Assimilating the Evidence in T2DM by Integritas Communications

MANAGING T2DM WITH COMORBID CARDIOVASCULAR DISEASE

CASE 1: Dolores

Regular Follow-up Visit With Endocrinologist • • • • • • • • • •

68-year-old white woman Known T2DM duration: 10 years; HbA1c, 6.6% Taking metformin + glimepiride + linagliptin BMI, 32 kg/m2 BP, 131/80 mm Hg; taking enalapril LDL-C, 90 mg/dL; taking simvastatin + ezetimibe Smoked 1 pack/day for 45 years, trying to quit MI 2 years ago, underwent PCI; taking aspirin daily Fatty liver Had TIA 14 years ago

BMI, body mass index; BP, blood pressure; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.

Epidemiology of CVD in T2DM CVD is the primary cause of morbidity and mortality in diabetes1

2â&#x20AC;&#x201C;4

$37.3

increased risk of CVD in T2DM vs general population1

CV-related spending annually associated with T2DM2

FOLD

CVD, cardiovascular disease. 1. King RJ, Grant PJ. Herz. 2016;41(3):184-192; 2. ADA. Diabetes Care. 2020;43(suppl 1):S11-S134.

BILLION

Is Your Patient at Risk for CVD? ACC/AHA ASCVD Risk Calculator1 • Estimate 10-year risk – Does not account for duration of diabetes or complications

Risk Factors2 • Advancing age • Increased total serum, non-HDL-C, and LDL-C levels • Low HDL-C levels • Hypertension • CKD • Smoking • Family history of ASCVD

Dolores has increased risk for future CV events due to: • T2DM and established CVD • LDL-C above target despite treatment • Smoking • Hypertension • Obesity

ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; HDL-C, high-density lipoprotein cholesterol. 1. ADA. Diabetes Care. 2020;43(suppl 1):S111-S134; 2. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.

ADA Treatment Algorithm in Patients With T2DM and CVD First-line therapy: metformin + lifestyle change

Consider independently of baseline A1c or individualized A1c target Established ASCVD or high ASCVD risk Preferably GLP-1 RA with proven CVD benefit OR SGLT2 inhibitor with proven CVD benefit if eGFR is adequate

If HbA1c above target If further intensification is required or patient cannot tolerate GLP-1 RA or SGLT2 inhibitor: Consider adding SGLT2 inhibitor with proven CVD benefit in patients on GLP-1 RA, DPP-4 inhibitor if not on GLP-1 RA, basal insulin, TZD, or SU

• Metformin + glimepiride + linagliptin • HbA1c, 6.6% • BP, 131/80 mm Hg; taking enalapril • LDL-C, 90 mg/dL; taking simvastatin + ezetimibe • MI 2 years ago, underwent PCI • Had TIA 14 years ago

ADA, American Diabetes Association; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2, sodiumglucose cotransporter-2; SU, sulfonylurea; TZD, thiazolidinedione. ADA. Diabetes Care. 2020;43(suppl 1):S98-S110.

AACE/ACE Glycemic Control Algorithm Lifestyle Therapy and Ongoing Glucose Monitoring Independent of glycemic control, if established or high ASCVD risk and/or CKD, recommend SGLT2 inhibitor and/or GLP-1 RA

Metformin GLP-1 RA SGLT-2 inhibitor DPP-4 inhibitor TZD AG inhibitor SU/GLN

Independent of glycemic control, if established ASCVD or high risk, CKD 3, or HFrEF, start longacting GLP-1 RA or SGLT2 inhibitor with proven efficacyc

Possible or few adverse events Use with caution

Symptoms

Triple Therapya

Dual Therapya

GLP-1 RAb,c SGLT-2 inhibitorb,c DPP-4 inhibitor TZD Basal Insulin Colesevelam Bromocriptine QR AG inhibitor SU/GLN

Entry A1c >9.0%

GLP-1 RAb,c SGLT-2 inhibitorb,c TZD Basal Insulin DPP-4 inhibitor Colesevelam Bromocriptine QR AG inhibitor SU/GLN

3 MONTHS

Monotherapya,b

Entry A1c ≥7.5%

3 MONTHS

Entry A1c <7.5%

YES

Dual Therapy

Insulin ± Other Agents

OR Triple Therapy

Add or Intensify Insulin

METFORMIN or other agent

AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; AG, alpha-glucosidase; GLN, glinides; HFrEF, heart failure with reduced ejection fraction; QR, quick release. aOrder of medications is a suggested hierarchy; bIf not at goal in 3 months, proceed to next therapy level; cIf CKD 3, use canagliflozin and if HFrEF, use dapagliflozin. Garber AJ, et al. Endocr Pract. 2020;26(1):107‐139.

