Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study)
Abstract
BACKGROUND:
Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).
METHODS:
A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups.
RESULTS:
We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54–0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55–0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28–0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13–2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24–2.48]).
CONCLUSIONS:
This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications.
REGISTRATION:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.
Clinical Perspective
What Is New?
•
GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study), which compared the effectiveness of 4 randomized medications (sitagliptin, glimepiride, insulin glargine, and liraglutide) added to metformin in patients with type 2 diabetes, permits comparison of cardiovascular outcomes by treatment group in a cohort largely without cardiovascular disease.
•
Cardiovascular event rates did not differ by individual treatment group; however, when compared with the other groups combined, the liraglutide-treated group had significantly lower risk of a composite cardiovascular outcome (myocardial infarction, stroke, cardiovascular death, unstable angina, or coronary revascularization) with and without heart failure hospitalization.
•
Recurrent cardiovascular events were more common with glimepiride and sitagliptin treatment compared with liraglutide.
What Are the Clinical Implications?
•
On the basis of cardiovascular outcomes trials enrolling patients with or at high risk for atherosclerotic cardiovascular disease, contemporary diabetes care guidelines recommend use of specific medications, including liraglutide, to reduce cardiovascular outcomes in patients with type 2 diabetes at high risk.
•
The GRADE cardiovascular outcomes data suggest that liraglutide may also reduce the risk of cardiovascular events in patients with diabetes considered at relatively low risk compared with treatment with other commonly used glucose-lowering medications.
•
Given the substantial lifetime cardiovascular risk associated with diabetes, the dichotomy in the care of patients with type 2 diabetes deemed to be at high versus lower cardiovascular risk may not be justifiable.
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2D).1 Traditional interventions to address cardiovascular risk factors such as hypertension, dyslipidemia, and hyperglycemia in this population have been effective in reducing rates of certain cardiovascular events.2 However, even when these risk factors are managed, substantial residual cardiovascular risk remains.3 Over the past decade, certain medications in the glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) classes, originally indicated solely for lowering glucose levels, have been shown to significantly reduce the risks of important cardiovascular and kidney complications in patients with T2D.4,5 However, these medications have primarily been studied in patients with T2D and established or high risk for atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF). The effect of these interventions on cardiovascular outcomes in individuals with T2D at low risk remains unclear, as does the optimal approach to lowering glucose levels in these patients.
GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study) provides a unique opportunity to assess the cardiovascular effects of randomized glycemic treatment assignment in a relatively low risk, contemporary cohort of individuals with T2D.6,7 In GRADE, participants with uncontrolled T2D of relatively recent onset were randomly assigned to insulin glargine U-100, the sulfonylurea glimepiride, the GLP-1RA liraglutide, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin added to maximally tolerated metformin therapy. Although GRADE was not specifically designed or powered to assess the effects of treatment on cardiovascular outcomes, such events were systematically collected and adjudicated throughout the study. Previously published analyses from GRADE found that participants randomized to liraglutide had significantly lower risk of a broad any-CVD outcome (defined as the first of any major adverse cardiovascular event [MACE, defined as nonfatal myocardial infarction or stroke, or death from cardiovascular causes], unstable angina requiring hospitalization, revascularization in any arterial bed, or hospitalization for HF [HHF]) when compared with those in the other treatment groups combined (hazard ratio [HR], 0.71 [95% CI, 0.56–0.90]).8 The current analyses expand these findings by assessing the relative effects of randomized, study-assigned glucose-lowering therapy on additional, prespecified secondary cardiovascular outcomes.
METHODS
Data Availability
This article is based on follow-up data and outcome assessments for the 5047 participants enrolled in GRADE. This database will be available in the National Institutes of Diabetes and Digestive and Kidney Diseases Central Repository in 2024.
Study Cohort and Study Medication
GRADE was a clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, which compared the effect of each of 4 randomly assigned glucose-lowering medications on glycemic outcomes in individuals with T2D on metformin monotherapy. The study design, participant baseline characteristics, schedule of assessments, and primary and key secondary results of GRADE have been published previously.6–9 An external data and safety monitoring board oversaw the conduct of the study. The protocol was approved by the institutional review board at each participating study site, and all participants provided written informed consent before study enrollment.
