J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y
`ª 2 0 2 0 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N
`
`P U B L I S H E D B Y E L S E V I E R
`
`V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`JACC FOCUS SEMINAR
`
`Diabetic Agents, From Metformin
`to SGLT2 Inhibitors and
`GLP1 Receptor Agonists
`JACC Focus Seminar
`
`Tanya Wilcox, MD,a Christophe De Block, MD, PHD,b Arthur Z. Schwartzbard, MD,a,c
`Jonathan D. Newman, MD, MPHa,c
`
`ABSTRACT
`
`Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat
`type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney
`disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although
`biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events,
`sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety
`and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools
`for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal
`protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of
`pharmacologic agents used to treat patients with type 2 diabetes. (J Am Coll Cardiol 2020;75:1956–74)
`© 2020 by the American College of Cardiology Foundation.
`
`T ype 2 diabetes mellitus (T2DM) is a well-
`
`established risk factor for cardiovascular dis-
`ease (CVD), and CVD is the leading cause of
`death in adults with T2DM. Compared with an individ-
`ual without T2DM, the life expectancy of a 50-year-old
`with T2DM is on average 6 years shorter. The lifespan
`of an individual with T2DM and a prior myocardial
`infarction (MI) is shortened further still by 12 years.
`Sixty percent of the difference in survival is attribut-
`able to excess CVD mortality (1). As previously charac-
`terized (2), heart failure (HF) is also under-recognized
`among T2DM patients and increases mortality (3). In
`
`recent years, the scope of diabetes treatment has
`broadened to reversal of known pathophysiologic de-
`fects and not simply on improving dysglycemia. Glyce-
`mic
`control,
`a
`traditional mainstay of T2DM
`management, overall does not correlate with reduced
`burden of CVD or mortality, particularly in the near-
`term (4,5). Insulin resistance in liver and muscle and
`eventual b-cell failure constitute the core pathophysi-
`ologic defects in T2DM. Additional mechanisms of dis-
`ease include hyperglucagonemia, incretin deficiency
`or resistance, and maladaptive increases in renal
`glucose reabsorption. Defects in the fat cells, such as
`
`Listen to this manuscript’s
`audio summary by
`Editor-in-Chief
`Dr. Valentin Fuster on
`JACC.org.
`
`From the aDepartment of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York;
`bDepartment of Endocrinology, Diabetology & Metabolism, University of Antwerp–Antwerp University Hospital, Antwerp,
`Belgium; and the cCenter for the Prevention of CVD, Department of Medicine, Division of Cardiology, New York University School
`of Medicine, New York, New York. Dr. De Block has received personal fees from AstraZeneca, Boehringer Ingelheim, Johnson &
`Johnson, Lilly, Merck Sharp & Dohme, Novo Nordisk A/S, and Sanofi. Dr. Schwartzbard has received institutional support to NYU
`Langone Medical Center from Merck/Pfizer, Amarin, Sanofi, Novartis, and Amgen; and has served as an advisor to the formulary
`committee for Optum Rx. Dr. Newman has received grants from the National Institutes of Health (NIH) National Heart, Lung, and
`Blood Institute (NHLBI) (K23HL K23HL125991); and has received honoraria from Creative Educational Concepts. Dr. Wilcox has
`reported that she has no relationships relevant to the contents of this paper to disclose.
`
`Manuscript received January 24, 2020; revised manuscript received February 25, 2020, accepted February 28, 2020.
`
`ISSN 0735-1097/$36.00
`
`https://doi.org/10.1016/j.jacc.2020.02.056
`
`Exhibit #
`
`Exhibit 2601
`
`07/09/24
`
`exhibitsticker.com
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`J A C C V O L . 7 5 , N O .
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`1 6 , 2 0 2 0
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`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6 – 7 4
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`Wilcox et al.
`Agents for Cardiovascular Care
`
`1957
`
`A B B R E V I A T I O N S
`
`A N D A C R O N Y M S
`
`the FDA mandate, 21 CVOT studies are on
`track to be completed by 2020, first in pre-
`dominantly high-risk T2DM patients with
`established CVD (secondary prevention) and
`later in broader populations with multiple
`CVD risk factors (primary prevention)
`(8).
`After the success of many of these trials, the
`FDA commissioned additional labels specif-
`ically evaluating CVD risk reduction for
`empagliflozin, canagliflozin, and liraglutide.
`The advent of CVOTs has led to a paradigm
`shift in the clinical practice recommendations
`for the management of T2DM. Until 2008, the
`approval of novel antidiabetic agents was
`based on their glucose-lowering potential (9).