SGLT2 Inhibitors

Therapeutic Implications in T2DM-Associated Comorbidities Vasoconstriction afferent arteriole

 Plasma glucose

Proximal tubular cell Lumen

Blood

Na+ SGLT2

Na/K ATPase

K+ Glucose

GLUT2 SGLT2 Inhibitor

Clinical Findings

Na+

 Na+  Glucose

Na+/Cldelivery macula densa

 Body weight  Blood pressure  Plasma uric acid  Albumin excretion Improved renal and CV outcomes

 Uric acid secretion  Glucosuria  Natriuresis

70-100 g glucose excreted/day

SGLT2 transporters are found in S1 and S2 of the proximal tubule ATPase, adenosine triphosphate enzymes; Cl-, chloride; GLUT2, glucose transporter 2; K+, potassium; Na+, sodium. Monica Reddy RP, Inzucchi SE. Endocrine. 2016;53(2):364-372; Sha S, et al. Diabetes Obes Metab. 2011;13(7):669-672; van Bommel EJ, et al. Clin J Am Soc Nephrol. 2017;12(4):700-710; Haas B, et al. Nutr Diabetes. 2014;4(11):e143.

SGLT2 Inhibitor CVOT Patient Populations Sex, male, % Age, median years BMI, median kg/m2 HbA1c, %, mean Median duration of T2DM, years • ≤1 years • >1–5 years • >5–10 years • >10 years ASCVD, % eGFR, % • ≥90 mL/min/1.73 m2 • ≥60 to <90 mL/min/1.73 m2 • <60 mL/min/1.73 m2 UACR, % • Normoalbuminuria (<30 mg/g) • Microalbuminuria (30 to ≤300 mg/g) • Macroalbuminuria (>300 mg/g) aInterquartile

EMPA-REG OUTCOME1 CANVAS Program2,3 DECLARE-TIMI 584,5 VERTIS-CV6 71.2 63.1 30.6 8.07

64.2 63.3 32.0 8.2 13.5

63.1 63.9 32.1 8.3 11.0a

70 64.4 32 8.2 12.9

100

22.4 51.7 25.9

24 55 20.1

39.9 50.9 9.1

24.8 53.3 22

59.5 28.5 10.9

69.8 22.6 7.6

67.9 23.4 6.8

57.8 30.2 9.2

2.7% 15.2% 25.1% 57.0% 100

range. CVOT, cardiovascular outcomes trial; UACR, urinary albumin-to-creatinine ratio. 1. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657; 3. Neuen BL, et al. Circulation. 2018;138(15):1537-1550; 4. Wiviott SD, et al. N Engl J Med. 2019;380(4):347-357; 5. Raz I, et al. Diabetes Obes Metab. 2018;20(5):1102-1110; 6. Cannon CP, et al. Am Heart J. 2018;206:11-23.

CV Event Rates in SGLT2 Inhibitors CVOTs Event Rate Per 1000 Patient Years

Treatment Arm

EMPA-REG OUTCOME1

CANVAS Program2,3

DECLARE-TIMI 584,5

100

Baseline CVD rate, % Population MACE

CV death or hHF

ASCVD

Total

ASCVD

Total

ASCVD

Total

Placebo

43.9

41.3

31.5

41.0

24.2

SGLT2 inhibitor

37.4

34.1

26.9

36.8

22.6

Placebo

30.1

27.4

20.8

23.9

14.7

SGLT2 inhibitor

19.7

21.0

16.3

19.9

12.2

MACE, major adverse cardiovascular event. 1. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657; 3. Mahaffey KW, et al. Circulation. 2018;137(4):323-334; 4. Wiviott SD, et al. N Engl J Med. 2019;380(4):347-357; 5. Zelniker TA, et al. Lancet. 2019;393(10166):31-39.