In brief, the study enrolled 5047 adult participants with T2D at 36 funded clinical centers, including 9 additional subsites in the United States between July 2013 and August 2017. They were followed for a mean (and median) of 5 years. Eligible participants had T2D for a duration of <10 years and were diagnosed at ≥30 years of age (or ≥20 years of age if American Indian or Alaska Native). At randomization, participants were required to have an HbA1c of 6.8% to 8.5% (50.8–69.4 mmol/mol) on maximally tolerated metformin at a dose of ≥1000 mg per day. Patients were excluded from participation if they had a major cardiovascular event in the year before randomization, HF with New York Heart Association functional class III or IV, an estimated glomerular filtration rate <30 mL/min/1.73 m2, or end-stage kidney disease requiring renal replacement therapy.
Participants were randomly assigned to the addition of study-supplied insulin glargine, glimepiride, liraglutide, or sitagliptin to their baseline metformin therapy. Study site staff and participants were unmasked to treatment assignment; however, staff of the study laboratories, reading centers, and adjudication committees were masked to participant identity and treatment assignment. Study medications were started and adjusted consistent with contemporary Food and Drug Administration–approved labeling, with the goal of achieving and maintaining an HbA1c <7% (53 mmol/mol) over an anticipated 4- to 7-year study period. Protocol-specified guidelines also required the addition of basal or mealtime insulin to the treatment of participants who reached a confirmed HbA1c >7.5% (58 mmol/mol) while taking the maximum tolerated dose of their assigned study medication. Otherwise, all nonglycemic care and management was deferred to the participants’ usual care providers. When national and international guidelines for the management of patients with T2D and CVD or kidney disease changed during GRADE, recommendations for the addition of GLP-1 receptor agonists or SGLT2 inhibitors were communicated to relevant participants and their usual care providers for consideration and implementation.10,11 Letters for participants with ASCVD were sent to usual care physicians in early 2019, with further updated letters for participants with ASCVD, HF, or CKD sent in mid-2020.
Study Assessments and Outcomes
Participants’ medical history, medication use, weight, and blood pressure (BP) were obtained at screening, baseline, and every 3 months during the study, and laboratory assessments were performed periodically. As previously published, the primary and secondary outcomes of GRADE were HbA1c levels indicating glycemic treatment failure.6,9 Cardiovascular events and procedures that occurred during the study period were reviewed and documented at each visit. The events and procedures specifically collected included the occurrence of myocardial infarction (MI), stroke (cerebrovascular accident [CVA]), unstable angina requiring hospitalization or revascularization, transient ischemic attack, HHF, interventional cardiology procedures (coronary artery stent placement or percutaneous coronary angioplasty), other vascular or peripheral vascular interventions, coronary artery bypass graft, or stent thrombosis. These events and all deaths were adjudicated and classified by an internal adjudication committee with an external expert cardiologist, all masked to treatment assignment, using definitions consistent with those outlined in the 2017 Cardiovascular and Stroke Endpoints for Clinical Trials.12,13 Two committee members independently reviewed each event; in the event of disagreement, a third member served as the tiebreaker.
The effects of randomized study treatment on the prespecified GRADE cardiovascular outcomes MACE-3 (a composite of nonfatal MI, nonfatal CVA, and cardiovascular death) and any CVD have been published previously.8 In the current analyses, we compare the incidence of a more expansive set of cardiovascular outcomes among the GRADE treatment groups. These outcomes include MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+HHF), and the individual components of MACE-5 and HHF separately. The outcome of MACE-6 is also analyzed as a recurrent event (all MACE-6). In addition, we analyze the risks of HHF and the composite outcomes MACE-3 through MACE-6 in the liraglutide-treated group compared with the other 3 treatment groups combined. To assess for potential heterogeneity of study treatment effect, we determined the incidence of outcomes MACE-3 through MACE-6 in prespecified subgroups of particular clinical interest, including sex; race (White, Black, or other) and ethnicity (Hispanic or non-Hispanic); baseline tertile of age, body mass index, duration of diabetes, and HbA1c; baseline kidney function (estimated glomerular filtration rate <60 or ≥60 mL/min/1.73 m2) and albuminuria category (moderately increased [urine albumin:creatinine ratio 30 to ≤300 mg/g] or severely increased [urine albumin:creatinine ratio >300 mg/g]); smoking (current, past, or never); hypertension (measured BP ≥130/80 mm Hg or treatment with blood pressure–lowering agents); and dyslipidemia (fasting low-density lipoprotein cholesterol ≥100 mg/dL [2.6 mmol/L], triglycerides ≥150 mg/dL [1.7 mmol/L], high-density lipoprotein cholesterol <40 mg/dL [1.0 mmol/L] in men or <50 mg/dL [1.3 mmol/L] in women, or use of lipid-lowering medication).
