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`Author manuscript
`J Am Coll Cardiol. Author manuscript; available in PMC 2020 October 09.
`
`Published in final edited form as:
`J Am Coll Cardiol. 2020 September 01; 76(9): 1117–1145. doi:10.1016/j.jacc.2020.05.037.
`
`2020 Expert Consensus Decision Pathway on Novel Therapies
`for Cardiovascular Risk Reduction in Patients With Type 2
`Diabetes
`
`Sandeep R. Das, MD, MPH, FACC [Co-Chair], Brendan M. Everett, MD, MPH, FACC [Co-
`Chair], Kim K. Birtcher, PharmD, MS, CDE, AACC, Jenifer M. Brown, MD, James L. Januzzi
`JR, MD, FACC, Rita R. Kalyani, MD, MHS, Mikhail Kosiborod, MD, FACC, Melissa Magwire,
`RN, MSN, CDE, Pamela B. Morris, MD, FACC, Joshua J. Neumiller, PharmD, CDCES,
`Laurence S. Sperling, MD, FACC, Ty J. Gluckman, MD, FACC [Chair], Niti R. Aggarwal, MD,
`FACC, Nicole M. Bhave, MD, FACC, Gregory J. Dehmer, MD, MACC, Olivia N. Gilbert, MD,
`MSc, FACC, Chayakrit Krittanawong, MD, Dharam J. Kumbhani, MD, SM, FACC, Andrea L.
`Price, CPHQ, RCIS, AACC, Javier A. Sala-Mercado, MD, PhD, David E. Winchester, MD,
`FACC, Martha Gulati, MD, FACC [Ex Officio]
`
`Keywords
`ACC Expert Consensus Decision Pathway; atherosclerotic cardiovascular disease; cardiovascular
`risk reduction; diabetes; GLP-1RA; SGLT2 inhibitor; type 2 diabetes
`
`PREFACE
`
`The American College of Cardiology (ACC) has a long history of developing documents
`(e.g., decision pathways, health policy statements, appropriate use criteria) to provide
`members with guidance on both clinical and nonclinical topics relevant to cardiovascular
`(CV) care. In most circumstances, these documents have been created to complement
`clinical practice guidelines and to inform clinicians about areas where evidence may be new
`and evolving or where sufficient data may be more limited. In spite of this, numerous care
`gaps continue to exist, highlighting the need for more streamlined and efficient processes to
`implement best practices in service to improved patient care.
`
`Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the
`express permission of the American College of Cardiology. Requests may be completed online via the Elsevier site (https://
`www.elsevier.com/about/policies/copyright/permissions?).
`PRESIDENT AND STAFF
`Athena Poppas, MD, FACC, President Cathleen C. Gates, Interim Chief Executive Officer John Rumsfeld, MD, PhD, FACC, Chief
`Science & Quality Officer
`Joseph M. Allen, MA, Team Leader, Clinical Standards and Solution Sets
`Amy Dearborn, Team Leader, Clinical Content Development
`Ashleigh Covington, MA, Team Leader, Clinical Pathways and Heart House Roundtables Amelia Scholtz, PhD, Publications Manager,
`Science & Quality, Education, and Publications
`Copies: This document is available on the World Wide Web site of the American College of Cardiology (www.acc.org). For copies of
`this document, please contact Elsevier Inc. Reprint Department via fax (212) 633-3820 or e-mail (reprints@elsevier.com).
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`Central to the ACC’s strategic plan is the generation of “actionable knowledge”–a concept
`that places emphasis on making clinical information easier to consume, share, integrate, and
`update. To this end, the ACC has evolved from developing isolated documents to the
`development of integrated “solution sets.” Solution sets are groups of closely related
`activities, policy, mobile applications, decision support, and other tools necessary to
`transform care and/or improve heart health. Solution sets address key questions facing care
`teams and attempt to provide practical guidance to be applied at the point of care. They use
`both established and emerging methods to disseminate information for CV conditions and
`their related management. The success of the solution sets rests firmly on their ability to
`have a measurable impact on the delivery of care. Because solution sets reflect current
`evidence and ongoing gaps in care, the associated content will be refined over time to best
`match changing evidence and member needs.