Primary Outcome

MACE in Patients With T2DM Treated With an SGLT2 Inhibitor 20 18 16 14 12 10 8 6 4 2 0

CANVAS2,b

Composite of CV death, nonfatal MI, or nonfatal stroke HR 0.86 (95.02% CI, 0.74–0.99) P=0.04 for superiority

Patients, %

EMPA-REG1,a

Placebo Empagliflozin 0

Month

20 18 16 14 12 10 8 6 4 2 0

Composite of CV death, nonfatal MI, or nonfatal stroke HR 0.86 (95% CI, 0.75–0.97) P<0.001 for noninferiority P=0.02 for superiority

Placebo Canagliflozin 0

78 104 130 156 182 208 234 260 286 312

Weeks Since Randomization

CrCL, creatinine clearance; HR, hazard ratio; QD, once daily. aN=7020 adults with T2DM, BMI <45 kg/m2, eGFR ≥30 mL/min/1.73 m2, and CVD were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo QD; bN=10,142 adults with T2DM, eGFR >30 mL/min/1.73 m2, and either CVD or multiple risk factors for CVD were randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo QD. 1. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657.

Primary Outcome

MACE in Patients With T2DM Treated With an SGLT2 Inhibitor DECLARE-TIMI 581,a

VERTIS-CV2,b

Cumulative Incidence, %

10.0 7.5 5.0

Placebo Dapagliflozin

2.5 0

aN=17,160

HR 0.93 (95% CI: 0.84–1.03) P=0.17 for superiority P<0.001 for noninferiority

180

360

540

720

Days

900 1080 1260 1440

Patients With Event, %

Composite of CV death, MI, or ischemic stroke

Composite of CV death, nonfatal MI, or nonfatal stroke 20 HR 0.97 (95% CI: 0.85–1.11) P<0.001 for noninferiority

15 10

Placebo Ertugliflozin

5 0

Month

patients aged ≥40 years with T2DM, CrCl ≥60 mL/min, and either CVD or risk factors for CVD were randomized to 10 mg dapagliflozin or placebo QD; bN=8246 patients aged ≥40 years with T2DM and ASCVD of the coronary, cerebral, and/or peripheral arterial systems were randomized to 5 mg ertugliflozin, 15 mg ertugliflozin, or placebo. 1. Wiviott SD, et al. N Engl J Med. 2019;380(4):347-357; 2. Cannon CP, et al. American Diabetes Association Scientific Sessions. Virtual conference; June 16, 2020.

Cumulative Incidence, %

Composite of hHF or CV Death With Dapagliflozin

HR 0.83 (95% CI: 0.73–0.95) P=0.005 for superiority

Placebo

Dapagliflozin

180

360

540

720

900

1080

1260

1440

Days Based on these results, dapagliflozin received FDA approval in October 2019 to reduce the risk of hHF in adults with T2DM and CVD or multiple CVD risk factors. FDA, US Food and Drug Administration. N=17,160 patients aged ≥40 years with T2DM, CrCl ≥60 mL/min, and either CVD or risk factors for CVD were randomized to 10 mg dapagliflozin or placebo QD. Wiviott SD, et al. N Engl J Med. 2019;380(4):347-357.

Adverse Events of Special Interest SGLT2 Inhibitor CVOTs

EMPA-REG1 Empagliflozin

• Significantly more genital infections vs placebo • Significantly less AKI vs placebo • No difference in fractures, DKA, hypoglycemia vs placebo

CANVAS2 Canagliflozin

• Significantly more amputations, fractures, genital infections vs placebo • No difference in DKA, hypoglycemia, AKI vs placebo

DECLARE-TIMI 583 Dapagliflozin

• Significantly more genital infections, DKA vs placebo • Significantly less hypoglycemia, AKI vs placebo • No difference in fractures, amputations vs placebo

AKI, acute kidney injury; DKA, diabetic ketoacidosis. 1. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657; 3. Wiviott SD, et al. N Engl J Med. 2019;380(4):347-357.

Considerations When Prescribing an SGLT2 Inhibitor

• Significantly increased risk of diabetic ketoacidosis in CVOTs (~2-fold) in patients receiving SGLT2 inhibitors1 – Low event rates

• Significant heterogeneity in fracture risk and amputations seen in CVOTs of SGLT2 inhibitors1

– Worse in CANVAS Program but no clear signal in non-CANVAS trials of canagliflozin or in other SGLT2 inhibitors2,3

• Increased frequency of genital mycotic infections, particularly in women4 – Due to increased glucose concentrations in urine

• Reports of Fournier gangrene5

– Assess patients who report pain, erythema, or swelling in genital or perineal area along with fever or malaise

1. Zelniker TA, et al. Lancet. 2019;393(10166):31-39; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657; 3. Mannucci E, Monami M. Drug Saf. 2017;40(2):115-119; 4. Monica Reddy RP, Inzucchi SE. Endocrine. 2016;53(2):364-372; 5. Bersoff-Matcha SJ, et al. Ann Intern Med. 2019;170(11):764-769.