Statistical Analysis
All analyses were prespecified in the statistical analysis plan and conducted under the intention-to-treat principle, including all randomized participants regardless of CVD history. Key baseline clinical characteristics were summarized by treatment group, with continuous values summarized as mean±SD or median (interquartile range). Categorical variables were summarized as counts and column percentages. The P values are based on t tests for continuous variables and χ2 tests for binary and categorical variables.
Analyses of the outcomes (MACE-3 through MACE-6 and the components of MACE-6) were conducted using standard methods for the analysis of event-time (survival) data. For each outcome, Kaplan-Meier curves by treatment group were generated and unadjusted P values from log-rank tests reported. The P values (other than that for MACE-3, which was prespecified in the protocol) were then adjusted for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure.14 For each outcome for which the adjusted P value was significant, Cox proportional hazards models were used with assigned treatment group as the only covariate to carry out the 6 pairwise comparisons of each treatment group against every other; these P values were adjusted for multiple comparisons using the Holm procedure.15
Informed by both the known cardiovascular benefits of liraglutide in patients at higher risk16 and the anticipated low number of cardiovascular events in GRADE, the cardiovascular effects of liraglutide were compared with those of the other 3 treatment groups combined, thereby increasing the power of this prespecified analysis to detect a difference. The same Cox proportional hazards models as described previously were used for each of the 4 MACE outcomes plus HHF with a binary treatment variable (liraglutide versus one of the other 3 treatments). The 5 resulting P values for each outcome were adjusted for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure.
A Cox proportional hazards model containing treatment group, the subgroup variable, and a treatment by subgroup interaction was used to evaluate each of the 4 MACE outcomes in the 13 specified subgroups. The test of the interaction term in the model tested for treatment heterogeneity among the levels of the particular subgroup. For each outcome, the 13 P values for subgroup heterogeneity were adjusted one outcome at a time using the Benjamini-Hochberg false discovery rate method. For any adjusted P values that were significant at the 0.05 level, we further tested the 6 pairwise treatment group differences with no adjustment for multiple comparisons.
The analysis of the all MACE-6 outcomes used a proportional rate model15 with treatment group as the only covariate. Sensitivity analyses using negative binomial and quasi-Poisson models were conducted, with both models also using treatment group as the only covariate and an offset for the log of time at risk. Where the treatment effect was significant in the proportional rate model, the 6 pairwise comparisons of each treatment group against every other were conducted using contrasts from that model; the 6 pairwise P values were adjusted for multiple comparisons using the Holm procedure. For the purposes of these analyses, multiple MACE-6 events that occurred on the same calendar day were counted as a single event. The mean number of events per participant was estimated using the mean cumulative function.17
RESULTS
Baseline Characteristics
Baseline characteristics of the overall study cohort and 4 treatment groups have been described previously7 (Table S1). In brief, the 5047 GRADE participants were 36.4% women, with a mean age of 57.2±10.0 years and a duration of diabetes of 4.0±2.7 years. A total of 65.7% of participants identified themselves as White; 19.8% as Black or African American; 4.2% as Asian, Hawaiian, or Pacific Islander; 2.7% as American Indian or Alaska Native; and 7.6% other or unknown, with 18.6% also self-identified as Hispanic. Mean body mass index was 34.3±6.8 kg/m2, systolic BP was 128.3±14.7 mm Hg, and diastolic BP was 77.3±9.9 mm Hg.
