Practical Implementation as a Discussion with the Patient

Practical Use of SGLT-2 Inhibitors in T2DM:

Clinical Pearls- Perlas de SabiduriaClinical Pearls- Perlas de Sabiduria

Stan Schwartz MD, FACPAffiliate, Main Line Health System

Emeritus, Clinical Associate Professor of Medicine, U of Pa.

stschwar@gmail.com

SGLT-2 Inhibitor Infection Risk: Principles

SGLT-2 Inhibitor Infection Risk: Principles

Increased incidence of urinary tract- 1%

• more common if history of frequent UTI’s or colonized;

•if get one, low risk recurrence

•Rare pyelonephritis/ urosepsis

Genital yeast infections : ~3X

•more common if history of frequent yeast infections

•If get 1, low risk of recurrence

•In men, rare if circumcised; vast majority occurred in uncircumcisedFerrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.

Practical Clinical Approaches To Maximize Benefits and Minimize Risks

Practical Clinical Approaches To Maximize Benefits and Minimize Risks

2 - 4 week visit-

Reinforce benefits they’ve seen; sugar, weight,

well-being; supports future compliance –

Check eGFR, BUN/Cr, K+, BP

If get’s a yeast infection/ UTI – not a reason to stop agent

as repeat infection rate low

Treat yeast infections- clotrimazole topical/vaginal;

diflucan 150 mg and repeat 2 days later

Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; Can Remind Patient :

Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; Can Remind Patient :

• Effective Glycemic Control with No undue risk for hypoglycemia (unless

combined with Insulin or Insulin Secretagogue Therapy) Durable- (2 yr data)

• Reduces HgA1c, Fasting and Postprandial Hyperglycemia1,

• Decreases variability, (related to increased risk of DM complications

• Additive benefits with incretins, esp. GLP-RA’s

• Delay, prevent need for insulin;

• delay, prevent need for fast-analog insulin in T2DM (thus decrease potential hypo-with insulin Rx (85% reduction if avoid fast-analogs)

• Works with FIRST DOSE- patients love to see QUICK benefit1. Blonde L. Am J Manag Care. 2007;13(suppl 2):S36-S40. 2.Blonde L, et al. J Manag Care Pharm. 2006;12(7 suppl A):S2-S12.

Weight Reduction Issues:Weight Reduction Issues:

Schwartz, Fabricatore, Diamond, Weight Reduction in Diabetes, Book Chapter “Diabetes: An Old Disease, a New Insight,” edited by Dr. Ahmad., Landes Bioscience, 2011

1. GLP-1 RA- SGLT-2, best

2. DPP-4 + SGLT-2 = GLP-1 RA( by the way, incretins counteract increased hepatic glucose production seen with SGLT-2 inh.)

1. SGLT-2 Before Pioglitazone- minimize edema and achieve weight loss

4. Keep on SGLT-2 Inhibitor (and other non-insulin Rx) when add Basal Insulin)

5.. If on insulin, decrease 25% as start NCS diet decrease 25% if was having hypoglycemia

add incretin , GLP-1 preferred; decrease adjusted dose 25% add SGLT-2 inh. ; decrease adjusted dose 20%

can add pioglitazone, metformin, if necessary May be able to stop bolus and even basal insulin, lose additional weight, avoid hypoglycemia

Thus Logic for SGLT-2 Inhibitor with IncretinsThus Logic for SGLT-2 Inhibitor with Incretins

ConclusionsConclusions

• Treat elements of pathophysiology-especially

– Improve Beta Cell Function-reduce glucotoxity, (SGLT-2),

– Use SIDE-BENEFITS of the various agents, (SGLT-2)-

Weight loss, BP control, potentially decrease CV risk

• SGLT-2 inhibitors act by a novel mechanism and are useful in patients who have not achieved goal HbA1c levels

• Research show that SGLT-2 inhibitors lower HbA1c levels and also have the benefit of weight reduction and modest BP improvements in patients with T2DM

• SGLT-2 inhibitors have been generally well tolerated, maybe surprisingly so, with most AEs being mild to moderate

They should be used in a patient-centric approach to the pharmaco-therapy of our patients with Diabetes

We and Our Patients Have Been Blessed with Multiple New, Safer Therapies

for Type II Diabetes

SGLT-2 Inhibitors Newest and Key Class:Logical, Effective, Safe

PRACTICAL APPROACHES CAN MAXIMIZE EFFICACY and SAFETY

Patients are Likely To Live Longer with Less Suffering

Pearl Summary

• The Age at presentation.

• The ‘Severity’ at presentation: •The Slope

•Argues for early discovery/Therapy

Phenotypic Presentation, defined by:

100% − − − − − − − − − − 0% −

Pre-Diabetes = FBS ≥100, PPG≥140

T2D = FBS ≥126, PPG ≥200

I I I I I/ ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Increasing Age

% β−CellFunction

Critical β−CellMass Severity:

Extent of beta cell loss

Slope:Rate of Loss

Age at Presentation:Where gene/env triggers Hyperglycemia

All mechanisms of hyperglycemia start in pre-DM

Pathogenesis of Diabetes

Variable insulitisβ-cell sensitivity to injury

Interactions betweengenes impartingsusceptibility and resistance

Environmentaltriggers andregulators

Immunedysregulation

Pre-diabetes

Overt diabetes

β-ce

ll M

ass

Time

Loss of first-phase

insulin response

Glucose intolerance

Adapted with permission from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221

May be relapsing/remitting

• The Age at presentation = tipping point when the combined Gene Effect Environmental trigger is exposed as phenotypic hyperglycemia.

• The ‘Severity’ at presentation: Reflects the β-cell loss-function/mass- at presentation

• The Slope = Progressive ‘Natural History’ over time ie: = Rate of β-cell loss

Phenotypic Presentation, defined by:

100% − − − − − − − − − − 0% −

Pre-Diabetes = FBS ≥100, PPG ≥140 T2D = FBS ≥126, PPG ≥200

I I I I I/ ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Increasing Age

% β−CellFunction

Critical β−CellMass

Severity:Extent of beta cell loss

Slope:Rate of Loss

Age at Presentation of Hyperglycemia