`In 2012, guidelines proposed that HbA1c tar-
`gets should be individualized according to
`patient’s risk profile, in the context of poten-
`tial risks associated with hypoglycemia and
`other adverse drug effects, disease duration, life ex-
`pectancy, comorbidities, vascular complications, pa-
`tient attitude, and expected treatment efforts and
`resources (10). The strategy for the management of
`type 2 diabetes was updated in 2018 in response to the
`abundance of new cardiovascular outcome data from
`the CVOTs published since 2015, which showed safety,
`tolerability, and cardiovascular and renoprotection
`with 2 classes of agents, sodium glucose cotransporter
`2 inhibitors (SGLT2i) and glucagon-like peptide re-
`ceptor agonists (GLP1RA) in patients with established
`CVD (11). In response to these findings, in 2018 Euro-
`pean Association for the Study of Diabetes (EASD) and
`the American Diabetes Association (ADA) consensus
`guidance provides a decision cycle for patient-
`centered management of T2DM, taking into account
`not only key patient characteristics (age, weight, CVD,
`and renal history), but also specific factors such as
`HbA1c lowering effect, hypoglycemic risk, effect on
`weight, side effects, complexity, costs, and car-
`diorenal effects. These guidelines integrate these data
`for recommendations on choice of treatment and a
`shared decision-making strategy to create a manage-
`ment plan. In this plan, the focus has shifted from a
`pure
`glucocentric
`approach towards
`a holistic
`approach, with a preferred use of agents with proven
`cardiorenal superiority (11).
`To synthesize this wealth of new data, we will pro-
`vide an updated overview of pharmacologic agents for
`cardiovascular care in T2DM from metformin, sulfo-
`nylureas, and glitazones to dipeptidyl peptidase 4 in-
`hibitors (DPP4i), SGLT2i, and GLP1RA, discussing
`mechanism of action, metabolic and cardiorenal ef-
`fects, and benefits and limitations of current design.
`The evidence for cardiovascular benefit of SGLT2i and
`
`CKD = chronic kidney disease
`
`CVD = cardiovascular disease
`
`CVOT = cardiovascular
`outcome trials
`
`DPP4i = dipeptidyl peptidase 4
`inhibitors
`
`GLP1RA = glucagon-like
`peptide 1 receptor agonist
`
`HbA1c = hemoglobin A1c
`
`HF = heart failure
`
`MI = myocardial infarction
`
`SGLT2i = sodium glucose
`transporter 2 inhibitor
`
`T2DM = type 2 diabetes
`mellitus
`
`TZD = thiazolidinediones
`
`HIGHLIGHTS
` Historically, glycemic control was the
`primary focus in reducing cardiovascular
`risk in patients with diabetes mellitus.
` Although historic agents effectively
`lower blood sugar, evidence for cardio-
`vascular benefit was lacking.
` Newer glucose-lowering medications
`target numerous novel pathways to
`reduce cardiovascular and renal events in
`patients with type 2 diabetes.
` These medications should be considered
`in patients with diabetes and CVD and
`may play a role in primary prevention of
`cardiovascular and renal disease.
`
`increased lipolysis, and impaired hypothalamic appe-
`tite regulation have also been implicated (6). Because
`of the progressive and multifaceted pathophysiology
`of type 2 diabetes, pharmacologic agents with distinct
`yet complementary actions are needed. Obesity, hypo-
`glycemia, and CVD risk are important considerations
`in the treatment of T2DM, and interventions aimed at
`reducing chronic micro- and macrovascular complica-
`tions and improving cardiorenal outcomes are of para-
`mount importance (7).
`The perceived cardiovascular risk with certain
`glucose-lowering agents and evidence that hemoglo-
`bin a1c (HbA1c) lowering per se did not significantly
`reduce cardiovascular risk or mortality led to the
`regulatory requirement for cardiovascular safety tri-
`als for new agents beginning in 2009. Before the
`EMPA-REG OUTCOME (Empagliflozin Cardiovascular
`Outcome Event Trial in Type 2 diabetes Mellitus Pa-
`tients) trial, antihyperglycemic agents were believed
`to prevent or delay the development of microvascular
`complications, but were not able to reduce major
`adverse cardiovascular events. Since December 2008,
`the U.S. Food and Drug Administration (FDA) regu-
`latory guidance for industry mandated cardiovascular
`outcome trials (CVOTs) for cardiovascular safety of
`novel antidiabetic agents to ensure their cardiovas-
`cular safety. This statute is met by blinding central
`adjudication of CVD events and inclusion of high-risk
`subjects such as those with advanced age, advanced
`CVD, and kidney disease. Medications must also be
`studied for 2 years or approximately 15,000 patient-
`years. In this setting, studies that evaluate novel
`medications for T2DM are well-positioned to evaluate
`cardiovascular risk, resulting in a surge of data on
`managing patients with both T2DM and CVD. Since
`
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`1958
`
`Wilcox et al.