Only 255 (5.1%) and 101 (2.0%) participants had a previous MI or CVA, respectively. However, CVD risk factors were common: 3339 (66.2%) had a history of hypertension, and 3321 (65.8%) were on lipid-lowering medication (3210 [63.6%] on statin therapy).8 Kidney disease was not common, with only 125 participants (2.5%) having an estimated glomerular filtration rate <60 mL/min/1.73 m2 or moderate or severe albuminuria (716 [14.2%] and 84 [1.7%], respectively). A total of 2933 participants (58.1%) were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 2288 (45.3%) were on aspirin. Baseline characteristics were similar between treatment groups, with the exception of use of any lipid-lowering medication, which was lowest (63.0%) in the liraglutide group and highest (68.3%) in the glimepiride group.
Comparisons of Outcomes Among Randomized Treatment Groups
Incidence of Cardiovascular Outcomes Among Treatment Groups
The cumulative incidence of the specified cardiovascular outcomes as assessed by time-to-first-event analysis did not differ significantly among treatment groups. Kaplan-Meier curves for each of the 10 specified outcomes are shown in Figure 1. The only significant differences among the treatment groups were for the MACE-6 composite outcome and coronary revascularization outcome; however, the adjusted P values were no longer significant after adjusting for multiple comparisons. The numbers of participants with at least one cardiovascular outcome, and the unadjusted and adjusted P values for all 10 comparisons are shown in Table 1.
| Cardiovascular outcome* | All, n (%) | Treatment group, n (%) | P value | ||||
|---|---|---|---|---|---|---|---|
| Glargine | Glimepiride | Liraglutide | Sitagliptin | Unadjusted† | Adjusted‡ | ||
| MI | 116 (2.3) | 30 (2.4) | 30 (2.4) | 21 (1.7) | 35 (2.8) | 0.320 | 0.371 |
| Stroke | 76 (1.5) | 23 (1.8) | 16 (1.3) | 19 (1.5) | 18 (1.4) | 0.725 | 0.725 |
| Cardiovascular death | 67 (1.3) | 21 (1.7) | 16 (1.3) | 9 (0.7) | 21 (1.7) | 0.136 | 0.245 |
| Unstable angina | 43 (0.9) | 9 (0.7) | 12 (1.0) | 7 (0.6) | 15 (1.2) | 0.330 | 0.371 |
| Coronary revascularization | 206 (4.1) | 54 (4.3) | 60 (4.8) | 33 (2.6) | 59 (4.7) | 0.021 | 0.164 |
| HHF | 100 (2.0) | 26 (2.1) | 30 (2.4) | 14 (1.1) | 30 (2.4) | 0.075 | 0.168 |
| MACE-3 | 241 (4.8) | 65 (5.1) | 59 (4.7) | 48 (3.8) | 69 (5.4) | 0.255 | — |
| MACE-4 | 270 (5.3) | 71 (5.6) | 67 (5.3) | 54 (4.3) | 78 (6.2) | 0.211 | 0.316 |
| MACE-5 | 352 (7.0) | 93 (7.4) | 91 (7.3) | 67 (5.3) | 101 (8.0) | 0.055 | 0.164 |
| MACE-6 | 407 (8.1) | 108 (8.6) | 106 (8.5) | 78 (6.2) | 115 (9.1) | 0.041 | 0.164 |
MACE indicates major adverse cardiovascular event.
*
MACE-3, cardiovascular death, myocardial infarction (MI), and stroke; MACE-4, MACE-3+unstable angina requiring hospitalization or revascularization; MACE-5, MACE-4+coronary revascularization; MACE-6, MACE-5+hospitalization for heart failure (HHF).
†
Unadjusted (nominal) P values from the log-rank test comparing all 4 treatment groups for each cardiovascular outcome.
‡
P values adjusted for 9 comparisons using a Benjamini-Hochberg false discovery rate adjustment. MACE-3 was prespecified in the protocol and is therefore unadjusted.