MANAGING T2DM WITH COMORBID HEART FAILURE

CASE 2: Arturo

Referred to New Endocrinologist by Cardiologist • 56-year-old Latino man • Known T2DM duration: 12 years; HbA1c, 7.5%

• Taking bisoprolol 1.25 mg • Taking sacubitril/valsartan 49/51 mg twice daily – Taking metformin + sitagliptin • eGFR, 65 mL/min/1.73 m2 • 14-year history of HTN; BP, 138/94 • UACR, 30 mg/g mm Hg • LDL-C, 75 mg/dL; taking atorvastatin • Diagnosed with HFrEF 4 months ago; 40 mg previous hHF • BMI, 32 kg/m2 – NYHA class II

– NT-proBNP, 475 pg/mL HTN, hypertension; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association.

ADA Treatment Algorithm in Patients With T2DM and HF First-line therapy: metformin + lifestyle change

Consider independently of baseline A1c or individualized A1c target HF Predominates • Particularly HFrEF (LVEF <45%) Preferably SGLT2i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR adequate OR If SGLT2 inhibitor is not tolerated, is contraindicated, or eGFR is less than adequate add GLP-1 RA with proven CVD benefit

If HbA1c above target Avoid TZD in patients with HF, consider adding GLP-1 RA with proven CVD benefit for patients on SGLT2 inhibitor, DPP-4 inhibitor (not saxagliptin) in HF if not on GLP-1 RA, basal insulin, SU LVEF, left ventricular ejection fraction; SGLT2i, SGLT2 inhibitor. ADA. Diabetes Care. 2020;43(suppl 1):S98-S110.

• HbA1c = 7.5% • Metformin + sitagliptin • 14-year history of HTN • Diagnosed with HFrEF 4 months ago; previous hHF • eGFR = 65 mL/min/1.73 m2 • UACR = 30 mg/g

Linking HF and T2DM Reciprocal Relationship Between HF and T2DM1 Lipogenesis

Gluconeogenesis Insulin resistance

Sympathetic activation

Obesity

RAAS 

HF LV restriction, HFpEF Inflammation

Diabetes Sarcomere stiffness

Fibrosis

Pancreatic insufficiency

Hyperglycemia

2–5 FOLD

 risk of HF in T2DM vs general population2 >50% of patients with T2DM and HF had HF-related mortality in a population cohort study3

LV dilation, HFrEF

AGEs, advanced glycation end products; HFpEF, heart failure with preserved ejection fraction; NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system. 1. Maack C, et al. Eur Heart J. 2018;39(48):4243‐4254; 2. Rosano GM, et al. Card Fail Rev. 2017;3(1):52-55; 3. Elder DH, et al. Eur J Heart Fail. 2016;18(1):94-102

Effect of SGLT2 Inhibitors on CV Death and hHF SGLT2 Inhibitor CVOTs

Placebo

Empagliflozin 0

Months

HR 0.78 (95% CI: 0.67–0.91)

Placebo

4 0

Canagliflozin 0

Years

Composite of CV Death and hHF With Dapagliflozin: 4 DECLARE-TIMI 58 6

Cumulative Incidence, %

HR 0.66 (95% CI: 0.55–0.79) P<0.001

Composite of CV Death and hHF With Canagliflozin: 2,3 CANVAS 16

Patients With Event, %

Composite of CV Death and hHF With Empagliflozin: 1 EMPA-REG 15

HR 0.83 (95% CI: 0.73–0.95) P=0.005 for superiority

Placebo 2

Dapagliflozin 0

180 360 540 720 900 1080 1260 1440

Days

1. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657; 3. Neal B, et al. Presented at American Diabetes Association. San Diego, CA, June 9 – 13, 2017. Abstract 3-CT-SY26; 4. Wiviott SD, et al. N Engl J Med. 2019;380(4):347-357.