`
`Expert consensus decision pathways (ECDPs) represent a key component of solution sets.
`The methodology for ECDPs is grounded in assembling a group of clinical experts to
`develop content that addresses key questions facing our members across a range of high-
`value clinical topics (1). This content is used to inform the development of various tools that
`accelerate real time use of clinical policy at the point of care. They are not intended to
`provide a single correct answer; rather, they encourage clinicians to ask questions and
`consider important factors as they define a treatment plan for their patients. Whenever
`appropriate, ECDPs seek to provide unified articulation of clinical practice guidelines,
`appropriate use criteria, and other related ACC clinical policy. In some cases, covered topics
`will be addressed in subsequent clinical practice guidelines as the evidence base evolves. In
`other cases, these will serve as stand-alone policy.
`
`Ty J. Gluckman, MD, FACC
`
`Chair, ACC Solution Set Oversight Committee
`
`1.
`
`INTRODUCTION
`
`Despite major therapeutic advances leading to improved outcomes over the past 2 decades,
`CV disease remains the leading cause of morbidity and mortality in patients with type 2
`diabetes (T2D) (2–4). Over this time, the prevalence of T2D has increased, while the excess
`risk of adverse CV events in patients with T2D (compared with patients without diabetes)
`has remained largely unchanged (5,6). Accordingly, the development of treatment strategies
`to improve CV outcomes in this vulnerable patient population remains a major priority.
`Diabetes is typically thought of as a disease of elevated blood glucose (7). Although large
`clinical trials have consistently demonstrated an improvement in microvascular outcomes in
`patients with T2D with intensive versus conservative glucose control, similar results have
`not been demonstrated for CV outcomes in patients with T2D, despite the clinically
`important differences in hemoglobin A1c (HbA1c) achieved between treatment groups in
`glucose-lowering trials (8–11). The opportunities for improving clinical outcomes in patients
`with T2D and CV disease have recently expanded.
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`Many sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1
`receptor agonists (GLP-1RAs) have been demonstrated to significantly reduce the risk of
`major adverse cardiovascular events (MACE) (12–19). SGLT2 inhibitors also substantially
`diminish the risks of heart failure (HF) hospitalization and progression of diabetic kidney
`disease (DKD). Although the exact mechanisms of CV and renal benefits remain uncertain,
`they appear to exceed the direct glucose-lowering effects of these agents and may be related
`to additional mechanisms of action of each class of medications (20,21). Data proving that
`SGLT2 inhibitors and GLP-1RAs improve outcomes in patients with T2D and CV disease
`have triggered a major paradigm shift beyond glucose control to a broader strategy of
`comprehensive CV risk reduction (2,22,23). The potential of these compounds has also
`stimulated re-examination of the traditional roles of various medical specialties in the
`management of T2D, compelling CV specialists to adopt a more active role in prescribing
`drugs that may previously have been seen primarily as glucose-lowering therapies. This
`evolving role has created a need for novel clinical care delivery models that are
`collaborative, interprofessional, and multidisciplinary in their approach to managing this
`high-risk patient group with multiple comorbidities. The purpose of this ECDP is to update
`the 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular
`Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular
`Disease (ASCVD) (24) with data from emerging studies, and continue to provide succinct,
`practical guidance on the use of specific agents for reducing CV risk in patients with T2D.
`
`1.1. A Focus on Comprehensive CV Risk Reduction in T2D
`
`Although the primary focus of patients, clinicians, and healthcare systems should be the
`prevention of T2D (25), a significant proportion of patients cared for by CV clinicians have
`known T2D, undiagnosed diabetes, or prediabetes (26). Because most morbidity and
`mortality in T2D comes from CV events (27), the CV specialist has a key role in optimizing
`these patients’ care and is well-positioned to address 3 key areas in the management of
`patients with T2D:
`
`1.
`
`2.
`
`3.
`
`Screening for T2D in their patients with or at high risk of CV disease;
`
`Aggressively treating CV risk factors; and
`
`Incorporating newer glucose-lowering agents with evidence for improving CV
`outcomes into routine practice.