Cardiovascular Outcomes With Liraglutide Compared With the Other Treatment Groups Combined
Results of the prespecified MACE and HHF comparisons of liraglutide treatment with the mean of the other 3 groups combined are shown in Table 2. The liraglutide treatment group had significantly lower risks of MACE-5, MACE-6, and HHF compared with the other groups combined. The P values for these comparisons remained significant after adjustment for multiple comparisons.
| Outcome* | HR | 95% CI | P value (unadjusted) | P value (adjusted) |
|---|---|---|---|---|
| MACE-3 | 0.75 | 0.54–1.03 | 0.071 | 0.071 |
| MACE-4 | 0.75 | 0.56–1.01 | 0.058 | 0.071 |
| MACE-5 | 0.70 | 0.54–0.91 | 0.008 | 0.021 |
| MACE-6 | 0.70 | 0.55–0.90 | 0.005 | 0.021 |
| HHF | 0.49 | 0.28–0.86 | 0.013 | 0.022 |
Hazard ratio (HR) is shown for the time-to-first-event analyses of liraglutide versus the mean of the other 3 treatment groups (HR <1 indicates a lower risk in the liraglutide group compared with the average of the other 3) along with its 95% asymptotic CI. Unadjusted P values testing that the HR is 1 as well as the P values adjusted for 5 comparisons are shown. MACE indicates major adverse cardiovascular event.
*
MACE-3, cardiovascular death, myocardial infarction, and stroke; MACE-4, MACE-3+unstable angina requiring hospitalization or revascularization; MACE-5, MACE-4+coronary revascularization; MACE-6, MACE-5+hospitalization for heart failure (HHF).
Recurrent Events Analysis of MACE-6
The treatment group effect for the models used in the recurrent events analysis were all significant, including the proportional rate model (P=0.0081) and the sensitivity analyses using negative binomial (P=0.0051) and quasi-Poisson models (P=0.0167). The pairwise comparisons based on contrasts from the proportional rate model are summarized in Figure 2. The glimepiride-treated and sitagliptin-treated groups had a significantly higher rate ratio of all MACE-6 events than the liraglutide group (rate ratio, 1.61 [95% CI, 1.13, 2.29] and 1.75 [95% CI, 1.24, 2.48], respectively). The higher risk with glargine treatment compared with liraglutide (rate ratio, 1.50 [95% CI, 1.08, 2.09]) was no longer significant after adjustment for the 6 pairwise treatment group comparisons using the Holm procedure (P=0.063). The remaining between-group pairwise comparisons were also not significant. The cumulative event rates (ie, number of incident events per 100 person-years) and 95% CIs for all MACE-6 events (first and recurrent) by treatment group are 2.44 [2.05, 2.82], 2.63 [2.22, 3.03], 1.63 [1.31, 1.94], and 2.85 [2.44, 3.27] for glargine, glimepiride, liraglutide, and sitagliptin, respectively. We show the mean number of all MACE-6 events per participant by treatment group in Figure 3. Overall, sitagliptin had the highest number of all MACE-6 events (180), followed by glimepiride (164), glargine (153), and liraglutide (102).
Cardiovascular Outcomes in Subgroups of Interest
As shown in Table S2, no significant treatment group differences were identified for any of the 4 MACE outcomes in the 13 subgroups of interest. Of note, the dyslipidemia subgroup models for MACE-3, MACE-4, and MACE-5 failed to converge because of the extremely small numbers of outcome events experienced by the 195 participants without dyslipidemia (2 MACE-3 events, 3 MACE-4 events, 4 MACE-5 events, and 9 MACE-6 events). Among the models that did converge, there were no significant treatment group differences across any subgroups. The smallest unadjusted P value was 0.062 for sex, with a corresponding adjusted P value of 0.569.