Effect of SGLT2 Inhibitors on CV Death and hHF Stratified by History of HF Events Per 1000 Patient-Years SGLT2i Placebo

Patients with history of HF: EMPA-REG Outcome 63.6 CANVAS Program 35.4 DECLARE-TIMI 58 45.1 Fixed effects modela Patients with no history of HF: EMPA-REG Outcome 15.5 CANVAS Program 13.6 DECLARE-TIMI 58 8.9 Fixed effects modela

0.72 (0.5-1.04) 0.61 (0.46-0.80) 0.79 (0.63-0.99) 0.71 (0.61-0.84)

24.9 15.2 10.5

0.63 (0.51-0.78) 0.87 (0.72-1.06) 0.84 (0.72-0.99) 0.79 (0.71-0.88)

Favors SGLT2i vs placebo. Zelniker TA, et al. Lancet. 2019;393(10166):31-39.

HR (95% CI)

85.5 56.8 55.5

0.35

aP<0.0001

0.50

1.00

2.50

Favors Placebo

Effect of Dapagliflozin on HF and Mortality Stratified by HF Status DAPA Placebo

Cumulative Incidence Rate, %

HFrEF HF with preserved or unknown EF No HF

25 20

vs vs

HR 0.64 (0.43-0.95) HR 0.72 (0.50-1.04)

HR 0.77 (0.60-0.97)

15 10 5 0

180

360

540

720

Days

900 1080 1260 1440

Reduction in All Cause Mortality for DECLARE-TIMI 58 Patients With HF DAPA Placebo

Cumulative Incidence Rate, %

Reduction in hHF for DECLARETIMI 58 Patients With HF

HFrEF HF with preserved or unknown EF No HF

25 20

vs vs

HR 0.59 (0.40-0.88) HR 1.02 (0.75-1.38)

HR 0.96 (0.84-1.10)

720

900 1080 1260 1440

15 10 5 0

180

360

540

CV death was reduced only in those with HFrEF Kato ET, et al. Circulation. 2019;139(22):2528â&#x20AC;?2536.

Effect of Dapagliflozin on HF in Patients With or Without T2DM DAPA-HF

Dapagliflozin, %

Placebo, %

hHF

47.4

47.5

LVEF

31.2

30.9

T2DM

41.8

eGFR <60 mL/min/1.73m2

40.6

40.7

Dapagliflozin Reduces Incidence of Primary Outcome1

Cumulative Incidence, %

Baseline Characteristic1

30 25 20 15 10 5 0

HR 0.74 (95% CI, 0.65–0.85) P<0.001

Placebo Dapagliflozin 0

Months Since Randomization

In May 2020, dapagliflozin received approval to treat HFrEF in adults with eGFR ≥30 mL/min/1.73 m2 with or without T2DM.2 N=4744 adults with or without T2DM, ejection fraction ≤40%, and NYHA class II-IV HF symptoms were randomized 1:1 to dapagliflozin 10 mg or placebo once daily. Patients were required to receive standard HF device and drug therapy unless contraindicated. The primary outcome was a composite of death from CV causes or worsening HF, defined as either unplanned hospitalization or urgent visit resulting in intravenous therapy for HF. 1. McMurray JJV, et al. N Engl J Med. 2019;381(21):1995‐2008; 2. FDA. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 7, 2020.

Comparison of Dapagliflozin on HF in Patients With T2DM vs Without T2DM 35

Patients With T2DM HR 0.75 (95% CI, 0.63–0.90)

30 25 20

Placebo

Dapagliflozin

10 5 0

Months Since Randomization

Cumulative Percentage, %

• HbA1c, 7.5% • Diagnosed with HFrEF 4 months ago; previous hHF

Cumulative Percentage, %

DAPA-HF

Patients Without T2DM

HR 0.73 (95% CI, 0.60–0.88)

30 25 20 15

Placebo

Dapagliflozin

5 0

Months Since Randomization

N=4744 adults with or without T2DM, ejection fraction ≤40%, and NYHA class II-IV HF symptoms were randomized 1:1 to dapagliflozin 10 mg or placebo once daily. Patients were required to receive standard HF device and drug therapy unless contraindicated. The primary outcome was a composite of death from CV causes or worsening HF, defined as either unplanned hospitalization or urgent visit resulting in intravenous therapy for HF. McMurray JJV, et al. American Heart Association. November 16-18, 2019; Philadelphia, Pennsylvania. Session LBS.01.