`
`Data from the NCDR PINNACLE registry from 2008 through 2009 show that only 13% of
`outpatients in the United States with coronary artery disease cared for primarily by
`cardiologists are screened for T2D (28). While the proportion screened is likely to have
`improved in the decade since that report was published, there remains a need for
`improvement in comprehensive CV risk factor control among patients with T2D (29,30), as
`current care delivery is often fragmented, episodic, and focused on treating acute events.
`Comprehensive CV risk factor control reduces events and improves survival in patients with
`T2D (31,32). This includes encouraging a healthy diet, regular physical activity, weight loss,
`smoking cessation, assiduous control of blood pressure (33), lowering of atherogenic blood
`lipids (34,35), and use of antiplatelet agents in accordance with current treatment guidelines
`(2,35,36). Only a minority of patients with diabetes achieve these key benchmarks (37).
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`Beyond these core recommendations, CV specialists should be aware of the strong clinical
`evidence regarding specific glucose-lowering therapies proven to lower CV risk. Given that
`patients with T2D and CV disease frequently follow up with their CV specialists, a firm
`understanding of the efficacy and safety profiles and net clinical benefits of these agents is
`important. Such encounters are an ideal time to review the patient’s overall management and
`consider the initiation of these novel agents to favorably impact patient care and outcomes.
`
`2. METHODS
`
`The ACC created the Heart House Roundtables, a structured format of interactive discussion
`among a broad group of stakeholders, to address high-value topics and issues that clinicians
`and patients face daily, such as the treatment of CV disease in patients with T2D (38). The
`planning committee for the Managing CV Disease Risk in Diabetes roundtable was led by
`Mikhail Kosiborod, MD, FACC, and Larry Sperling, MD, FACC. To accommodate the
`multiple perspectives concerning new therapeutic options for patients with T2D, the
`roundtable included several experts in diverse medical specialties, such as cardiology, family
`medicine, internal medicine, and endocrinology, and included physicians, nurses, advanced
`practice providers, and pharmacists. Recognizing the significant impact of recently available
`CV outcomes trial data, discussions focused on the real-world challenges faced in working
`toward comanaging T2D and CV disease for improved patient outcomes. As a result, the
`ACC saw an opportunity to provide guidance to fill the current gap between CV clinicians
`and diabetes care providers who jointly manage patients with T2D and ASCVD, HF, and/or
`DKD. To support this effort, a writing committee of multidisciplinary experts was convened
`in 2017 to develop an ECDP providing guidance on the use of antidiabetic agents proven to
`reduce CV risk in patients with T2D (24). For this update, the writing committee convened
`in late 2019 via conference call attended only by writing committee members and ACC staff.
`Differences were resolved by consensus among the group, and no portions of the ECDP
`required administrative decision overrides. The work of the writing committee was
`supported only by the ACC and did not have any commercial support. Writing committee
`members were all unpaid volunteers.
`
`The ACC and the Solution Set Oversight Committee (SSOC) recognize the importance of
`avoiding real or perceived relationships with industry (RWI) or other entities that may affect
`clinical policy. The ACC maintains a database that tracks all relevant relationships for ACC
`members and persons who participate in ACC activities, including those involved in the
`development of ECDPs. ECDPs follow ACC RWI Policy in determining what constitutes a
`relevant relationship, with additional vetting by the SSOC.
`
`ECDP writing groups must be chaired or co-chaired by an individual with no relevant RWI.
`While vice chairs and writing group members may have relevant RWI, this must constitute
`less than 50% of the writing group. Relevant disclosures for the writing group, external
`reviewers, and SSOC members can be found in Appendixes 1 and 2. Participants are
`discouraged from acquiring relevant RWI throughout the writing process.
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`3. ASSUMPTIONS AND DEFINITIONS
`
`To facilitate interpretation of the recommendations provided in this ECDP, specific
`assumptions were made by the writing committee as specified in Section 3.1.
`
`3.1. General Clinical Assumptions
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`The principal focus of this effort, including ECDP considerations, applies to
`patients with T2D and CV disease or who are at high risk for CV disease.
`
`The writing committee endorses the evidence-based approaches to CV disease
`risk reduction recommended in the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/
`APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection,
`Evaluation, and Management of High Blood Pressure in Adults (33), the 2018
`AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA
`Guideline on the Management of Blood Cholesterol (34), and the 2019
`ACC/AHA Guidelines on the Primary Prevention of Cardiovascular Disease
`(39).