DISCUSSION
GRADE offers an opportunity to compare cardiovascular outcomes across randomly assigned treatments, including insulin glargine, glimepiride, liraglutide, and sitagliptin, in a relatively low-risk contemporary cohort of patients with T2D. In these prespecified secondary analyses, the pairwise comparisons of cardiovascular outcomes did not differ across treatment groups. However, in the time-to-first-event analysis, reduced risks of MACE-5, MACE-6, and HHF alone were found when liraglutide was compared with the other groups combined. Subgroup analyses suggest that the effects of treatment assignment on MACE outcomes did not vary on the basis of characteristics such as sex, age, or diabetes duration; however, some of these analyses were limited by small numbers of events. In the recurrent events analysis, the liraglutide-treated group also had significantly lower risk of the broad, HHF-inclusive MACE-6 outcome when compared with treatment with glimepiride or sitagliptin.
T2D conveys an increased risk of cardiovascular complications that is not fully addressed with traditional risk-reduction strategies.18 Decreasing rates of MI, CVA, end-stage kidney disease, and amputation noted over recent decades are likely attributable to enhanced management of risk factors such as smoking, blood pressure, lipids, and glucose.2 However, patients with diabetes are still at higher risk of these complications compared with those without diabetes, and the numbers of such events are rising because of the increasing prevalence of T2D.2 HF has also been recognized as both a diabetes-related complication and a comorbidity indicative of poor outcomes, and is often the first presentation of CVD in people with diabetes.19,20 An excess risk of HF persists in patients with diabetes even if they do not smoke and have optimal levels of HbA1c, low-density lipoprotein cholesterol, and urinary albumin.3
Opportunities to further mitigate cardiovascular risk in T2D have expanded after the completion of recent cardiovascular outcomes trials of newer diabetes medications. These trials, intended to determine the cardiovascular safety of newer agents in patients with T2D at high risk, have identified significant cardiovascular or kidney outcomes benefits with the use of several agents in the GLP-1RA and SGLT2i classes.4,5,21 These benefits appear independent of the glucose-lowering effects of the agents. In addition, SGLT2i agents have now been found to improve cardiorenal outcomes in patients with HF or CKD, with or without diabetes.22–27 Clinical care guidelines for the management of patients with T2D at high risk have rapidly evolved to incorporate these findings, most now recommending preferential use of SGLT2i or GLP-1RA in patients with or at high risk of ASCVD, and SGLT2i for patients with HF or CKD, regardless of metformin use or the need for additional glucose-lowering.28–30 However, because the cardiovascular outcomes trials to date have largely enrolled patients with or at high risk for ASCVD, CKD, or HF, the optimal pharmacological treatment of patients with T2D at lower risk remains unclear. Current guidelines for the care of patients with T2D at low risk instead focus upon management of hyperglycemia, weight, and cardiovascular risk factors to reduce the risks of diabetes-related complications and disease progression, rather than emphasizing use of specific medications to reduce the risk of cardiovascular events.28,31 Although these differences reflect the lack of outcomes data in lower-risk populations, such dichotomy in guidelines may not be justifiable, given that, over a lifespan, diabetes will confer substantial cardiovascular risk.
The GRADE cohort differs from those enrolled in recent cardiovascular outcomes trials. Overall, GRADE participants were younger, healthier, and had a shorter duration of T2D than those enrolled in the cardiovascular outcomes trials, and more were men. At baseline, only 6.4% had a previous MI or CVA, and only 2.5% had an estimated glomerular filtration rate <60 mL/min/1.73 m2.8 Nonetheless, the GRADE cohort was on average obese, and the majority had hypertension or used lipid-lowering medication. All of the study-assigned treatments have been well-studied in previous cardiovascular outcomes trials. Use of insulin glargine to intensively manage glucose in the ORIGIN trial (Outcome Reduction With Initial Glargine Intervention) did not significantly alter cardiovascular outcomes in patients with prediabetes or early T2D compared with standard care32; the cardiovascular effects of glimepiride in patients with T2D and high cardiorenal risk enrolled in CAROLINA (Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes) did not differ from those of the proven-neutral DPP-4 inhibitor linagliptin33,34; and cardiovascular outcomes with sitagliptin added to the care of patients with T2D and established ASCVD in TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) did not differ from placebo.35 Liraglutide was the only study-assigned GRADE treatment with a demonstrated cardiovascular outcomes benefit, as the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) found significant reductions in the risk of MACE with liraglutide compared with placebo in patients with T2D and high cardiovascular risk; however, it could not be assumed that such benefits would extend to a lower-risk population.16 In addition, the LEADER results were not known until several years after GRADE had been designed and begun enrollment.
