Role of SGLT2 Inhibitors in Current Treatment Paradigms How does - - PowerPoint PPT Presentation

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Role of SGLT2 Inhibitors in Current Treatment Paradigms How does inhibition of excessive renal glucose absorption improve glycemic control (HbA 1c )? SGLT2 Inhibitors 1 : Reduce increased renal glucose absorption ~150

SLIDE 1

Role of SGLT2 Inhibitors in Current Treatment Paradigms

SLIDE 2

How does inhibition of excessive renal glucose absorption improve glycemic control (HbA1c)?

SLIDE 3

SGLT2 Inhibitors

1◦
: Reduce increased renal glucose

absorption ~150 gm/24 hr

2 ◦
: Reduce glucose toxicity
Improvement in cell function
Improvement in insulin sensitivity

SLIDE 4

A Patient-centered Approach

Adapted from Inzucchi SE, et al. Diabetologia. 2015;58(3):429-42.

Management of Hyperglycemia

More stringent Less stringent HbA1c 7% Patient/Disease Features Risks potentially associated with hypoglycemia and other drug adverse effects Disease duration Life expectancy Important comorbidities Established vascular complications Patient attitude and expected treatment efforts Resources and support system

Low High Newly diagnosed Longstanding Long Short Absent Severe Few/mild Absent Few/mild Severe

Highly motivated, adherent, excellent self- care capacities Less motivated, nonadherent, poor self-care capacities

Readily available Limited Usually not modifiable Potentially modifiable

SLIDE 5

Glucose reabsorption Glucagon secretion

Pathophysiology of Type 2 Diabetes:

Therapies

Hyperglycemia

Insulin secretion

Glucose

production Lipolysis DeFronzo RA. Diabetes. 2009;58(4):773-795.

Neurotransmitter function

Incretin effect Glucose uptake Metformin Metformin Metformin TZDs TZDs TZDs Insulin Insulin GLP-1s GLP-1s GLP-1s DPP-4s DPP-4s Sulfonylureas SGLT2s

SLIDE 6

Diabetes Drugs Impact Multiple Endpoints

Drug BW Hyper- tension Dys- lipidemia

( LDL, HDL, TG)

Hypoglycemia Risk α-glucosidase inhibitors Neutral Improved Neutral/ Improved Low DPP-4 inhibitors Loss/Neutral Neutral Improved Low GLP-1 agonists Loss Improved Improved Low Insulin Gain Neutral* Improved High Meglitinides Gain Neutral Neutral Moderate Metformin Loss/Neutral Neutral Improved Low SGLT2 inhibitors Loss Improved ? Low Sulfonylureas Gain Neutral Variable Moderate TZD Gain Improved Improved Low

Basile JN. J Diabetes Complications. 2013;27(3):280-286. *Hyperinsulinemia is associated with hypertension

SLIDE 7

SGLT2 Inhibitors Reduce Systolic Blood Pressure: Monotherapy

Trial Duration (wks) Baseline (mm Hg) Change from Baseline Canagliflozin1 26 126.7-128.5 100 mg/d

3.3%

300 mg/d

5.0%

Dapagliflozin2 24 NR 5 mg/d

2.3%

10 mg/d

3.6%

Empagliflozin3 90 131.6-131.9 10 mg/d 0.1% 25 mg/d

1.7%

1.Stenlöf K, et al. Diabetes Obes Metab. 2013;15:372-382. 2.Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-24. 3.Ferrannini E, et al. Diabetes Care. 2013;36(12):4015-4021.

SLIDE 8

SGLT2 Inhibitors Increase LDL: Monotherapy

Trial Duration (wks) Baseline (mg/dL) Change from Baseline Canagliflozin1 26 112-120 100 mg/d +2.9% 300 mg/d +7.1% Dapagliflozin2 12 101.2 5 mg/d NR 10 mg/d +2.9% Empagliflozin3 12 66 10 mg/d

0.3%

25 mg/d +2.6%

1.Stenlöf K, et al. Diabetes Obes Metab. 2013;15:372-382. 2.FDA Background Document Dapagliflozin. www.fda.gov. Accessed March 2015. 3.Ferrannini E, et al. Diabetes Care. 2013;36(12):4015-4021.

SLIDE 9

Cardiovascular Outcomes: CV Death, MI, Stroke

Canagliflozin

HR=0.91 (95% CI: 0.68, 1.22)

Dapagliflozin

HR=0.81 (95% CI: 0.59, 1.09)

Inzucchi SE et al. Diab Vasc Dis Res. 2015;12(2):90-100.

SLIDE 10

Renal Impairment Restricts Options

Adapted from Scheen AJ. Expert Opin Drug Metab Toxicol. 2013;9(5):529-550; Alsahli M et al. Mayo Clin Proc. 2014;89(11):1564-71.

Insulin (Rosi) Pioglitazone Repaglinide Linagliptin Alo, Sita, Vildagliptin Saxagliptin Nateglinide Acarbose/Miglitol Sulfonylureas Metformin Dapagliflozin Canagliflozin Empagliflozin Exenatide Liraglutide Glomerular Filtration Rate (mL/min/1.73m2) >60 <60->30 <30 Hemodialysis

Dose reduction Dose reduction Dose reduction Caution dose Caution dose

SLIDE 11

SGLT2 Inhibitors in Renal Insufficiency

eGFR Dapagliflozin Canagliflozin Empagliflozin >60 mL/min/1.73 m2 Up to 10 mg/d Up to 300 mg/d

45-60 mL/min/1.73 m2

Discontinue Up to 100 mg/d

<45 mL/min/1.73 m2

Discontinue Discontinue Discontinue

SLIDE 12

Candidates for SGLT2 Inhibitors

Those who do not tolerate metformin
Lack of glycemic control on metformin

– Addition of SGLT2 inhibitor – Triple combination therapy

Patients desiring weight loss
Good renal function