`Agents for Cardiovascular Care
`
`J A C C V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6– 7 4
`
`T A B L E 1 SGLT2i Cardiovascular Outcome Trials
`
`Median follow-up, yrs
`Mean age, yrs
`Female, %
`Mean BMI, kg/m2
`HbA1c, %
`Baseline metformin, %*
`Baseline eGFR†
`eGFR† <60 ml/min/1.73 m2, %
`Prior CVD, %
`Prior HF, %
`3P-MACE
`CV death
`MI
`Stroke
`CV death or HHF
`All-cause mortality
`HHF
`Renal events‡
`Other primary outcome§
`
`EMPA-REG
`Empagliflozin
`(n ¼ 7,020)
`3.1
`63
`29
`30.6
`8.1
`73
`74
`26
`99
`10
`0.86 (0.74–0.99)
`0.62 (0.49–0.77)
`0.87 (0.70–1.09)||
`1.18 (0.89–1.56)||
`0.66 (0.55–0.79)
`0.68 (0.57–0.82)
`0.65 (0.50–0.85)
`0.61 (0.53–0.70) (103)
`NR
`
`CANVAS Program
`Canagliflozin
`(n ¼ 10,142)
`2.4
`63
`36
`32.0
`8.3
`77
`77
`20
`66
`14
`0.86 (0.75–0.97)
`0.87 (0.72–1.06)
`0.89 (0.73–1.09)||
`0.87 (0.69–1.09)||
`0.78 (0.67–0.91)
`0.87 (0.74–1.01)
`0.67 (0.52–0.87)
`0.60 (0.47–0.77)
`NR
`
`DECLARE
`Dapagliflozin
`(n ¼ 17,160)
`4.2
`64
`37
`32.1
`8.3
`82
`85
`7
`41
`10
`0.93 (0.84–1.03)
`0.98 (0.82–1.17)
`0.89 (0.77–1.01)
`1.01 (0.84–1.21)
`0.83 (0.73–0.95)
`0.93 (0.82–1.04)
`0.73 (0.61–0.88)
`0.53 (0.43–0.66)
`NR
`
`CREDENCE
`Canagliflozin
`(n ¼ 4,401)
`2.6
`63
`34
`31.3
`8.3
`66
`56
`59
`50
`15
`0.80 (0.67–0.95)
`0.78 (0.61–1.00)
`NR
`NR
`0.69 (0.57–0.83)
`0.83 (0.68–1.02)
`0.61 (0.47–0.80)
`0.66 (0.53–0.81)
`0.70 (0.59-0.82)
`
`DAPA-HF
`Dapagliflozin
`(n ¼ 4744)
`1.5
`66
`23
`28.2
`NR
`73
`65
`40
`
`NR
`0.82 (0.69–0.98)
`NR
`NR
`0.75 (0.65-0.85)
`0.83 (0.71-0.97)
`0.70 (0.59–0.83)
`0.71 (0.44-1.16)
`0.74 (0.65-0.85)
`
`Values are hazard ratio (confidence interval) unless otherwise indicated. *Average of entire study group (treatment and control). †eGFR units ml/min/1.73 m2. ‡Definition varied across trials.
`§Primary outcome DAPA-HF: heart failure hospitalization or urgent visit for heart failure resulting in intravenous therapy, cardiovascular death. Primary outcome CREDENCE: ESRD (dialysis,
`transplantation, or a sustained estimated GFR of < 15 ml/min), doubling serum creatinine, death from renal or CV causes. ||Fatal or nonfatal outcome. Bold as follows: Bold indicates outcomes
`meeting prespecified significance of P <0.05.
`3P-MACE ¼ 3-point major adverse cardiac events; BMI ¼ body mass index; CANVAS ¼ Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes; CREDENCE ¼ Canagliflozin and
`Renal Outcomes in Type 2 Diabetes and Nephropathy; CV ¼ cardiovascular; CVD ¼ cardiovascular disease; DAPA-HF ¼ Dapagliflozin in Patients with Heart Failure and Reduced Ejection
`Fraction; DECLARE ¼ Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes; eGFR = estimated glomerular filtration rate; EMPA-REG ¼ Empagliflozin, Cardiovascular Outcomes, and
`Mortality in Type 2 Diabetes; HbA1c ¼ hemoglobin A1c; HF ¼ heart failure; HHF ¼ hospitalization for heart failure; NR ¼ not reported; SGLT21 ¼ sodium glucose cotransporter 2 inhibitor.
`
`GLP1RA has rightfully prompted the diabetes and
`cardiovascular communities to incorporate these new
`classes of agents into clinical management guidance.
`
`BIGUANIDES
`
`Metformin has remained first-line treatment for T2DM
`due to its efficacy, safety, duration of evidence,
`affordability, and limited side-effect profile. The
`biguanide was developed in the 1920s, before the era
`of target-specific drug development; therefore, exact
`cellular mechanisms of metformin remain ill-defined.
