Case Study: Role of Sodium-Glucose Cotransporter 2 Inhibitors in Managing Residual Cardiovascular Risk

The following case involves a 58-yearold gentleman with a history of complex cardiovascular disease and several cardiometabolic risk factors as listed below.

Pertinent PMHx:
1. Premature and progressive coronary artery disease (CAD) with anterior myocardial infarction (MI) at age 45 requiring four vessel coronary artery bypass surgery (CABG) and stent to the left circumflex artery at age 51
2. Heart failure with reduced ejection fraction (HFrEF) secondary to ischemic and methamphetamine induced cardiomyopathy
    a. The patient is established on guideline directed medical therapy (GDMT) for HFrEF including metoprolol succinate 50mg twice daily, sacubitrilvalsartan 49-51mg twice daily, and spironolactone 25mg daily. He is unable to uptitrate to target HF doses due to                   symptomatic hypotension and episodes of acute kidney injury and hyperkalemia
    b. He is euvolemic on exam, but reports sporadic orthopnea despite taking torsemide 40mg daily.
3. Left ventricular (LV) thrombus in 2018
    a. Never anticoagulated due to ongoing methamphetamine use at that time and patient wishes to avoid anticoagulation
4. Recurrent ventricular tachycardia with an automatic internal cardiac defibrillator (AICD)
5. Severe hypercholesterolemia
    a. Peak low density lipoprotein cholesterol (LDL-C) of 193mg/dL
    b. Meets criteria for familial hypercholesterolemia (FH) by American Heart Association, probable by Dutch Lipid Clinic Criteria (score of 6), and has never undergone genetic testing
    c. Current lipid values on atorvastatin 80mg daily, ezetimibe 10mg daily, and alirocumab 75 mg SubQ every 14 days reveal LDL-C at goal of <55mg/dL, variable triglycerides, and low high-density lipoprotein cholesterol (HDL-C) (see table 1)
6. Type 2 diabetes mellitus (T2DM)
    a. Diagnosed with a hemoglobin A1C (HgbA1C) of 8.8% in 10/2019, reduced to 6.7% with lifestyle interventions and addition of metformin
7. Obesity
8. Hypertension
9. Stage 2-3 chronic kidney disease (CKD)
10. Tobacco use

Physical exam:
Unremarkable including no physical manifestations of FH (i.e., arcus, xanthelasmas, or xanthomas)

Social history:
History of methamphetamine abuse but reports no use since November 2019
Current tobacco abuse (3-5 cigarettes per day) with a 35 year pack history

Family history:
Father – CAD s/p CABG at age 50, died at age 62 from MI
Mother – CAD s/p CABG at age mid-late 40’s, died at 79 for hemorrhage stroke
Sister – MI at age 37 s/p stent placement at age mid 40’s, severe hypercholesterolemia
Brother – MI s/p CABG at age 50 and PCIs in mid-late 50’s, hypercholesterolemia

Medications:
Alirocumab 75mg SubQ every 14 days
Aspirin 81mg daily
Atorvastatin 80mg daily
Ezetimibe 10mg daily
Magnesium 400mg daily
Metformin 1000mg twice daily
Metoprolol succinate 50mg twice daily
Potassium chloride SR 20mEq twice daily
Sacubitril-valsartan 49-51mg twice daily
Spironolactone 25mg daily
Torsemide 40mg daily

He presents for follow-up proud of the positive lifestyle changes accomplished over the past year including dietary changes, adherence to all prescribed medications, and complete abstinence from methamphetamines. He announced
an upcoming quit date for tobacco cessation with an appropriate plan and support structure in place. However he still remains at high risk for subsequent cardiac events – the question remains what risk factor(s) do we address to significantly, yet
realistically, reduce this patient’s residual cardiovascular risk?

Residual Risk
Potential strategies for reducing residual cardiovascular risk are abundant and may include the following targets: intensified LDL-C lowering, triglyceride rich lipoproteins, elevated lipoprotein(a) (Lp[a]), smoking, hypertension, hyperglycemia, thrombotic disorders, obesity and the metabolic syndrome, hepatic steatosis, CKD, inflammation, physical inactivity, and adverse dietary habits.(1) We will focus on the conditions pertinent to this case – residual lipid, thrombotic, and diabetes risks.