Timing of Onset of Benefit Stratified by hHF Cumulative Incidence, %

DAPA-HF

RRR ARR

None

>12 Months Ago

16% 2.1%

28% 4.1%

HR 0.84 (95% CI, 0.69-1.02) N=2493

â&#x2030;¤12 Months Ago 36% 9.9%

HR 0.72 (95% CI, 0.54-0.98) N=950

Placebo Dapagliflozin

12 15 18 21 24

ARR, absolute risk reduction; RRR, relative risk reduction. Sabatine MS, et al. Circulation. 2019;140(25):e973.

Placebo

Dapagliflozin

12 15 18 21 24

Months

HR 0.64 (95% CI, 0.51-0.81) N=1301

P=0.076 P=0.052

Placebo

Dapagliflozin

5 0

12 15 18 21 24

Ongoing Clinical Outcomes Trials in HF Drug

Empagliflozin

Dapagliflozin

Trial

Primary Endpoint

Inclusion Criteria

Estimated Enrollment

EMPERORreduced1

Time to first event of CV death or hHF

Adults with HFrEF and elevated NT-proBNP

3600

EMPERORpreserved2

Time to first event of CV death or hHF

Adults with HFpEF, elevated NT-proBNP, structural heart disease or hHF

5750

Time to first occurrence of Patients â&#x2030;¥40 years with HFpEF CV death, hHF, or urgent and NYHA class II-IV HF visit

4700

DELIVER3

EMPEROR-Reduced met its primary endpoint, a composite of CV death or hHF, in patients with HFrEF and with or without T2DM.4 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03057977. Accessed June 8, 2020; 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03057951. Accessed June 8, 2020; 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03619213. Accessed June 8, 2020; 4. AP. https://apnews.com/ebec8f4342574d36ae02e3fc348fc224. Accessed July 30, 2020.

MANAGING T2DM WITH COMORBID CHRONIC KIDNEY DISEASE

CASE 3: Charlotte

Regular Follow-up Appointment With Endocrinologist • 62-year-old black woman • 15-year history of T2DM; taking basal insulin + metformin; HbA1c, 8% • CKD stage 3; eGFR, 52 mL/min/1.73 m2; UACR, 300 mg/g • 20-year history of HTN; BP, 140/90 mm Hg; taking losartan, amlodipine, hydrochlorothiazide • 1-year history of diabetic neuropathy; taking gabapentin • LDL-C, 88 mg/dL, taking simvastatin • BMI, 30 kg/m2 • Little exercise, somewhat unhealthy diet

Defining Stages of CKD eGFR, mL/min/1.73 m2

UACR <30 mg/g

UACR 30-299 mg/g

UACR ≥300 mg/g

≥90

1 if CKD —

1 Treat

2 Refera

60-89

1 if CKD —

1 Treat

2 Refera

45-59

1 Treat

2 Refera

3 Refer

30-44

2 Refera

3 Refera

3 Refer

15-29

3 Refera

4+ Refer

<15

4+ Refer

aReferring

clinician may wish to discuss with their nephrology service, depending on local arrangements regarding treating or referring patients. Adapted from: ADA. Diabetes Care. 2020;43(suppl 1):S135-S151; Courtesy of Kumar Sharma, MD.

• HbA1c, 8% • CKD stage 3 • eGFR, 52 mL/min/1.73 m2 • UACR, 300 mg/g

Comprehensive Patient Assessment Is Your Patient at Risk for CKD?

• CKD occurs in 20%-40% of patients with diabetes • Annual screening is recommended – UACR • Normal is <30 mg/g

– eGFR • Calculate from serum Cr using CKD-EPI or another validated equation • If <60 mL/min/1.73 m2, evaluate and manage potential complications of CKD

– Serum electrolytes

CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; Cr, creatinine. Adapted from ADA. Diabetes Care. 2020;43(suppl 1):S135-S151.

