.8%)
Race (self-reported)
White/Caucasian	70 (61.9%)	43 (71.7%)	113 (65.3%)
Black/African-American	32 (28.3%)	12 (20.0%)	44 (25.4%)
Asian	6 (5.3%)	3 (5.0%)	9 (5.2%)
Other or multiple*	5 (4.4%)	2 (3.3%)	7 (4.0%)
Hispanic (self-reported)	3 (2.7%)	0	3 (1.7%)
Health insurance	112 (99.1%)	60 (100.0%)	172 (99.4%)
Insurance plan
Medicare	67 (42.4%)	35 (43.8%)	102 (42.9%)
Medicaid	15 (9.5%)	8 (10.0%)	23 (9.7%)
Employer/Union	34 (21.5%)	19 (23.8%)	53 (22.3%)
Other†,	42 (26.6%)	18 (22.5%)	60 (25.2%)
Insurance deductible
$0-$500	23 (20.4%)	11 (18.3%)	34 (19.7%)
$501-$1,000	5 (4.4%)	0	5 (2.9%)
$1,001-$1,500	2 (1.8%)	0	2 (1.2%)
$1,501-$2,000	0	1 (1.7%)	1 (0.6%)
$2,001 or more	2 (1.8%)	4 (6.7%)	6 (3.5%)
I don’t know.	62 (54.9%)	32 (53.3%)	94 (54.3%)
Missing	19 (16.8%)	12 (20.0%)	31 (17.9%)
Education n(%)
< High school diploma	4 (3.5%)	5 (8.3%)	9 (5.2%)
High school diploma/GED	24 (21.2%)	11 (18.3%)	35 (20.2%)
College credit/associate degree	33 (29.2%)	13 (21.7%)	46 (26.6%)
College completion or higher	52 (46.0%)	31 (51.7%)	83 (48.0%)
Medical history
Established ASCVD‡	76 (67.3%)	39 (65.0%)	115 (66.5%)
History of heart attack	27 (23.9%)	16 (26.7%)	43 (24.9%)
History of stroke	16 (14.2%)	8 (13.3%)	24 (13.9%)
CABG	18 (15.9%)	9 (15.0%)	27 (15.6%)
Hospitalized for heart failure >12 months ago	14 (12.4%)	10 (16.7%)	24 (13.9%)
Diabetic neuropathy	41 (36.3%)	20 (33.3%)	61 (35.3%)
High blood pressure	96 (85.0%)	51 (85.0%)	147 (85.0%)
Atrial fibrillation	18 (15.9%)	10 (16.7%)	28 (16.2%)
Baseline medications
Concordant therapy	26 (23.0%)	1 (1.7%)	27 (15.6%)
Metformin	77 (68.1%)	45 (75.0%)	122 (70.5%)
Sulfonylurea or glinide	21 (18.6%)	11 (18.3%)	32 (18.5%)
SGLT2 inhibitors	25 (22.1%)	10 (16.7%)	35 (20.2%)
GLP-1 receptor agonists	33 (29.2%)	21 (35.0%)	54 (31.2%)
Insulin use	28 (24.8%)	16 (26.7%)	44 (25.4%)
DPP-4 inhibitor	8 (7.1%)	5 (8.3%)	13 (7.5%)
Other glucose lowering medication	11 (9.7%)	7 (11.7%)	18 (10.4%)
Statins	95 (84.1%)	49 (81.7%)	144 (83.2%)
ACE inhibitor	39 (34.5%)	20 (33.3%)	59 (34.1%)
Angiotensin receptor blocker	34 (30.1%)	23 (38.3%)	57 (32.9%)
Laboratory values §
HbA1c (%)	7.2 (6.7, 8.3)	7.4 (6.7, 8.2)	7.3 (6.7, 8.3)
HbA1c category
<6	2 (1.8%)	0	2 (1.2%)
≥6-<6.5	20 (17.7%)	10 (16.7%)	30 (17.3%)
≥6.5-<8	49 (43.4%)	29 (48.3%)	78 (45.1%)
≥8	42 (37.2%)	21 (35.0%)	63 (36.4%)
Total cholesterol (mg/dL)	143.5 (118, 172)	149 (126, 188.8)	146.5 (119, 177.2)
HDL cholesterol (mg/dL)	40.5 (34.2, 48)	42.5 (37, 51.8)	41 (35, 48)
Triglycerides (mg/dL)	123.5 (95, 207.8)	144 (99, 227)	133 (97.5, 219.5)
LDL cholesterol (mg/dL)	72 (48, 99)	72.5 (59, 100.5)	72 (52, 99)
eGFR ml/min/1.73m^2
<45 mL	0	0	0
45-59mL	29 (25.7%)	19 (31.7%)	48 (27.7%)
≥60mL	84 (74.3%)	41 (68.3%)	125 (72.3%)
UACR (mg/g)	6 (0.7, 19)	10 (4.6, 20.7)	7 (1, 20.1)

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