For those unable to reach LDL-C goal with gold standard statin therapy and ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce LDL-C an additional 45% - 65%.(2,3) Additionally, bempedoic acid, an adenosine triphosphate-citrate lyase (ACL) inhibitor, lowers LDL-C by up to 25%.(4) While both classes are approved for use in patients with FH or atherosclerotic cardiovascular disease (ASCVD), only PCSK9i have published data and Food and Drug Administration (FDA) approval for ASCVD event risk reduction up to 20%,(2,3) However, many high risk patients continue to suffer from ASCVD events despite optimal LDL-C levels, even at LDL-C <10 mg/dL.(5)

Triglyceride rich lipoproteins are implicated by several lines of data to contribute to residual ASCVD risk, but controversy remains regarding treatment recommendations due to inconsistent cardiovascular outcome results.(6) The Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial (REDUCE-IT) showed a 25% reduction in cardiovascular events after the administration of 4 grams of icosapent ethyl, purified eicosapentaenoic acid (EPA), in a high-risk population with elevated
triglycerides, despite only a modest reduction in triglyceride levels.(7) This finding was not replicated with mixed EPA and docoseahexaenoic acid (DHA) omega-3 fatty acids.(8)

Antiplatelet treatment, predominantly with low dose aspirin, is essential for secondary prevention of ASCVD. In patients with stable ASCVD, attempts at intensifying the antithrombotic strategy (i.e., aspirin + other antiplatelets and/or anticoagulants) has yielded further risk reduction but at the expense of increased bleeding risk.(9) The combination that appears to have the optimal benefit : risk ratio, is inhibition of both the platelet and coagulation cascade with aspirin 100mg daily + rivaroxaban
2.5mg twice daily as demonstrated in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial.(10) However, antithrombotic intensification has not been established as a routine strategy in targeting residual risk within clinical practice.

Metformin remains the mainstay for initial treatment of T2DM. But with the serendipitous discovery of two new classes of medications, glucagon-like peptide 1 receptor agonist (GLP-1 RA) and sodiumglucose cotransporter 2 inhibitor (SGLT2i), the treatment paradigm for managing T2DM shifted substantially towards a focus on cardiovascular risk reducing therapies and away from attainment of specific HgbA1C goals.(11) These sentiments are highlighted by professional organizations now recommending use of GLP-1 RA or SGLT2i as add on therapy after metformin in patients with or at high risk for cardiovascular disease and even without a metformin pre-requisite.(11,12)

SGLT2i Mechanisms
SGLT2 is a transport protein found in the proximal convoluted tubule and is responsible for reabsorption of >90% of the glucose filtered at the glomerulus. SGLT2i block filtered glucose reabsorption leading to increased glycosuria.(13) This effect results in decreased plasma glucose, body mass, visceral fat, and oxidative stress. The cardiovascular and renal benefits derived from SGLT2i are not solely due to glycemic control but also from an array of mechanisms leading to reduced plasma volume, systemic blood pressure, neurohormonal stimulation, and improved natriuresis, vascular function, metabolic efficiency, and changes in tissue sodium handling.

SGLT2i Data
A meta-analysis incorporating data from three clinical trials, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin Cardiovascular Assessment Study (CANVAS Program), and The Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58), demonstrated the use of SGLT2i in patients with T2DM reduced the risk of hospitalizations for heart failure by 31% (HR 0.69 [95% CI 0.61 – 0.79], p < 0.0001) and progression of renal disease by 45% (HR 0.55 [95% CI 0.48 – 0.64], p=0.0001).(14) The report also showed a more modest but significant reduction in major adverse cardiovascular events (MACE) in patients with established ASCVD (HR 0.89 [95% CI 0.83-0.96], p=0.0014).(14)

Another meta-analysis incorporating data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trials further emphasized the role of SGLT2i in patients with HFrEF on reducing first hospitalization for heart failure (HR 0.74 [95% CI 0.68 - 0.82], p<0.0001), improvement of renal outcomes (HR 0.62 [95% CI 0.43 - 0.90], p=0.013), and decreasing cardiovascular death (HR 0.87 [95% CI 0.77 - 0.98], p=0.018). Furthermore, these benefits prevailed irrespective of the presence or absence of T2DM.(15)

