1. CV Risk of SU and Insulin
So benefit of both SU/Insulin in
research studies –UKPDS, DCCT/EDIC
But adverse risk in ‘real world’ use
Pharmacoepidemiology and Drug Safety. 2008;(17):

2. Link between hypoglycemia and acute cardiovascular events in type 2 diabetes
Retrospective, observational study (n=860,845) assessing association between hypoglycemia and acute CV events
Patients who experienced hypoglycemia had 79% higher odds of an acute CV event than patients without hypoglycemia
The final study cohort comprised 860,845 patients with type 2 diabetes.
Johnston et al. Diabetes Care 2011; 34:1164–70

3. No SULFONYLUREAS or Glinides
No SULFONYLUREAS or Glinides lose ischemic preconditioning; beta-cell apoptosis, could not pass FDA CV safety if new one applied not cheap, if consider test strip cost, accidents ER visits, hospitalizations Delay Insulin HYPOGLYCEMIA- cv risk Increase Weight Increase Insulin Resistance

4. Exquisitely controlled levels of insulin released into the portal vein
NOTE: There is NO perfect Exogenous Insulin: All result in HyperInsulinemia and Potential Hypoglycemia
Exquisitely controlled levels of insulin released into the portal vein
Fine-tuned, physiologically appropriate insulinemia
Endogenous Insulin
‘Obligatory’ excess peripheral insulin to get modicum of reduced hepatic glucose production
Exogenous Insulin
Insulin Resistance
β-cell Dysfunction
Potential
β-cell Exhaustion
Hypoglycemia
Obesity
Hyperinsulin-emia
Atherosclerosis
All because all insulin results in hyperinsulinemia with risk of negative consequences
Weight gain
Hypertension
Dyslipidemia
Cancer
Chronic Inflammation
Type II Diabetes

5. THUS: SELECT AGENTS THAT CAN PRESERVE
Reduced Need for Insulin:Debunking a Myth: Taking DeFronzo’s EASD 2015 Lecture 1 step further 
MYTH: “Most Patients with ‘T2DM’ will eventually progress to insulin because of inexorable β-Cell loss”
- But data obtained on SU=apoptosis
Hyperinsulinism with weight gain> increased IR> adipocytokines and increased TG which
decrease beta-cell function
- Think of bariatric patients –no insulin after 25 years DM/ 20 years
insulin
- Most patients dying with DM have > 20% β-Cell mass- Butler
- Need to remove >80% pancreas in sub-total pancreatectomies to
leave patient with DM post-op
Triple therapy Durable Effect in Improving Beta-Cell Function-
DeFronzo(Diabetes, Obesity, Metab 2015)
THUS: SELECT AGENTS THAT CAN PRESERVE
β-Cell function/mass

6. ADA 2015 Goals
WRONG ANSWER- as long as don’t use Hypoglycemic Agents

7. β-Cell Centric Classification of DM:
SEGUE INTO THERAPY
The β-cell centric classification A. individualizes care B. Identifies and treats patient-specific etiologies and mediating pathways of hyperglycemia EGREGIOUS ELEVEN
One CORE Defect- the β-Cell
(at least) 6 treatable Causes of
β-Cell Damage / HYPERGLYCEMIA
4 treatable mediators
of HYPERGLYCEMIA
resulting from β-Cell Damage

8. Hyperglycemia 3A. β-Cell-Centric Construct: Egregious Eleven
The β-Cell is the FINAL COMMON DENOMINATOR of β-Cell Damage
8. Colon/Biome
Increased appetite
Decreased morning dopamine surge
Increased sympathetic tone
7. Brain
1. Pancreatic β-cells
↓ β-Cell function
↓ β-Cell mass
Abnormal-microbiota;
possible decreased
GLP-1 secretion
Insulin
9. Immune
Dysregulation/
Inflammation
FINAL COMMON DENOMINATOR
INSULIN RESISTANCE
2. ↓Incretin
effect
3. α-cell
defect
6. Liver
Increased
glucose
production
↓Amylin
↑ Glucagon
5. Muscle
10. Stomach/
Small intestine
Hyperglycemia
Decreased peripheral muscle uptake
Increased rate of glucose absorption
Upregulation of SGLT-2
4. Adipose
Increased lipolysis
11. Kidney
Increased glucose re-absorption

9. Hyperglycemia 3B. β-Cell-Centric Construct: Egregious Eleven
Targeted Treatments for Mediating Pathways of Hyperglycemia
8. Colon/Biome
1. Pancreatic β-cells
↓ β-Cell function
↓ β-Cell mass
7. Brain
Probiotics
Incretins
Metformin
Incretins
Dopamine agonist-QR
Appetite Suppressants
Insulin
Incretins,
Ranolazine
9. Immune
Dysregulation/
Inflammation
FINAL COMMON DENOMINATOR
INSULIN RESISTANCE
Incretins,
Anti-Inflammatories
Immune modulators
2. ↓Incretin
effect
3. α-cell
defect
6. Liver
Metformin
TZDs
Incretins
↓Amylin
↑ Glucagon
Incretins
Pramlintide
5. Muscle
10. Stomach/
Small intestine
TZDs
Metformin
Hyperglycemia
GLP-1 Agonists
Pramlintide
AGI
4. Adipose
11. Kidney
TZDs
Metformin
SGLT2 inhibitors
Use Least Number of Agents that treat Most Number of Mechanisms of hyperglycemia

10. - HYPERGLYCEMIA - - SGLT2 3.Muscle- Hepatic glucose production:
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, Match Patient Characteristics to Drug Characteristics- Consider glycemic efficacy, weight reduction and CV benefits NOT COMPETITION- EARLY COMBINATION
1.Pancreatic insulin
Secretion:
Incretin, ranolazine
5.Gut CHO
Absorption:
Incretin,
Pramlintide,
Glucosidase inh. -
7.Brain-
TZD,INCRETIN,
bromocryptine
2.Pancreatic glucagon
Secretion- Incretin
8.Kidney-
SGLT2
HYPERGLYCEMIA
Peripheral
glucose
uptake De - -
3.Muscle-
TZD, Incretin
Hepatic glucose
production:
Metformin, incretin
4.Liver
6.Fat- TZD, metformin 10

11. Patient-Centric Diagnosis & Process of Care/Therapy
Traditional Labs/Testing
FBS, RBS, HgA1c
Specific Therapy addressing Genotype
At Risk
Individuals
Genes
Etiologic Diagnostic Markers:
β-Cell, Insulin resistance, Inflammation, Environment, Genes
Pre-Diabetes Targeted Therapies-
All Mechanisms Start Early
B = β-cell: (Incretins)
Br= Brain: (Bromocriptine-QR)
I = Inflammation: (Incretin, drugs in development)
R = Resistance: Metformin, pioglitazone
E = Environment: Diet/exercise; regulators of the
gut microbiota
Might consider Multiple Agents [ per DeFronzo pre-dm protocol*]
Diabetes Targeted Therapies
B = β-cell: Incretin, glucagon-suppressing agents, SGLT-2 inhibitors
Br= Brain: Bromocriptine-QR, appetite suppressants
I = Inflammation: Incretin (Drugs in development)
R = Resistance: Metformin, pioglitazone (Drugs in development)
E = Environment: Diet/exercise; regulators of the gut microbiota
( ) = Not proven

13. But Guidelines Gluco-Centric
Shouldn’t we take into account avoiding hypo
Shouldn’t we take into account avoiding weight gain
Shouldn’t we take into account CV risk