`Metformin has been used in Europe since the 1950s
`whereas phenformin, another biguanide, was pri-
`marily used in the United States until metformin was
`approved in 1990 (12). Metformin lowers blood glucose
`by increasing peripheral uptake of glucose and
`decreasing hepatic glucose production, likely via in-
`hibition of mitochondrial enzymes. Metformin’s role
`in inflammatory pathways may also underpin the non-
`metabolic benefits of the drug (13). In the last decade,
`our understanding of metformin’s mechanism has
`expanded from alterations in liver metabolism leading
`to improvements in glycemic control, to a much more
`
`complex picture reflecting its multiple modes of ac-
`tion, including a key role in the gut (13).
`Data on the cardiovascular impact of metformin
`rely heavily on the United Kingdom Prospective Dia-
`betes Study (UKPDS). In the 1970s, the study group
`assigned a total of 1,704 overweight adults with T2DM
`aged 25 to 65 years to a number of glucose control
`strategies: diet only versus intensive control with
`metformin only. The metformin control group was
`then compared to chlorpropramide, glibenclamide, or
`insulin, and followed for changes in metabolic, renal,
`and cardiovascular outcomes over 10 years (14).
`Compared to diet alone, in the group of 342 newly
`diagnosed overweight patients with T2DM treated
`with metformin, MI was reduced by 39%, coronary
`deaths by 50%, stroke by 41%, and all-cause mortality
`by 36% after a median 10.7 years (14). These re-
`ductions in major CVD events with diet plus metfor-
`min were greater than diet with either a sulfonylurea
`or insulin. Additional follow-up for 8 to 10 years when
`all patients received intensive therapy found that the
`reduced risk of MI and mortality with initial metfor-
`min therapy persisted over time compared with early
`treatment using a sulfonylurea or
`insulin (15).
`
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`J A C C V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6 – 7 4
`
`Wilcox et al.
`Agents for Cardiovascular Care
`
`1959
`
`F I G U R E 1 Algorithm for Choosing Pharmacologic Therapy for Type 2 Diabetes
`
`SGLT2i
`Empagliflozin
`Canagliflozin
`
`GLP1RA
`Liraglutide
`Semaglutide
`
`Type 2
`Diabetes
`Mellitus
`
`Metformin
`
`Hemoglobin
`a1C above
`goal
`
`Cost
`Limitations
`
`Weight Loss
`
`ASCVD
`
`Renal
`Disease
`
`Heart Failure
`
`GLP1RA
`
`SGLT2i
`
`SGLT2i
`
`SGLT2i
`
`Sulfonylureas
`or
`TZD
`
`GLP1RA
`
`GLP1RA
`
`In patients with type 2 diabetes on metformin with hemoglobin a1c above goal, second-line therapy depends on cost limitations, comorbid disease, and desire for
`weight loss. ASCVD ¼ atherosclerotic cardiovascular disease; GLP1RA ¼ glucagon-like peptide 1 receptor agonist; SGLT2i ¼ sodium glucose cotransporter 2 inhibitor;
`TZD ¼ thiazolidinedione.
`
`Metformin use was also associated with fewer hypo-
`glycemic episodes and less weight gain.
`However, any conclusions drawn from the UKPDS
`data is tempered by major limitations in study design.
`For example, the study population was low risk and
`excluded recent acute coronary syndrome, HF, or
`microvascular disease events and was performed in the
`absence of contemporary lipid-lowering therapy with
`statins. Moreover, compared to recent CVOTs, the
`UKPDS study population was small, incompletely blin-
`ded, and lacked placebo-control. Additional data on the
`cardiovascular benefits of metformin relative to placebo
`remain sparse, limited to meta-analyses with wide con-
`fidence intervals (CIs) for most cardiovascular endpoints
`(16). The VA-IMPACT trial is attempting to fill this gap by
`evaluating cardiovascular outcomes in patients with
`pre-diabetes and established CVD treated with metfor-
`min versus placebo (NCT02915198).
`Patients with chronic kidney disease (CKD) are also
`under-represented in the evidence base of metformin
`
`use for CVD risk reduction in T2MD. Per current FDA
`guidelines, metformin is
`contraindicated at an
`estimated
`glomerular
`filtration
`rate
`(eGFR)
`<30 ml/min/1.73 kg/m2, and initiation is not recom-
`mended at an eGFR between 30 and 45 ml/min/1.73 kg/
`m2 (17). For patients tolerating the drug who experi-
`ence a decreases in glomerular filtration rate (GFR),
`new guidelines state reduced renal dosing is a safe
`option (17,18). This was supported in a post hoc anal-
`ysis of SAVOR-TIMI 53 (Saxagliptin and Cardiovascular
`Outcomes in Patients with Type 2 Diabetes Mellitus–
`Thrombolysis In Myocardial Infarction 53) participants
`showing that exposure to metformin did not signifi-
`cantly affect cardiovascular outcomes in patients with
`severe CKD (19). Metformin’s major adverse effect is a
`type B lactic acidosis that may develop at the upper
`therapeutic limit of drug dosing, which current evi-
`dence indicates is rare in contemporary practice (20).