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that canagliflozin reduced advers renal events, defined as a composite of end stage renal disease, doubling of baseline serum creatinine, or death from renal or ASCVD (HR 0.70 [95% CI 0.59-0.82], p=0.00001) among patients with T2DM and established CKD.(16) Furthermore, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial demonstrated use of dapagliflozin in established CKD patients was associated with less progression of CKD, renal mortality, or CVD mortality (HR 0.61 [95% CI 0.51-0.72], p<0.001). This effect held true irrespective of T2DM status.(17)

In the recent Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS-CV), a fourth SGLT2i, ertugliflozin, demonstrated noninferiority to placebo for primary composite outcome of MACE in patients with T2DM and established ASCVD; however, it was superior for reducing hospitalizations for heart failure.(18) Sotagliflozin, a combined SGLT1 and SGLT2 inhibitor, recently showed consistent cardio-renal benefits in a population with T2DM + CKD or acute heart failure.(19,20)

The three most common SGLT2i in the United States – empagliflozin, dapagliflozin, and canagliflozin – share two common indications:

- Adjunct to diet and exercise to improve glycemic control in adult patients with T2DM
- Reduction of risk of cardiovascular events in adult patients with T2DM with and without established cardiovascular disease

More specifically, dapagliflozin is approved for reducing the risk of cardiovascular death and hospitalization for heart failure in adult patients with NYHA class II-IV HFrEF. Canagliflozin also has a specific indication for reducing the risk of endstage kidney disease and doubling of serum creatinine in adults with T2DM and diabetic nephropathy with albuminuria. Furthermore, there are several ongoing large clinical trials examining other potential clinical benefits of SGLT2i (Table 2).

Adverse events of SGLT2i reported in clinical trials include the following:

- Urinary tract and genital infections, most commonly genital mycotic infections(21)
- Fournier’s gangrene leading to FDA warning, although association is unclear(22)
- Hypotension due to osmotic diuresis and intravascular volume contraction(23)
- Risk of euglycemic diabetic ketoacidosis(24)
- Higher incidence for bone fractures, although results are inconclusive(25)
- Risk of lower limb amputations, though the FDA has recently removed a black box warning for this risk(26)

Of these side effects, infectious complications are the most prevalent; however, SGLT2i tend to be well tolerated among the general population. Also worth mentioning, the SGLT2i class are oral, once daily medications, traversing pill burden and parenteral adherence issues. In our patient’s case, all of the abovementioned drug classes possess potential to reduce residual cardiovascular risk but require careful attention to shared decision making based on his comorbidities, risk for side effects, modulation of cardiovascular risk factors, affordability, patient preference, and overall benefit. Targeting further LDL-C control would reduce his risk but the magnitude of benefit would likely be inferior to other risk reducing therapies - for example, lowering LDL-C to zero
would predict roughly a 15% risk reduction in ASCVD events (27) as compared to a 25% reduction in ASCVD events (7) with addition of icosapent ethyl or an approximate 20-40% reduction in heart failure (15) or renal outcomes (16,17) with adding a SGLT2i. Focusing attention to his triglyceride rich lipoprotein burden is appropriate, but given patient’s concern about pill burden and optimal triglyceride control (<150 mg/dL) historically with more intensive lifestyle interventions, his therapy was not pursued. Intensifying his antithrombotic regimen could afford further risk reduction, but he was not interested given bleeding risk concerns with his heart failure status and fluctuating renal function. Addition of a GLP-1 RA would also seem an appealing option but
given the patients past medical history (specifically HFrEF), the most appropriate therapy appears to be initiation of SGLT2i which possess heart failure, ASCVD, CKD, glycemic, blood pressure, and weight loss benefits - targeting residual risk from multiple vantage points (Figure 1). This is a high risk patient and close monitoring for the side effects mentioned above (specifically hypotension and possible need for diuretic dose adjustments), and repeat lab work (basic metabolic panel in 1 month) is vital to ensure the safe and effective use of SGLT2i therapy.