`
`The writing committee endorses the evidence-based approaches to diabetes
`management outlined in the American Diabetes Association (ADA) Standards of
`Medical Care in Diabetes: Chapter 10. Cardiovascular Disease and Risk
`Management (2).
`
`The writing committee endorses the evidence-based approaches to HF therapy
`and management enumerated in the 2013 ACCF/AHA Guideline for the
`Management of Heart Failure, the 2016 ACC/AHA/HFSA Focused Update on
`the New Pharmacological Therapy for Heart Failure: an Update of the 2013
`ACCF/AHA Guideline for the Management of Heart Failure, and the 2017 ACC
`Expert Consensus Decision Pathway for Optimization of Heart Failure
`Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced
`Ejection Fraction (40–42). It is important to note that the 2013 and 2017 HF
`guidelines as well as the 2017 ECDP do not include major trials that are
`described in this ECDP because of the timing of those publications.
`
`Optimal patient care decisions should properly reflect the patient’s preferences
`and priorities as well as those of the managing clinician.
`
`This ECDP is not intended to supersede good clinical judgement. The treating
`clinician should seek input as needed from relevant experts (e.g., pharmacists,
`cardiologists, endocrinologists).
`
`This ECDP is based on the best data currently available. New information is
`being generated rapidly (e.g., CV outcomes trials of additional agents and
`including other patient populations), and as these data become available, they
`will impact the considerations made here. Clinicians should be careful to
`incorporate relevant information published after this ECDP.
`
`A background effort aimed at comprehensive CV risk reduction is essential,
`using the full complement of diet, exercise, and lifestyle recommendations, as
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`well as CV risk factor modification and other preventive medical therapies
`described in the ADA Standards of Care and/or the applicable AHA/ACC
`guidelines or ACC ECDPs.
`
`9.
`
`Although implementing relevant portions of these recommendations in the acute
`inpatient setting may be reasonable, this ECDP is primarily focused on
`management in the outpatient ambulatory setting.
`
`3.2. Definitions
`
`Atherosclerotic cardiovascular disease (ASCVD): a history of an acute coronary
`syndrome or myocardial infarction (MI), stable or unstable angina, coronary heart disease
`with or without revascularization, other arterial revascularization, stroke, or peripheral artery
`disease assumed to be atherosclerotic in origin. This definition is intended to be consistent
`with that used in the 2017 Focused Update of the 2016 ACC Expert Consensus Decision
`Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the
`Management of Atherosclerotic Cardiovascular Disease Risk (34).
`
`Cardiovascular (CV) disease includes ASCVD, HF, and CV-related death.
`
`Diabetic kidney disease (DKD): a clinical diagnosis marked by a decrease in estimated
`glomerular filtration rate (eGFR), the presence of albuminuria, or both in a patient with
`diabetes. This definition is intended to be consistent with those used in the ADA Standards
`of Medical Care for Diabetes and the clinical trials referenced throughout this ECDP
`(19,43).
`
`Heart failure (HF): defined per criteria outlined in the 2013 ACCF/AHA Guideline for the
`Management of Heart Failure and the 2017 ACC Expert Consensus Decision Pathway for
`Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure
`With Reduced Ejection Fraction (42,44). An HF event, including hospitalization, is defined
`by the criteria outlined by the 2014 ACC/AHA Key Data Elements and Definitions for
`Cardiovascular Endpoint Events in Clinical Trials (45).
`
`Heart failure with reduced ejection fraction (HFrEF): clinical diagnosis of HF and
`left ventricular ejection fraction ≤40% (42,46).
`
`High risk for ASCVD: patients with end organ damage such as left ventricular
`hypertrophy, retinopathy, or multiple risk factors (e.g., age, hypertension, smoking, obesity,
`dyslipidemia)
`
`Major adverse cardiovascular event (MACE): either a “3-point MACE” composite
`endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, or CV death, or a “4-point
`MACE” composite endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable
`angina, or CV death.
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`4. PATHWAY SUMMARY GRAPHIC
`
`Figure 1 provides an overview of what is covered in the ECDP. See each section for more
`detailed considerations and guidance.