Although GRADE was not primarily designed to assess the cardiovascular effects of study medications, cardiovascular events were prospectively collected, recorded, and adjudicated throughout the study. During the study design, the projected rate of the any CVD outcome was expected to be 1% per year, which would have provided 72% power to detect a 50% difference. Initial concerns regarding the expected low rate of events, as well as the later LEADER trial results, prompted inclusion of the prespecified recurrent events analyses and the comparisons of liraglutide with the other treatment groups combined in this statistical analysis plan. These additional analyses, which were prespecified before the conclusion of the trial, were enacted to increase the statistical power to detect between-group differences. However, the overall numbers of cardiovascular events in GRADE were low, making the outcomes findings more hypothesis-generating than definitive of a benefit to liraglutide treatment in patients at lower risk.
Our findings suggest that compared with the alternative therapies studied, treatment with liraglutide may decrease the total cardiovascular event burden (MACE and HF) in patients with T2D at relatively low risk. The current analyses cannot identify the mechanisms or mediators of protective benefit potentially conveyed by liraglutide treatment in GRADE. However, others have suggested that the outcomes benefits are in part attributable to improvements in multiple cardiovascular risk factors commonly associated with GLP-1RA use.36 In GRADE, participants in the treatment groups assigned to glargine and liraglutide were more likely to achieve and sustain an HbA1c <7% (53 mmol/mol) than those receiving sitagliptin or glimepiride; however, these glycemic differences were modest (mean HbA1c 7.1% in the liraglutide and glargine groups, 7.2% in the sitagliptin group, and 7.3% in the glimepiride group at 4 years), and thus unlikely to explain the between-group differences found in cardiovascular outcomes.9 All treatment groups experienced a decrease in weight, but with mean weight loss at 4 years being greater in the liraglutide and sitagliptin groups (3.5 and 2.0 kg, respectively) than in the glimepiride and glargine groups (0.73 and 0.61 kg, respectively).9 Small differences in systolic BP over time were also present, being highest in the glargine and glimepiride groups (129.1 and 128.7 mm Hg, respectively), lower in the sitagliptin group (128.1 mm Hg), and lowest in the liraglutide group (126.9 mm Hg).9 Although these differences are notable, it is unlikely that these small improvements in traditional cardiovascular risk factors fully explain the differences identified in cardiovascular outcomes. Despite the divergence in these known risk factors for both microvascular and macrovascular complications, there were no important between-group differences in the rates of microvascular complications that occurred during the study.9
Many aspects of the GRADE study strengthen our analyses and conclusions, including the enrollment of a large, highly diverse patient population followed long-term and with minimal dropout. Randomized treatments included commonly prescribed glucose-lowering medications, and the care provided by GRADE was embedded in otherwise usual care. Previously reported use of nonstudy SGLT2i or GLP-1RA by GRADE participants was low and was less frequent in the group assigned to liraglutide treatment.9 The current analyses do not include or adjust for the use of these nonstudy medications. However, the most likely effect of this drop-in treatment would be to minimize the differences in cardiovascular outcomes between liraglutide and the other treatment groups. Given the small proportion of participants with previous MI or CVA, the current analyses also do not include assessment of outcomes in subgroups with or without ASCVD at baseline. Higher rates of cardiovascular events in the GRADE participants with previous CVD have been previously reported, but nominally lower rates of cardiovascular events with liraglutide treatment in patients with and without established CVD were also noted.8
Limitations beyond those previously mentioned include the selection of steering committee members and institutions based on their expertise in clinical trials and ability to recruit a representative population of individuals with T2D, rather than taking an approach designed to ensure diversity of steering committee members themselves. There is also an absence of complete HF-related data at baseline. Although patients with HF and New York Heart Association class III or IV functional status were excluded, it is possible that participants with less severe manifestations of HF were enrolled. These data were not captured at baseline; however, as seen with the other baseline characteristics, randomization was highly effective, and it is unlikely that the prevalence of this complication would have differed significantly among treatment groups. In addition, although HHF events were adjudicated, there was not a systematic capture of data such as ejection fraction for the incident HF events. SGLT2i were not included in GRADE because the study was designed before the approval of the first SGLT2 inhibitor. Thus, the absence of an SGLT2i treatment group limits our ability to fully translate the GRADE findings into contemporary management of T2D. Further studies are warranted to more fully evaluate the cardiovascular effects of glucose-lowering medications, including SGLT2i, in patients with T2D at relatively low risk. However, the GRADE results suggest that GLP-1RA treatment may play a beneficial role in reducing cardiovascular risk in patients with T2D at relatively low risk for cardiovascular events.