Summary and Conclusion

With unprecedented progress over the past few years in the treatment of cardiovascular disease, numerous options to target residual cardiovascular risk and improve outcomes are available to high risk patients including: SGLT2i, GLP-1 RA, purified EPA, PCSK9i, ACL inhibitor, and antithrombotic intensification. Fortunately, SGLT2i offers significant cardiovascular and renal benefits among a myriad of patient populations and coupled with a good safety profile, this class of medication is posed to play a vital role in reducing residual cardiovascular risk. 

Disclosure statement:
Ms. Osborn has no financial disclosures to report. Dr. Warden has received honoraria from Akcea Therapeutics. Dr. Nguyen has no financial disclosures to report.

References: 

1. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019;73:e285-e350.
2. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017;376:1713-
1722.
3. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. The New England journal of medicine. 2018;379:2097-2107.
4. Banach M, Duell PB, Gotto AM, Jr., Laufs U, Leiter LA, Mancini GBJ, Ray KK, Flaim J, Ye Z and Catapano AL. Association of Bempedoic Acid Administration With Atherogenic Lipid Levels in Phase 3 Randomized Clinical Trials of Patients With Hypercholesterolemia. JAMA cardiology. 2020;5:1-12.
5. Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, Toth K, Gouni-Berthold I, Lopez-Miranda J, Schiele F, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet (London, England). 2017;390:1962-1971.
6. Nordestgaard BG. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. Circulation research. 2016;118:547-63.
7. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Jr., Juliano RA, Jiao L, Granowitz C, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England journal of medicine. 2019;380:11-22.
8. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular
Risk: The STRENGTH Randomized Clinical Trial. Jama. 2020.
9. Fox KAA, Eikelboom JW, Anand SS, Bhatt DL, Bosch J, Connolly SJ, Harrington RA, Steg PG and Yusuf S. Anti-thrombotic options for secondary prevention in patients with chronic atherosclerotic vascular disease: what does COMPASS add? European heart journal. 2019;40:1466-1471.
10. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. The New England journal of medicine. 2017;377:1319-1330.
11. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2020. Diabetes care. 2020;43:S111-s134.
12. Das SR, Everett BM, Birtcher KK, Brown JM, Januzzi JL, Jr., Kalyani RR, Kosiborod M, Magwire M, Morris PB, Neumiller JJ, et al. 2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type  Diabetes: A Report of the American College of Cardiology Solution Set Oversight Committee. Journal of the American College of Cardiology. 2020;76:1117-1145.
13. Cowie MR and Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nature reviews Cardiology. 2020;17:761-772.
14. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet (London, England). 2019;393:31-39.
15. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet (London, England). 2020;396:819-829.
16. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. The New England journal of medicine. 2019;380:2295-2306.
17. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, et al. Dapagliflozin in Patients with Chronic Kidney Disease. The New England journal of medicine. 2020;383:1436-1446.
18. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. The New England journal of medicine. 2020;383:1425-1435.
19. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. The New England journal of medicine. 2020.
20. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. The New England journal of medicine. 2020.
21. Li D, Wang T, Shen S, Fang Z, Dong Y and Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes, obesity & metabolism. 2017;19:348-355.
22. Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C and Chong WH. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Annals of internal medicine. 2019;170:764-769.
23. Weir MR, Januszewicz A, Gilbert RE, Vijapurkar U, Kline I, Fung A and Meininger G. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich). 2014;16:875-82.
24. Liu J, Li L, Li S, Wang Y, Qin X, Deng K, Liu Y, Zou K and Sun X. Sodium-glucose co-transporter-2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes, obesity & metabolism. 2020;22:1619-1627.
25. Tang HL, Li DD, Zhang JJ, Hsu YH, Wang TS, Zhai SD and Song YQ. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of
randomized controlled trials. Diabetes, obesity & metabolism. 2016;18:1199-1206.
26. Chang HY, Singh S, Mansour O, Baksh S and Alexander GC. Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes. JAMA Intern Med. 2018;178:1190-1198.
27. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R and Simes R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-78.