`Withholding metformin during “sick days” may miti-
`gate this risk, but trial evidence to support this
`
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`1960
`
`Wilcox et al.
`Agents for Cardiovascular Care
`
`J A C C V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6– 7 4
`
`F I G U R E 2 Selecting Pharmacologic Therapy for Patients With Type 2 Diabetes
`
`Primary Prevention
`No Risk Factors
`
`Primary Prevention
`Risk Factors
`
`Established
`ASCVD, RF, HF, CKD
`
`Evidence Base
`
`ASCVD
`
`ASCVD
`CKD
`HF
`
`Metformin
`
`SGLT2i
`GLP1RA
`With proven CVD
`benefit
`
`Cost:
`Sulfonylureas
`TZDs
`
`DPP4i
`
`Proportion of Population
`
`Increasing Evidence from CVOTs
`
`The evidence base for selecting pharmacologic therapy for patients with type 2 diabetes depends on presence of risk factors, comorbid heart failure,
`atherosclerotic disease, and renal disease. CKD ¼ chronic kidney disease; CVD ¼ cardiovascular disease; CVOT ¼ cardiovascular outcome trial;
`DPP4i ¼ dipeptidyl peptidase 4 inhibitor; HF ¼ heart failure; RF ¼ risk factor; other abbreviations as in Figure 1.
`
`approach is lacking. Metformin was background
`medical therapy for most patients in recent CVOTs,
`further enshrining its use as first-line therapy for most
`patients with T2DM. Given the duration of evidence,
`low cost, favorable safety profile, and background use
`in recent CVOTs, metformin has, until now, remained
`first-line therapy onto which additional agents can be
`considered for cardiovascular risk reduction in T2DM
`(Figure 1). However, new European Society of Cardi-
`ology (ESC)/EASD guidelines recommend initiating
`SGLT2i or GLP1RA monotherapy in drug-naive patients
`with T2DM with established or high risk for CVD (21).
`This recommendation is made despite high prevalence
`(51% to 83%) of baseline metformin use in these trials
`(Table 1).
`
`SULFONYLUREAS
`
`Sulfonylureas have historically been considered
`second-line treatment for T2DM for patients with
`uncontrolled
`hyperglycemia
`on metformin.
`In
`contrast to metformin, sulfonylureas increase blood
`insulin concentration via stimulation of pancreatic
`beta cells. Augmented insulin secretion and sensi-
`tivity can increase risk of hypoglycemia and lead to
`
`weight gain (22). Although sulfonylureas are associ-
`ated with slightly greater upfront reductions in gly-
`cosylated hemoglobin levels (HbA1c, 1% to 1.25%
`reduction) relative to metformin (0.5% to 1.25%) (23)
`in the UKPDS study, after 6 months, reduction in a1c
`levels were similar between groups on either therapy.
`Over 6 years, 54% of patients allocated sulfonylureas
`alone required the addition of insulin to achieve
`the prespecified target of a fasting glucose under
`106 mg/dl (24).
`The UKPDS and ADVANCE trials have shown
`microvascular benefits of sulfonylureas, including a
`reduction in the incidence or worsening of nephrop-
`athy and retinopathy, and no increase in all-cause
`mortality. However, whether these benefits were
`due to sulfonylurea therapy versus an overall
`glucose-lowering effect could not be confirmed (4).
`Since the 1960s, sulfonylureas have been impli-
`cated with increased risk of adverse cardiovascular
`outcomes. The University Group Diabetes Program
`observed increased risk of all cause and cardiovas-
`cular mortality in those treated with the first-
`generation sulfonylurea tolbutamide versus placebo
`(25). The UKPDS study randomized patients to either
`first- (chlorpropamide) or second- (glibenclamide)
`
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`J A C C V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6 – 7 4
`
`Wilcox et al.