ADA Treatment Algorithm in Patients With T2DM and CKD First-line therapy: metformin + lifestyle change

Consider independently of baseline A1c or individualized A1c target CKD Predominates • Specifically eGFR 30-60 mL/min/1.73 m2 or UACR >30 mg/g, particularly UACR >300 mg/g Preferably SGLT2i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR adequate OR If SGLT2 inhibitor is not tolerated, is contraindicated, or eGFR is less than adequate add GLP-1 RA with proven CVD benefit

• HbA1c, 8% • Basal insulin + metformin • CKD stage 3; eGFR, 52 mL/min/1.73 m2; UACR, 300 mg/g • 20-year history of HTN • 1-year history of diabetic neuropathy

SGLT2 Inhibitors

Therapeutic Implications in T2DM-Associated Comorbidities Vasoconstriction afferent arteriole Proximal tubular cell Lumen

Blood

Na+ SGLT2

Na/K ATPase

K+ Glucose

GLUT2 SGLT2 Inhibitor

Na+

 Na+  Glucose

Na+/Cldelivery macula densa

 Uric acid secretion  Glucosuria  Natriuresis

• The kidney plays a role in gluconeogenesis: – Renal cortical cells produce glucose – Renal medullary cells use glucose 70-100 g glucose excreted/day

SGLT2 transporters are found in S1 and S2 of the proximal tubule Monica Reddy RP, Inzucchi SE. Endocrine. 2016;53(2):364-372; Sha S, et al. Diabetes Obes Metab. 2011;13(7):669-672; van Bommel EJ, et al. Clin J Am Soc Nephrol. 2017;12(4):700-710; Haas B, et al. Nutr Diabetes. 2014;4(11):e143; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13(1):11-26.

Mechanisms by Which Diabetes May Lead to CKD Mitochondrial dysfunction

Endothelial dysfunction

Renal hypoxia

Inflammation and cytokines

Oxidative stress

Glomerular podocyte dysfunction

Autonomic dysregulation

Hypertension

Insulin resistance/ Hyperinsulinemia

Tubulointerstitial fibrosis Hyperglycemia

Thomas MC, et al. Nat Rev Dis Primers. 2015;1:15018.

Epidemiology of CKD in T2DM Presence of CKD2 • 97% higher risk for all-cause mortality

• 119% higher risk for CV mortality Up to 40% of patients with T2DM develop CKD1

• 87% higher risk of MACE

1. Gheith O, et al. J Nephropharmacol. 2015;5(1):49-56; 2. Papademetriou V, et al. Kidney Int. 2015;87(3):649-659.

Effect of Canagliflozin on Renal Outcomes CREDENCE Study

Composite of ESRD, doubling of serum creatinine, or renal or CV death Patients, %

HR 0.70 (95% CI, 0.59â&#x20AC;&#x201C;0.82) P=0.00001

25 20

Placebo

Canagliflozin

10 5 0

Months

Based on these results, canagliflozin received FDA approval in September 2019 to reduce the risk of ESRD, doubling of serum creatinine, CV death, and hHF in adults with T2DM and diabetic nephropathy with albuminuria. ESRD, end stage renal disease. N=4401 adults (67% white, 5% black) with T2DM and CKD, defined as eGFR 30 to <90 mL/min/1.73 m2 and UACR >300-5000 mg/g, who were taking either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) were randomized to either canagliflozin 100 mg or placebo daily. Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.

Canagliflozin in T2DM, CKD, and Primary or Secondary CV Prevention CREDENCE Study

Patients, %

Composite of ESRD, doubling of serum creatinine, or renal or CV death 20 18 16 14 12 10 8 6 4 2 0

16.4

14.5 10.2

Primary Prevention (n=2181)

15.5

Placebo Canagliflozin

Secondary Prevention (n=2220)

11.1

Total (N=4401)

N=4401 adults with T2DM and CKD, defined as eGFR 30 to <90 mL/min/1.73 m2 and UACR >300-5000 mg/g, who were taking either an ACE inhibitor or ARB were randomized to either canagliflozin 100 mg or placebo daily. Mahaffey KW, et al. Circulation. 2019;140(9):739-750.