ARTICLE INFORMATION
Supplemental Material
Tables S1–S2
GRADE Study Research Group Member Listing
Acknowledgments
The GRADE Research Group thanks the study participants.
Footnote
Nonstandard Abbreviations and Acronyms
- ASCVD
- atherosclerotic cardiovascular disease
- BP
- blood pressure
- CKD
- chronic kidney disease
- CVA
- cerebrovascular accident
- CVD
- cardiovascular disease
- DPP-4
- dipeptidyl peptidase 4
- GLP-1RA
- glucagon-like peptide-1 receptor agonist
- GRADE
- Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study
- HF
- heart failure
- HHF
- hospitalization for heart failure
- HR
- hazard ratio
- MACE
- major adverse cardiovascular event
- MACE-3
- composite outcome comprising nonfatal myocardial infarction, nonfatal cerebrovascular accident, and cardiovascular death
- MACE-4
- MACE-3+unstable angina requiring hospitalization or revascularization
- MACE-5
- MACE-4+coronary revascularization
- MACE-6
- MACE-5+hospitalization for heart failure
- MI
- myocardial infarction
- SGLT2i
- sodium-glucose cotransporter-2 inhibitor
- T2D
- type 2 diabetes
Supplemental Material
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© 2024 American Heart Association, Inc.
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History
Received: 9 August 2023
Accepted: 5 January 2024
Published online: 12 February 2024
Published in print: 26 March 2024
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Disclosures
Disclosures Dr Green reports research support from Boehringer Ingelheim/Lilly, Merck, Bluedrop, Sanofi/Lexicon, and Roche, and serving as an advisor or consultant for Boehringer Ingelheim/Lilly, Bayer, AstraZeneca, Merck, Hawthorne Effect, Sanofi/Lexicon, Pfizer, Valo, Anji, Vertex, and Novo Nordisk. Dr Everett reports research support from Novo Nordisk and PCORI; consulting fees from the American Heart Association, Eli Lilly and Company, Ipsen Pharmaceuticals, Janssen Pharmaceuticals, and Novo Nordisk; and royalties from UpToDate. Dr Desouza reports serving as a consultant for Novo Nordisk, AstraZeneca, Asahi, and Bayer. Dr Inzucchi reports serving as an advisor or consultant to Boehringer Ingelheim, AstraZeneca, Bayer, Novo Nordisk, Merck, Pfizer, Lexicon, Abbott, VTV Therapeutics, and Esperion, and delivering lectures sponsored by Boehringer Ingelheim and AstraZeneca. Dr Tan is a retiree of and receives a pension from Eli Lilly and Company. Dr Utzschneider reports personal fees from Nevro Corporation, research support from Eli Lilly and Company, and research support from AVID, outside the submitted work. Dr Mudaliar reports serving as a speaker for AstraZeneca and a consultant for Bayer. The other authors have nothing to disclose.
Sources of Funding
GRADE was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award No. U01DK098246. GRADE planning was supported by a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (U34-DK-088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The Department of Veterans Affairs provided resources and facilities. Additional support was provided by grants P30 DK017047, P30 DK020541-44, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541, and UL1 TR002548. Educational materials were provided by the National Diabetes Education Program. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Material support in the form of donated medications and supplies was provided by Becton, Dickinson and Company, Bristol-Myers Squibb, Merck & Co, Inc, Novo Nordisk, Roche Diagnostics, and Sanofi.
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