`Agents for Cardiovascular Care
`
`1961
`
`T A B L E 2 DPP4i Cardiovascular Outcome Trials
`
`Median follow-up, yrs
`Mean age, yrs
`Female, %
`Mean BMI, kg/m2
`HbA1c, %
`Baseline metformin,* %
`Baseline eGFR†
`eGFR† <60 ml/min/1.73 m2, %
`Prior CVD, %
`Prior HF, %
`3P-MACE
`CV death
`MI
`Stroke
`CV death or HHF
`All-cause mortality
`HHF
`Renal events‡
`
`SAVOR-TIMI 53
`Saxaglipitin (n ¼ 16,492)
`2.1
`65
`33
`31.2
`8.0
`69
`73
`<50 ml/min: 16
`78
`13
`1.00 (0.89–1.12)
`1.03 (0.87–1.22)
`0.95 (0.80–1.12)
`1.11 (0.88–1.39)
`NR
`1.11 (0.96–1.27)
`1.27 (1.07–1.51)
`1.08 (0.88–1.32)
`
`EXAMINE
`Alogliptin (n ¼ 5,380)
`1.5
`61
`32
`28.7
`8.0
`NA
`71
`29
`100
`28
`0.96 (#1.16)
`0.85 (0.66–1.10)
`1.08 (0.88–1.33)||
`0.91 (0.55-1.50)||
`1.00 (0.82–1.21) (42)
`0.88 (0.71–1.09)
`1.07 (0.79–1.46) (42)
`NR
`
`TECOS
`Sitagliptin (n ¼ 14,523)
`3.0
`65
`29
`30.2
`7.2
`81
`75
`NR
`100
`18
`0.98 (0.89–1.08)
`1.03 (0.89–1.19)
`0.95 (0.81–1.11)
`0.97 (0.79–1.19)
`1.02 (0.90–1.15)
`1.01 (0.90–1.14)
`1.00 (0.83–1.20)
`NR
`
`CARMELINA
`Linagliptin (n ¼ 6,979)
`2.2
`66
`37
`31.4
`8.0
`54
`55
`62
`57
`27
`1.02 (0.89–1.17)
`0.96 (0.81–1.14)
`1.12 (0.90–1.40)§
`0.91 (0.67–1.23)§
`NR
`0.98 (0.84–1.13)
`0.90 (0.74–1.08)
`1.04 (0.89–1.22)
`
`CAROLINA
`Linagliptin vs.
`Glimepiride (n ¼ 6,033)
`5.9
`64
`40
`30.1
`7.2
`83
`77
`19
`42
`4
`0.98 (0.84–1.13)
`1.00 (0.81–1.24)
`1.03 (0.82-1.29)§
`0.86 (0.66–1.12)§
`1.00 (0.84–1.20)
`0.91 (0.78–1.06)
`1.21 (0.92–1.59)
`NR
`
`Values are hazard ratio (confidence interval) unless otherwise indicated. *Average of entire study group (treatment and control). †eGFR units ml/min/1.73 m2. ‡Definition varied across trials.
`§Fatal or nonfatal outcome. ||Nonfatal outcome.
`CARMELINA ¼ Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk; CAROLINA ¼ Effect of Linagliptin vs
`Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes; DPP4i ¼ dipeptidyl peptidase 4 inhibitor; EXAMINE ¼ Alogliptin after Acute Coronary Syndrome in
`Patients with Type 2 Diabetes; SAVOR-TIMI 53 ¼ Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus-Thrombolysis In Myocardial Infarction 53; TECOS ¼ Effect
`of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes; other abbreviations as in Table 1.
`
`generation sulfonylureas, but did not report differ-
`ences in outcomes between the two. Subsequent data
`have been inconclusive, with observational studies
`corroborating these results while underpowered ran-
`domized control trials have not (26). A recent meta-
`analysis identified selected observational studies
`comparing only second- and third-generation sulfo-
`nylureas to metformin, most of which evaluated the
`outcome of death. After excluding studies
`for
`misclassification or other biases, the relative risk of
`cardiovascular
`events with
`sulfonylureas was
`consistently elevated (odds ratio range: 1.16 to 1.55)
`compared to metformin, with the exception of one
`trial comparing sulfonylurea plus metformin to met-
`formin alone, which found no difference in all-cause
`mortality (26). The recently published CAROLINA
`trial comparing second-generation sulfonylurea gli-
`mepiride to linagliptin (a DPP4i) found no differences
`for incidence of nonfatal MI, nonfatal stroke, and CVD
`during a median of 6 years (27). As discussed below, a
`large body of evidence has supported the cardiovas-
`cular safety of the entire class of DPP4i. Taken in this
`context, the findings of non-inferiority of glimepiride
`in CAROLINA provide reassuring evidence for car-
`diovascular safety. Overall, the sulfonylurea data
`indicate that second- and third-generation agents,
`such as glimepiride,
`likely have a
`reassuring
`
`cardiovascular safety profile similar to that of newer
`glucose-lowering therapies such as linagliptin. Trials
`have not shown the cardiovascular benefit of sulfo-
`nylureas. Given their adverse side-effect profile, they
`should be reserved for a select group of patients in
`whom medications with cardiovascular benefit, dis-
`cussed below, are not an option (Figure 2).
