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

Structure of Our Discussion:1.Following Flow of Discussion with Patient

1. General principles2. SGLT-2 Principles

2.First Visit Process of Care3.Follow-up Visit Process of Care

Updated Natural History of Type 2 Diabetes

Risk of Dev. Complications

ETOHBPSmoking

EyeNerveKidney

BlindnessAmputationCRF

Disability

Disability

MICVAAmp

Age 0-15 15-40+ 15-50+25-70+

Macrovascular Complications

IGT Type II DM

Microvascular Complications

DEATHpp>7.8

β-Cell secretion/massGene

Environmental Inflam. Triggerseg: viral,endocrine disruptors, food AGE’s, biome

endocrine disruptors, food AGE’s ,biomeEnvironmental Triggers

Resistance inflammatory, adipokines

Resistance-FFAPoor diet, inactivity

EPIGENITICS

EPIGENITICS

Polygenic- other

Monogenic (HLA)

Polygenic

Monogenic – MODY

IR Phenotype

Treat Aggressivelyto Delay or Prevent

Complications

Pearl

Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials:

BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications

Study Microvascular Macrovascular Mortality

UGDP ↔ ↔ ↔UKPDS ↓ ↓ ↔ ↓ ↔ ↓

DCCT/EDIC* ↓ ↓ ↔ ↓ ↔ ↔ACCORD ↓ ↔ ↑(unadj.), ↔ (adj.)

ADVANCE ↓ ↔ ↔VADT ↔ ↔ ↔

Initial Trial Long Term Follow-up

↑↑- likely due to hypoglycemia and weight gain- likely due to hypoglycemia and weight gain

Early Treatment Decreases Micro and Macro Vascular RISK/

OUTCOMES

As long as do without Undue Hypoglycemia or Weight Gain

Pearl

Consequences of Hypoglycemia• Prolonged QT- intervals- Diabetologia 52:42,2009

– Can be of pronged duration IJCP Sup 129, 7/02

– Greater with higher catecholamine levels Europace 10,860

• Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010

• Associated with Arrhythmias• Associated with Sudden Death Endocrine Practice 16,¾ 2010

• Increased Variabilty- explains highest mortality in intensive group had highest HgA1c in ACCORD ( increases inflammation, ICU mortality Hirsch ADA2010)

• Sulfonylureas block Ischemic Preconditioning

There is No perfect Exogenous Insulin:All result in HyperInsulinemia and Potential Hypoglycemia

Exogenous Insulin

Perfect glucose sensor-Insulin secretion modulator

Hypoglycemia/ Wt. Gain

NORMAL:Insulin into portal system

and B-cell=

CONCLUSION:DELAY INSULIN THERAPY;AVOID BOLUS RX if possible

PearlNo more Sulfonylureas or Glinides

Delay InsulinMost will not need Bolus Insulin

HYPERGLYCEMIA

7. Stomach/Small intestine

10. Kidney

11. Immune System / Inflammation

4. Increased hepatic glucose production

8. Colon / Biome

6. Adipose

5. Decreased peripheral muscle uptake

9. Brain

IncretinDopa agonist

SGLT2 Inhibitors

Anti-Inflam-matories,Immune modulators Metformin, TZDs

Metformin, TZDs

Metformin, TZDs

Incretins/Probiotics

GLP-1 RAsAGIPramlintide

1. Decreased insulin secretion

Incretins Ranolazine

2. Unsuppressed

glucagon secretion

Incretins Pramlintide

3. Decreased incretin effect

Incretins

BETA CELL-CENTRIC VIEW OF DIABETES: Matching Rx with Etiologyuse least number agents treating maximal # of modes of hyperglycemiaFOCUS on SGLT-2 Inhibition- addresses 5/11 MOH

COREDEFECT

Resistance IssuesNew ConstructOlder ConstructIslet Cell Issues