`
`5. DESCRIPTION AND RATIONALE
`
`CV specialists should be aware of the evidence supporting the use of specific SGLT2
`inhibitors and GLP-1RAs to reduce risk in patients with T2D and established CV disease.
`
`5.1. SGLT2 Inhibitors
`
`SGLT2 inhibitors have emerged as important new oral therapies for patients with T2D.
`Large, randomized controlled trials in patients with T2D have demonstrated that many of
`these agents reduce MACE in patients with established ASCVD and/or DKD, and reduce the
`risk of HF hospitalizations (see Table 1).
`
`These benefits may be similar for agents within this class, although there are differences that
`seem likely to reflect the patient populations enrolled in the trials (48–50). The benefit of
`reducing HF hospitalizations in these trials reflected primarily prevention of symptomatic
`HF in T2D patients at high risk, as ~90% did not have HF at baseline (and those who did
`were not well-characterized). The benefits of an SGLT2 inhibitor in treating established HF
`were demonstrated in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the
`Incidence of Worsening HF or CV Death in Patients With Chronic HF) trial, in which
`dapagliflozin significantly reduced the risk of CV death or worsening HF, and improved HF-
`related symptoms in ~4,800 patients with HFrEF. Of note, more than half of patients in this
`trial did not have T2D, and there was no difference in the treatment benefit of dapagliflozin
`across the subgroups of patients with or without T2D. Beneficial effects of dapagliflozin on
`symptoms, functional status, and quality of life in patients with HFrEF were also seen in the
`DEFINE-HF (Dapagliflozin Effect on Symptoms and Biomarkers in Patients With HF) trial
`(51). Additional trials in both HFrEF and heart failure with preserved ejection fraction
`(HFpEF) are ongoing with various agents. Furthermore, consistent reductions in the
`secondary outcome of risk of kidney disease progression were seen with all agents in the CV
`outcomes trials (although the number of “hard” renal events was small). The CREDENCE
`(Evaluation of the Effects of Canagliflozin on Renal and CV Outcomes in Participants With
`Diabetic Nephropathy) trial–the first dedicated renal outcome trial of the SGLT2 inhibitor
`class–reported that canagliflozin significantly reduced the risk of DKD progression,
`including development of end-stage kidney disease and initiation of dialysis. Patients in the
`CREDENCE trial were enrolled with an eGFR as low as 30 ml/min/1.73 m2 and continued
`to be treated with canagliflozin even if their eGFR was below that threshold. Benefits and
`adverse effects in the group with the lowest eGFR were consistent with those in the
`remainder of the cohort (19).
`
`5.1.1. SGLT2 Inhibitors: Mechanism of Action—SGLT2 is a sodium-glucose
`cotransporter in the proximal tubule of the nephron that is responsible for approximately
`90% of urinary glucose reabsorption. Inhibition of SGLT2 results in glucose lowering
`through induction of glucosuria. This effect is more pronounced in the setting of
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`hyperglycemia, where significant amounts of glucose are filtered into the urine. Glucosuria
`diminishes significantly as blood glucose normalizes (9). In addition, as eGFR decreases, the
`effects of SGLT2 on blood glucose are smaller. The risk of hypoglycemia for patients taking
`an SGLT2 inhibitor is extremely low unless such an agent is used concomitantly with insulin
`or insulin secretagogues (such as sulfonylureas and glinides). Beyond their effect on blood
`glucose, SGLT2 inhibitors also cause diuretic and natriuretic effects, promote weight loss,
`and lower systolic blood pressure (52). Interestingly, changes in traditional risk factors such
`as elevated HbA1C and lipids do not seem to be the key determinants of the beneficial
`effects of SGLT2 inhibitors on CV and renal outcomes (20,21). Although the mechanisms of
`SGLT2 inhibitor benefit have not been fully elucidated, a number of putative mechanisms
`have been proposed, including reductions in preload and afterload through diuresis,
`alterations in myocardial metabolism, and prevention of myocardial fibrosis, among others
`(53).