`Patients older than 75 years are poorly represented
`in sulfonylurea trials, with a mean age of 57 years in a
`large meta-analysis of 37,650 patients using sulfo-
`nylureas (26). However, because of the known risk of
`hypoglycemia, most expert
`consensus opinions,
`including those issued by the ADA and the Choosing
`Wisely campaign, recommend against sulfonylurea
`use in older, frail patients (28,29). Similarly, in pa-
`tients with advanced CKD stage 3 or higher, first-
`generation sulfonylureas should be avoided due to
`risk of prolonged hypoglycemia from active metabo-
`lites (28).
`
`GLITAZONES
`
`Thiazolidinediones (glitazones) (Figure 1) are nuclear
`peroxisome proliferator–activated receptor agonists
`that increase insulin sensitivity in muscle, adipose
`tissue, and liver (30). Similar to metformin, glitazones
`may have anti-inflammatory properties and have
`
`Novo Nordisk Exhibit 2601
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`1962
`
`Wilcox et al.
`Agents for Cardiovascular Care
`
`J A C C V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6– 7 4
`
`T A B L E 3 GLP1RA Cardiovascular Outcome Trials
`
`ELIXA
`Lixisenatide
`(n ¼ 6,068)
`2.1
`60
`30
`30.2
`7.7
`76
`
`LEADER
`Liraglutide
`(n ¼ 9,340)
`3.8
`64
`36
`NR
`8.7
`73
`
`SUSTAIN-6
`Semaglutide
`(n ¼ 3,297)
`2.1
`54
`39
`NR
`8.7
`76
`
`EXSCEL
`Exenatide
`Every Week
`(n ¼ 14,752)
`3.2
`62
`38
`NR
`8.1
`74
`
`HARMONY
`Albiglutide
`Every Week
`(n ¼ 9,463)
`1.6
`64
`31
`32.3
`8.8
`81
`
`76
`75
`75
`76
`18
`28.5
`23
`23
`73
`83
`81
`100
`16
`24
`18
`22
`0.87 (0.78–0.97) 0.74 (0.58–0.95)
`0.91 (0.83–1.00)
`1.02 (0.89–1.17)
`0.78 (0.66–0.93) 0.98 (0.65–1.48)
`0.88 (0.76–1.02)
`0.98 (0.78–1.22)
`0.97 (0.85–1.10)‡
`0.86 (0.73–1.00)‡ 0.74 (0.51–1.08)§
`1.03 (0.87–1.22)
`0.86 (0.71–1.06)‡ 0.61 (0.38–0.99)§ 0.85 (0.70–1.03)‡
`1.12 (0.79–1.58)
`0.85 (0.74–0.97)
`0.94 (0.78–1.13)
`1.05 (0.74–1.50)
`0.86 (0.77–0.97)
`0.87 (0.73–1.05)
`1.11 (0.77–1.61)
`0.94 (0.78–1.13)
`0.96 (0.75–1.23)
`0.81 (0.66–0.99) (104) 0.78 (0.67–0.92) 0.64 (0.46–0.88) 0.85 (0.73–0.98) (105)
`0.7 (0.9–0.5)
`2.3 (2.5–2.0)
`2.9 (2.3–3.5)/4.3
`1.3 (1.1–1.4)
`(3.8–4.9)#
`
`79
`23
`100
`20
`0.78 (0.68–0.90)
`0.93 (0.73–1.19)
`0.75 (0.61–0.90)‡
`0.86 (0.66–1.14)‡
`0.95 (0.79–1.16)
`NR
`NR
`0.83 (0.6–1.1) at
`16 months
`
`Median follow-up, yrs
`Mean age, yrs
`Female, %
`Mean BMI, kg/m2
`HbA1c, %
`Baseline metformin,
`%*
`Baseline eGFR†
`eGFR† <60, %
`Prior CVD, %
`Prior HF, %
`3P-MACE
`CV death
`MI
`Stroke
`All-cause mortality
`HHF
`Renal events||
`Weight loss¶
`
`REWIND
`Dulaglutide
`Every Week
`(n ¼ 9,901)
`5.4
`66
`46
`32.3
`7.3
`57
`
`PIONEER-6
`Semaglutide Oral
`(n ¼ 3,182)
`1.3
`66
`32
`32.3
`8.2
`51
`
`74
`75
`27
`22
`85
`32
`NR
`9
`0.88 (0.79–0.99)
`0.79 (0.57–1.11)
`0.91 (0.78–1.06) 0.49 (0.27–0.92)
`0.96 (0.79–1.16)§
`1.18 (0.73–1.90)§
`0.76 (0.61–0.95)§ 0.74 (0.35–1.57)§
`0.90 (0.80–1.01)
`0.51 (0.31–0.84)
`0.93 (0.77–1.12)
`0.86 (0.48–1.55)
`0.85 (0.77–0.93)
`NR
`1.5 (1.3–1.7)
`3.6
`
`Values are hazard ratio (confidence interval) unless otherwise indicated. *Average of entire study group (treatment and control). †eGFR units ml/min/1.73 m2. ‡Fatal or nonfatal outcome. §Nonfatal outcome.
