Download the β-Cell - Diabetes in Control

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):753-759.
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
Johnston et al. Diabetes Care 2011; 34:1164–70
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
NOTE:
There is NO perfect Exogenous Insulin:
All result in HyperInsulinemia and Potential Hypoglycemia
Fine-tuned, physiologically
appropriate insulinemia
Exquisitely controlled levels of
insulin released into the portal vein
Endogenous Insulin
‘Obligatory’ excess peripheral insulin
to get modicum of reduced hepatic
glucose
production
Exogenous Insulin
Insulin
Resistance
Hypoglycemia
Obesity
Atherosclerosis
Hyperinsulinemia
Hypertension
Weight gain
Dyslipidemia
Cancer
Type II Diabetes
Chronic
Inflammation
β-cell
Dysfunction
------Potential
β-cell
Exhaustion
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 FunctionDeFronzo(Diabetes, Obesity, Metab 2015)
THUS: SELECT AGENTS THAT CAN PRESERVE
β-Cell function/mass
ADA 2015 Goals
WRONG ANSWER- as long as don’t use Hypoglycemic Agents
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
1. One CORE Defect- the β-Cell
1. (at least) 6 treatable Causes of
β-Cell Damage / HYPERGLYCEMIA
3.4 treatable mediators
of HYPERGLYCEMIA
resulting from β-Cell Damage
3A. β-Cell-Centric Construct: Egregious Eleven
The β-Cell is the FINAL COMMON DENOMINATOR of β-Cell Damage
8. Colon/Biome
Abnormal-microbiota;
possible decreased
GLP-1 secretion
1. Pancreatic β-cells
↓ β-Cell function
↓ β-Cell mass
Insulin
9. Immune
Dysregulation/
Inflammation
7. Brain
Increased appetite
Decreased morning
dopamine surge
Increased sympathetic
tone
FINAL COMMON
DENOMINATOR
INSULIN RESISTANCE
2. ↓Incretin
effect
↓Amylin
3. α-cell
defect
6. Liver
Increased
glucose
production
↑ Glucagon
5. Muscle
10. Stomach/
Small intestine
Increased rate of
glucose absorption
HYPERGLYCEMIA
Decreased
peripheral muscle
uptake
Upregulation of SGLT-2
11. Kidney
Increased glucose re-absorption
4. Adipose
Increased lipolysis
3B. β-Cell-Centric Construct: Egregious Eleven
Targeted Treatments for Mediating Pathways of Hyperglycemia
8. Colon/Biome
Probiotics
Incretins
Metformin
1. Pancreatic β-cells
7. Brain
↓ β-Cell function
↓ β-Cell mass
Insulin
9. Immune
Dysregulation/
Inflammation
Incretins,
Anti-Inflammatories
Immune modulators
Incretins,
Ranolazine
FINAL COMMON
DENOMINATOR
INSULIN RESISTANCE
2. ↓Incretin
effect
3. α-cell
defect
Incretins
↓Amylin
GLP-1 Agonists
Pramlintide
AGI
6. Liver
Metformin
TZDs
↑ Glucagon
Incretins
Pramlintide
10. Stomach/
Small intestine
Incretins
Dopamine agonist-QR
Appetite Suppressants
HYPERGLYCEMIA
5. Muscle
TZDs
Metformin
4. Adipose
11. Kidney
SGLT2 inhibitors
TZDs
Metformin
Use Least Number of Agents that treat Most Number of Mechanisms of hyperglycemia
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes,
Match Patient Characteristics to Drug CharacteristicsConsider glycemic efficacy, weight reduction and CV benefits
NOT COMPETITION- EARLY COMBINATION
5.Gut CHO
Absorption:
8.Kidney-
SGLT2
-
Incretin,
Pramlintide,
Glucosidase inh.
1.Pancreatic
insulin
Secretion:
Incretin, ranolazine
2.Pancreatic
glucagon
Secretion- Incretin
7.BrainTZD,INCRETI
bromocryptine
HYPERGLYCEMIA
De
-
-
3.Muscle-
TZD, Incretin
4.Liver
Hepatic glucose
production:
Metformin, incretin
Peripheral
glucose
uptake
6.Fat- TZD, metformin
Patient-Centric Diagnosis & Process of Care/Therapy
Traditional
Labs/Testing
FBS, RBS, HgA1c
At Risk
Individuals
Etiologic Diagnostic Markers:
β-Cell, Insulin resistance,
Inflammation, Environment, Genes
Specific
Therapy
addressing
Genotype
Genes
Pre-Diabetes Targeted TherapiesAll Mechanisms Start Early
Diabetes Targeted Therapies
B = β-cell: (Incretins)
B = β-cell: Incretin, glucagon-suppressing agents, SGLT-
I = Inflammation: (Incretin, drugs in development)
2 inhibitors
Br= Brain: Bromocriptine-QR, appetite suppressants
I = Inflammation: Incretin (Drugs in development)
R = Resistance: Metformin, pioglitazone
R = Resistance: Metformin, pioglitazone (Drugs in
E = Environment: Diet/exercise; regulators of the
development)
Br= Brain: (Bromocriptine-QR)
gut microbiota
E = Environment: Diet/exercise; regulators of the gut
microbiota
Might consider Multiple Agents [ per
DeFronzo pre-dm protocol*]
( ) = Not proven
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