Practical Implementation as a Discussion with the Patient, Part 2

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

PEARL:Match Patient characteristics to Drug

Characteristics and Vice VersaAACE/ACE: Recommendations Based on A1C

Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

A1C 6.5%-7.5% A1C 7.6%-9.0% A1C > 9.0%If undertreatment

If drugnaive

Insulin plusother

agent(s)*Insulin plus

other agent(s)*

Symptom

s

No

sym

ptom

s

Lifestyle Modifications

*

Monotherapy

Dual therapy

Triple therapy

Dual therapy

Triple therapy

Triple therapy

PEARLNot first ,second, third line;

not competition between classes;It’s early combination therapy

350300250200150100

50

250

200

150

100

50

0

Insulin-Resistance

Rel

ativ

e -

cell

Fun

ctio

n (%

)

Insulin Level

FastingGlucose

Glu

cose

(m

g/dl

)

Onset of Diabetes

Postmeal Glucose

Incretins* (GLP-1 RA, DPP-4 Inh.)

Insulin

TZD (Pioglitazone), metformin, bromocriptine QR

Insulin

-10 -5 -0 5 10 15 20 25 30

Insulin

Modified from Bergenstal RM, International Diabetes Center.Rx PRINCIPLES-Rx PRINCIPLES-Uses Across Continuum of Care

• Consider therapyfor prevention (future)

• Early treatment,even with IGT

• FASTTHERAPEUTICCHANGES

• Not 1st,2nd ,3rd line;• not competition betw.

classes;

early combo therapy

-Delay Need for Insulin-No need for Early Insulin-If need Insulin, Continue Non-Insulin RX(Avoids need for Meal-Time Insulin- Decrease Risk Hypoglycemia 85%- Get Patients off insulin Who had been given early Insulin

Combo therapy-inAACE >7.5

PICK RIGHT DRUG FOR RIGHT PT.

Nutrition Exercise, NO SMOKING

.SGLT-2 Inhibitors *with caution re:Immune Sup. Levels

Logic for SGLT-2 Inhibition:

Logic for SGLT-2 Inhibition:

My Own Comment on MOA- Logic for Benefit:

1.Kidney is an ‘active player’ in Hyperglycemia--2.EARLY (in pre-diabetes) Up-regulation of SGLT-2 protein is a Mal-adaptive response to body perceiving lose of glucose as a risk for insufficient glucose for brain function

3.Lowering blood sugar by reducing tubular re-absorption of glucose treats THE Core defect in Diabetes- abnormal b-cell function, by decreasing glucotoxicity, AND, by virtue of weight loss, improves Insulin Resistance

But Won’t Sugar Hurt My Kidneys?But Won’t Sugar Hurt My Kidneys?

Likely No Undue Risk to KidneyFamilial Renal GlucosuriaLikely No Undue Risk to KidneyFamilial Renal Glucosuria

PresentationPresentation• Glucosuria: 1-170 g/dayGlucosuria: 1-170 g/day

• AsymptomaticAsymptomatic

BloodBlood• Normal glucose concentration

• No hypoglycemia or hypovolemiaNo hypoglycemia or hypovolemia

Kidney / bladderKidney / bladder• No tubular dysfunction

• Normal histology and function

ComplicationsComplications

• No increased incidence of

– Chronic kidney disease

– Diabetes

– Urinary tract infection

Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882;Wright EM, et al. J Intern Med. 2007;261:32-43.

Likely Benefit, Not Harm, to Kidneys Over Time:if Wanted to Protect Kidney in DM, one would want

Likely Benefit, Not Harm, to Kidneys Over Time:if Wanted to Protect Kidney in DM, one would want

• Decrease glucose; Decrease BP; Decrease weight

• Decrease Hyperfiltration; Decrease microalbuminuria

Canagliflozin (SGLT-2 Inhibitors do it All)

david.cherneyCurr Opin Nephrol Hypertens 2015, 24:96–103DOI:10.1097/MNH.0000000000000084

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

Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; Can Tell 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.

Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; I’ve seen:

Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; I’ve seen:

• Minimal GI side effects (only with volume depletion)

• No edema, in fact, decreases modest existing edema;decreases/obviates edema of pioglitazone

• Acceptable side effect profile that can be minimized by quality pro-active care- volume depletion, UTI, yeast infections

1. 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. GI: gastrointestinal.

CV Risk Factor Changes with SGLT-2 Inhibitors- Can Reassure Patient

CV Risk Factor Changes with SGLT-2 Inhibitors- Can Reassure Patient

• Changes in fasting lipids

–Increases in LDL-C–Increases in HDL-C–Minimal change in LDL-C/HDL-C ratio–Decreases in TGSmaller increases in non-HDL-C, Apo B, LDL particle number

• Decreases in systolic and diastolic blood pressure

• Improved glycemic control

• Decrease in body weight

Practical Clinical Approaches To Maximize Benefits and Minimize Risks

Practical Clinical Approaches To Maximize Benefits and Minimize Risks

• As Write Initial Script–Check eGFR, BUN/Cr,

eGFR appropriate dosing

lower doses for lower eGFR, older, on loop-diuretic;

Advise push PO fluids, hold med with a GI flu, sweaty exercise etc;

Note to patient increased urination expected=

12-14oz/d early, later ~6 oz/d

– Check K- if K+ high nml- adjust K=sparing diuretic,ACE/ARB

decrease high K+ foods

– Check BP- if Low BP- cut back/stop something- HCTZ, spironolactone, or BP med- ACE inh.

– Check Recent Sugars- Very High sugar- start other meds

and NCS diet first, start SGLT-2 3 days later

Practical Clinical Approaches To Maximize Benefits and Minimize Risks

Practical Clinical Approaches To Maximize Benefits and Minimize Risks

• As Write Initial Script– Teach Volume Issues

Keep Urine Dilute (let kidney tell patient if they’re drinking

‘enough’)

– UTI/ Yeast Infection IssuesMake sure ho history frequent issues in past- if so, don’t use

Female- careful bathroom habits, urinate after intercourse before sleep

Male- especially uncircumsized- get tip of penis dry before leave bathroom