`||Definition varied across trials. ¶Kilogram difference from placebo, 95% confidence interval. #0.5 mg dose/1 mg dose.
`ELIXA ¼ The Evaluation of Lixisenatide in Acute Coronary Syndrome; EXSCEL = Exenatide Study of Cardiovascular Event Lowering; GL1PRA ¼ glucagon-like peptide 1 receptor agonist;
`HARMONY ¼ Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease; LEADER ¼ Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes; PIONEER ¼ Efficacy
`and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only; REWIND ¼ Dulaglutide and cardiovascular outcomes in type 2 diabetes; SUSTAIN
`6 ¼ Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes; other abbreviations as in Table 1.
`
`shown salutary vascular effects in preclinical trials
`(31). In clinical trials, however, preclinical cardiovas-
`cular benefits were not sustained, and increased
`hospitalizations for HF and fractures were observed.
`Published in 2005, the PROACTIVE trial prospectively
`enrolled 5,328 patients with T2DM and established
`CVD to treatment with pioglitazone versus placebo
`(Figure 3). Four years later, the RECORD was pub-
`lished, which trial enrolled 4,447 patients with un-
`controlled
`T2DM
`on
`maximum
`tolerated
`monotherapy for at least 2 months and assigned them
`to rosiglitazone versus sulfonylurea or metformin. In
`PROACTIVE, there was no difference in the composite
`primary outcome of death, nonfatal MI, nonfatal
`stroke, acute coronary syndrome, endovascular or
`surgical
`intervention in the coronary or lower ex-
`tremity arteries, or amputation above the ankle after
`a median follow-up of just under 3 years (hazard ratio
`[HR]: 0.90; 95%; CI: 0.8 to 1.02) (32), with a signal of
`benefit in the pre-specified secondary composite of
`death, nonfatal MI and nonfatal stroke (HR: 0.84;
`95% CI: 0.72 to 0.98). RECORD had a significantly
`longer median follow-up of 5.5 years, and similar to
`PROACTIVE found no difference in the primary
`outcome of cardiovascular hospitalization or CVD
`
`(HR: 0.99; 95% CI: 0.85 to 1.16; p ¼ 0.93) (33). There
`was also no between-group difference in the sec-
`ondary outcomes of cardiovascular mortality with or
`without MI and stroke (mortality HR: 0.84; 95% CI:
`0.59 to 1.18; mortality stroke or MI HR: 0.93; 95% CI:
`0.74 to 1.15).
`Both trials were concerning for an increase in HF
`events for patients in the glitazones treatment arms
`(PROACTIVE 11% vs. 8%, p < 0.0001; RECORD 3.7%
`vs. 1.9%, p ¼ 0.0003, respectively). Although patients
`enrolled in both trials were at high cardiovascular
`risk, patients with symptomatic HF or those receiving
`medications for HF were excluded, making these
`findings more concerning. Moreover, treatment with
`pioglitazone in PROACTIVE trended toward increased
`risk of lower-extremity revascularization (n ¼ 80 of
`2,605 pioglitazone vs. n ¼ 65 of 2,633 placebo; HR:
`1.25; 95% CI: 0.9 to 1.73), and weight gain (þ3.6 kg vs.
`0.4 kg, p < 0.0001). In response to these and other
`data, including a meta-analysis of 42 trials suggesting
`that rosiglitazone was associated with increased risk
`of MI (34), the FDA briefly issued a black box warning
`for cardiovascular risk with rosiglitazone in 2007.
`However, following the results of the RECORD trial
`published in 2009, this warning was reconsidered and
`
`Novo Nordisk Exhibit 2601
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`J A C C V O L . 7 5 , N O .
`
`1 6 , 2 0 2 0
`
`A P R I L 2 8 , 2 0 2 0 : 1 9 5 6 – 7 4
`
`Wilcox et al.
`Agents for Cardiovascular Care
`
`1963
`
`2008: FDA mandates CVOT
`for all novel antidiabetic
`agents
`
`2016: FDA issues warnings
`of risk of heart failure
`hospitalization for
`saxagliptin and alogliptin
`
`1998:
`UKPDS 34
`Trial
`published
`
`2005:
`First GLP1RA
`approved for
`T2DM
`
`2012:
`First CVOT
`for DPP4i
`
`2015:
`First CVOT
`for GLP1RA
`
`Future:
`CVOTs for
`GLP1RA &
`SGLT2i for
`primary
`prevention of
`CVD and HF*
`
`□ □□
`□ □ o
`
`F I G U R E 3 Timeline of Pharmacologic Agents Used in Type 2 Diabetes
`
`1836:
`Phlorizin
`isolated
`from tree
`bark
`
`1956:
`First
`sulfonylurea
`approved for
`T2DM
`
`1984:
`Second
`gen