`
`5.1.2. SGLT2 Inhibitors and ASCVD Events—The EMPA-REG OUTCOME
`(Empagliflozin CV Outcome Event Trial in T2D Patients) trial (12) showed a 14% relative
`risk reduction in the primary endpoint of 3-point MACE (hazard ratio [HR]: 0.86; 95%
`confidence interval [CI]: 0.74 to 0.99) compared with placebo. This reduction in the primary
`outcome and the observed 32% reduction in all-cause mortality (HR: 0.68; 95% CI: 0.57 to
`0.82) were driven predominantly by a 38% reduction in CV death (HR: 0.62; 95% CI: 0.49
`to 0.77) (54). The effects of empagliflozin on fatal or nonfatal MI were more modest, with
`confidence intervals that overlapped 1.0 (HR: 0.87; 95% CI: 0.70 to 1.09), and there was no
`significant difference in fatal or nonfatal stroke, with confidence interval limits also broadly
`overlapping 1.0 (HR: 1.18; 95% CI: 0.89 to 1.56). Importantly, the secondary endpoint of
`HF hospitalization was reduced by 35% (HR: 0.65; 95% CI: 0.50 to 0.85). Separation in the
`cumulative event curves suggested an early benefit of the compound (55) and was consistent
`across patient subgroups with or without prevalent HF at study entry (56). Empagliflozin is
`specifically approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of
`CV death in adults with T2D and established CV disease (57).
`
`Two large CV outcomes trials have assessed the impact of canagliflozin on MACE; the
`CANVAS (Canagliflozin CV Assessment Study) and CANVAS-R (Study of the Effects of
`Canagliflozin [JNJ-28431754] on Renal Endpoints in Adult Participants With T2D) trials
`(13) enrolled 4,330 and 5,812 patients, respectively, 72% of whom had established ASCVD.
`Study participants were randomized to placebo or canagliflozin (100 or 300 mg in
`CANVAS, and 100 mg with an optional increase to 300 mg in CANVAS-R). Results from
`CANVAS and CANVAS-R are mostly consistent with those of EMPA-REG OUTCOME.
`Analyses of the effects of canagliflozin versus placebo on the secondary endpoints of CV
`and all-cause death were directionally consistent with the primary endpoint (16,58). As with
`EMPA-REG OUTCOME, no difference in outcomes was seen between SGLT2 inhibitor
`doses. The combined analysis of the 2 CANVAS trials demonstrated a 14% relative
`reduction in the primary endpoint of triple MACE (HR: 0.86; 95% CI: 0.75 to 0.97 from
`31.5 to 26.9 events per 1,000 person-years) compared with placebo (16,58). Although
`CANVAS was underpowered for the individual components of the primary outcome and
`thus none were statistically significant on their own, the point estimates for each component
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`were consistently in favor of SGLT2 inhibitor therapy-CV death (HR: 0.87; 95% CI: 0.72 to
`1.06); fatal or nonfatal MI (HR: 0.89; 95% CI: 0.73 to 1.09), and fatal or nonfatal stroke
`(HR: 0.87; 95% CI: 0.69 to 1.09)-as was the point estimate for reduction in all-cause
`mortality (HR: 0.87; 95% CI: 0.74 to 1.01).
`
`Three-point MACE was a prespecified secondary outcome of the CREDENCE trial (19),
`which studied patients with established DKD (see Table 1). In CREDENCE, patients
`randomized to canagliflozin 100 mg daily experienced a 20% relative risk reduction in the
`composite MACE endpoint of CV death, MI, or stroke (HR: 0.80; 95% CI: 0.67 to 0.95). A
`qualitatively similar, although not statistically significant, 17% reduction was seen in all-
`cause mortality (HR: 0.83; 95% CI: 0.68 to 1.02). Canagliflozin is now approved by the
`FDA to reduce the risk of MACE in patients with established CV disease, to prevent
`hospitalizations for HF in patients with DKD and albuminuria, and to reduce the risk of
`progression of diabetic nephropathy.