Renal and CV Benefits of Canagliflozin Stratified by Baseline HbA1c Outcome

CREDENCE Study

Hazard Ratio (95% CI)

ESRD, doubling of serum creatinine, renal or CV death

HbA1c <7% HbA1c 7% to <8% HbA1c ≥8%

0.63 (0.41-0.98) 0.84 (0.63-1.13) 0.63 (0.51-0.79)

HbA1c <7% HbA1c 7% to <8% HbA1c ≥8%

0.56 (0.31-1.01) 0.74 (0.52-1.06) 0.68 (0.53-0.87)

HbA1c <7% HbA1c 7% to <8% HbA1c ≥8%

0.98 (0.56-1.71) 0.77 (0.55-1.09) 0.76 (0.61-0.96)

CV death or hHF

CV death, MI, or stroke

Favors Canagliflozin

0.5

1.0 1.5

P Value 0.277

0.725

0.633

Favors Placebo

N=4401 adults with T2DM and CKD, defined as eGFR 30 to <90 mL/min/1.73 m2 and UACR >300-5000, who were taking either an ACE inhibitor or ARB were randomized to either canagliflozin 100 mg or placebo daily. Cannon CP, et al. Circulation. 2020;141(5):407‐410.

Renal Benefits of Canagliflozin Stratified by eGFR CREDENCE

Renal-specific composite outcome of ESRD, doubling of serum creatinine, or renal death Hazard Ratio (95% CI) Screening estimated GFR Baseline UACR

30 to <45 mL/min/1.73 m2

0.71 (0.53-0.94)

45 to <60 mL/min/1.73 m2

0.47 (0.31-0.72)

60 to <90 mL/min/1.73 m2

0.81 (0.52-1.26)

≤1000

0.90 (0.54-1.50)

>1000

0.61 (0.49-0.76)

Favors Canagliflozin

0.25

0.5

1.0

2.0

4.0

• HbA1c, 8% • CKD stage 3 • eGFR, 52 mL/min/1.73 m2 • UACR, 300 mg/g

Favors Placebo

N=4401 adults with T2DM and CKD, defined as eGFR 30 to <90 mL/min/1.73 m2 and UACR >300-5000 mg/g, who were taking either an ACE inhibitor or ARB were randomized to either canagliflozin 100 mg or placebo daily. Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.

Effect of SGLT2 Inhibitors on Stroke Stratified by eGFR

Analysis of EMPA-REG, CANVAS, DECLARE, and CREDENCE Stroke Data Hazard Ratio (95% CI) All in

0.96 (0.82-1.12)a

â&#x2030;¥90 mL/min/1.73 m2

1.24 (0.98-1.57)

60 to <90 mL/min/1.73 m2

0.95 (0.80-1.13)

45 to <60 mL/min/1.73 m2

0.92 (0.66-1.28)

<45 mL/min/1.73 m2

0.50 (0.31-0.79) 0.1

0.5

1.0

Favors SGLT2 inhibitor

2.0

4.0

Favors Placebo

No significant effect of SGLT2 inhibitors on stroke occurrence across CVOT and renal trials overall for heterogeneity. Zhou Z, et al. American College of Cardiology. Virtual conference. March 28-30, 2020. Abstract 1422-162. aP=0.01

Ongoing Clinical Outcomes Trials in CKD Trial EMPAKIDNEY1

SGLT2 Inhibitor

Primary Endpoint

Inclusion Criteria

Estimated Enrollment

Empagliflozin

Time to first occurrence of kidney disease progression or CV death

Adults without T2DM, with eGFR ≥20 to <45 mL/min/1.73 m2, or eGFR ≥45 to <90 mL/min/1.73 m2 with UACR ≥200 mg/g

5000

DAPA-CKD was stopped early due to benefit. It met the primary endpoint, a composite of worsening of renal function or risk of death, and all secondary endpoints in patients with and without T2DM.2 In August 2019, US FDA Fast Track Designation was granted to dapagliflozin to delay the progression of renal failure and prevent CV and renal death in patients with CKD.3 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03594110. Accessed June 8, 2020; 2. CathLab Digest. https://www.cathlabdigest.com/content/farxigamet-primary-secondary-endpoints-phase-iii-dapa-ckd-trial-treatment-patients-chronic-kidney-disease. Accessed July 29, 2020; 3. Gavidia M. https://www.ajmc.com/newsroom/fda-grants-fast-track-designation-for-dapagliflozin-to-prevent-kidney-failure-. Accessed June 8, 2020.

Summary • Reciprocal pathophysiologic connections between T2DM and CVD, HF, and CKD • SGLT2 inhibitor CVOT, HF, and renal trial data demonstrate multidimensional efficacy and safety in common T2DM comorbidities • Recently updated guidelines state CVD, HF, and CKD should be considered independently of HbA1c when selecting treatment • Referral and collaboration with nephrologists and cardiologists are necessary to individualize treatment