`
`The DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the
`Incidence of CV Events-Thrombolysis In Myocardial Infarction 58) (17,60) is the largest
`SGLT2 inhibitor trial to date. More than half of the trial participants did not have established
`ASCVD; the overwhelming majority also had normal kidney function and no significant
`albuminuria. MACE was 1 of 2 primary endpoints, along with the composite of CV death or
`hospitalization for HF. In DECLARE-TIMI 58, patients randomized to receive dapagliflozin
`10 mg compared with placebo had a nonstatistically significant 7% relative risk reduction in
`MACE (HR: 0.93; 95% CI: 0.84 to 1.03). Again, this was quite close to the 7%
`nonsignificant reduction seen in all-cause mortality (HR: 0.93; 95% CI: 0.82 to 1.04).
`Whether the smaller treatment effect of dapagliflozin 10 mg on reducing MACE seen in
`DECLARE-TIMI 58 reflects the much lower-risk patient cohort (as compared with EMPA-
`REG and CANVAS), a true drug-specific effect, or a combination of both, is not known.
`Importantly, dapagliflozin significantly reduced the risk of the second dual primary
`endpoint-composite of CV death or hospitalization for HF (HR: 0.83; 95% CI: 0.73 to 0.95).
`The 10-mg dose of dapagliflozin is now approved by the FDA to reduce the risk of HF in
`patients with T2D who have established or are at high risk for ASCVD. The results of the
`VERTIS-CV trial (Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2
`Diabetes Mellitus Participants with Vascular Disease) were presented at the American
`Diabetes Association Virtual Scientific Sessions on June 16, 2020. The risk of the primary
`endpoint of CV death, nonfatal MI, or stroke was similar in the ertugliflozin and placebo
`groups (HR 0.97%, 95% CI 0.85-1.11), and ertugliflozin reduced the rate of hospitalization
`for heart failure (59). A prospective CV outcomes trial of SGLT2 inhibitor ertugliflozin (60)
`and the SGLT2 and SGLT1 inhibitor sotagliflozin (61) is currently underway.
`
`5.1.3. SGLT2 Inhibitors in Patients With and Without Established ASCVD—A
`recently published meta-analysis of data from CANVAS, CREDENCE, DECLARE-TIMI
`58, and EMPA-REG OUTCOME reported a 12% reduction in MACE (HR: 0.88; 95% CI:
`0.82 to 0.94) with no statistically significant interaction based on primary versus secondary
`prevention (P interaction = 0.252) (62). Note that these observations do not apply to the
`effect of SGLT2 inhibitors on the risk of hospitalization for HF or progression of DKD,
`which are outlined in the following text.
`
`J Am Coll Cardiol. Author manuscript; available in PMC 2020 October 09.
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`Author Manuscript
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`Author Manuscript
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`Author Manuscript
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`Author Manuscript
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`Novo Nordisk Exhibit 2092
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
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`Das et al.
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`5.1.4. SGLT2 Inhibitors and HF Events—HF is increasingly common and is a source
`of considerable morbidity and mortality for patients with diabetes. All of the published
`randomized trials, as well as several observational studies of claims databases and registries,
`have demonstrated substantial benefits for an SGLT2 inhibitor in the prevention of
`hospitalization for HF and in the composite of hospitalization for HF and CV death.
`
`The effects of SGLT2 inhibitors on HF hospitalization appear remarkably consistent across
`the class. In the EMPA-REG OUTCOME trial, CV death or hospitalization for HF was an
`exploratory secondary outcome. Patients randomized to empagliflozin had a 34% reduction
`in this endpoint (HR: 0.66; 95% CI: 0.55 to 0.79) (12). The individual effects on HF
`hospitalization alone (HR: 0.65; 95% CI: 0.50 to 0.85) were similar. In the CANVAS
`program, a 33% reduction in HF hospitalization was seen (HR: 0.67; 95% CI: 0.52 to 0.87).
`In CREDENCE, patients randomized to canagliflozin experienced a 39% relative risk
`reduction in HF hospitalization (HR: 0.61; 95% CI: 0.47 to 0.80) (48). The composite of CV
`death or hospitalization for HF was one of the dual primary endpoints in DECLARE-TIMI
`58, in which patients randomized to receive dapagliflozin had a 17% relative risk reduction
`in that dual primary endpoint (HR: 0.83; 95% CI: 0.73 to 0.95) compared with placebo. This
`reduction was driven by a 27% reduction in HF hospitalization (HR: 0.73; 95% CI: 0.61 to
`0.88) (60). This observation was consistent