The Obesity/Diabetes Epidemic:
Adiposopathy & ObesityThe New Disease!
Dx & (Rx) of Insulin Resistance & early
DM
Part 7 Final
Stan Schwartz MD, FACP, FACE
Private Practice, Ardmore
Obesity Program
Cardiometabolic Diabetes Center and Affiliate,
Main Line Health System
Emeritus, Clinical Associate Professor
University of Pennsylvania
Outline
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•
•
•
•
Epidemiology and Economics of obesity/diabetes
Perspectives on Obesity
Consequences of Obesity, Prediabetes, Obesity
Obesity/ Diabetes Risk Factors,
Obesity/ Diabetes Onset can be Prevented or Delayed –
Early Risk Identification and Intervention.
• Medical Benefits to Weight Loss
• Treatment-– Basics,
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
Initial Trial
Long Term Follow-up
Study
Microvascular
Macrovascular
Mortality
UGDP
↔
↔
↔
UKPDS
DCCT/EDIC*
ACCORD
ADVANCE
VADT
↓
↓
↓
↓
↓
↓
↔
Meinert CL. Diabetes. 1970;19(suppl):789-830.
Goldner MG. JAMA. 1971;218(9):1400-1410.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
Holman RR. N Engl J Med. 2008;359(15):1577-1589.
DCCT Research Group. N Engl J Med. 1993;329;977-986.
Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.
↔
↔
↓
↓
↔
↔
↔
↔
↔
↑(unadj.), ↔ (adj.)
↔
↔
↑- likely due to
Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559.
Patel A, et al. N Engl J Med. 2008;358:2560-2572.
Duckworth W, et al. N Engl J Med. 2009;360.
*T1DM study.
↓
↔
hypoglycemia
and weight gain
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes,
Treating Defronzo’s Octet: WITHOUT HYPOGLYCEMIA or
WEIGHT GAIN
Match Patient Characteristics to Drug Characteristics
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
Especially with hypoglycemic agents
All Insulin Regimens Improve Glycemic
Control, but Often With Weight Gain
Landmark Insulin Studies in Which Exenatide Was Not a Comparator
11
A1C (%)
10
9
-2.6%
8
ADA
GOAL
7
6
-2.1%
-2.1%
-2.1%
-0.8%
5
-1.3%
Biphasic
Insulin
BASAL Insulin
-1.4%
-2.2%
Prandial
Insulin
BID
Insulin
+19.2 lb
∆ Weight (lb)
20
16
+12.6 lb
+10.4 lb
12
8
Intensive
Insulin
+10.1 lb
+8.6 lb
+6.6 lb
+6.2 lb
Riddle
et al1
Riddle
et al1
+4.2 lb
4
0
Yki-Jarvinen
et al2
Holman
et al3
Holman
et al3
Holman
et al3
Yki-Jarvinen
et al2
1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086. 2. Yki-Jarvinen H, et al. Ann Intern Med. 1999;130:389-396.
3. Holman RR. N Engl J Med. 2007;357:1716-1730. 4. Henry RR, et al. Diabetes Care. 1993;16:21-31.
Henry
et al4
GLP-1 RAs effect on A1c and weight
Exenatide
Liraglutide
Changes in Glycemia and Weight in
3 Head-to-Head Studies Exenatide vs. Insulin
Added by Dr S
EXENATIDE
AND NO undue HYPOglycemia
Heine R, et al. Ann Int Med. 2005;143:559-569.
Barnett A, et al. Clin Thera. 2007;29(11):2333-2348.
Nauck M, et al. Diabetologia. 2007;50(2):259-267.
SGLT-2 Inhibitor with Incretins
Pick Right Drug for Right Patient and Vice Versa: next slide
Initial Triple Combination Therapy is Superior to Stepwise Add-On
ConventionalTherapy in Newly Diagnosed T2DM; RALPH A.
DEFRONZO,
147 newly diagnosed T2DM initial combination therapy with
metformin + pioglitazone + exenatide (Triple Therapy, n=71) or
escalating dose of metformin followed by sequential addition of glipizide (5→20 mg/d) and then basal insulin
to maintain A1c < 6.5% (Conventional Therapy, n= 76).
Results:
Triple Therapy, A1c
Conventional Therapy,
8.6 to 6.1% at 6 mo and remained stable at 6.1% at 24
6.1% at 6 mo and then increased to 6.6% at 24 mo (p < 0.01).
More subjects in Conventional Arm failed to achieve the treatment A1c goal <6.5%
(46 vs 22%, p<0.0001).,
Triple Therapy subjects had a 13.6-fold lower rate of hypoglycemia
compared to subjects receiving Conventional Therapy.
Triple Therapy subjects had mean weight loss of 1.2 kg versus 3.6
in subjects on Conventional Therapy.
kg weight gain (p=0.02)
Conclusion:
Antidiabetic therapy targeting the core metabolic defects (insulin resistance and
beta cell dysfunction) responsible for hyperglycemia is more effective and safer
than therapy simply aimed at lowering the plasma glucose conc without correcting the underlying pathophysiologic disturbances present in
T2DM.
Can avoid bolus insulin in most by use
of GLP-1 Agonists and SGLT-2 Inhibitor
Diabetic Management of the
Obese Patient
• Screen Patients for Diabetes
• Address Potential Causes of Weight Gain in Diabetes treatment
• Though drugs aimed at reducing insulin resistance and increasing
beta cell function are logical pathophysiologically, ‘standard’ current
pharmacologic therapy for Type 2 Diabetes increase weight
(sulonylureas, glinides, insulin)
• BUT anything that reduces obesity (specifically visceral fat) will have
the most significant benefit in preventing, treating and even
reversing overt Diabetes. (even pioglitazone, GLP-1 RA’s,
pramlintide, SGLT-2 inhibitors)
• Bariatric surgery, in many patients with Type 2 Diabetes has become
a logical approach to prevent, treat , and even reverse , overt
Diabetes AND reduce MORTALITY
Weight Reduction Issues
1. In Metabolic Syndrome-consider Incretins/ SGLT-2 inh.
2. Incretins Before Pioglitazone- then don’t gain weight from pio3. GLP-1 RA’s and SGLT-2s have added wt. loss benefit
4. GLP-1 RA’s preferred over DPP-4 in ‘right patient’
5. GLP-1 RA’s always before start Insulin, even a short trial6. Unless ‘sick’, avoid insulin if not following NCS diet
7. Keep on Incretin/SGLT-2 inhibitor (others) when add insulinneed for bolus insulin decreased
8. If on insulin- as start NCS diet, decrease 25%
if was having hypoglycemia decrease 25%
add incretin , GLP-1 preferred – dec. insulin as do so
add SGLT-2 inhibitor- decrease insulins 25%
add pioglitazone, metformin, if possible
May be able to stop insulin, lose weight
Schwartz, Fabricatore, Diamond, Weight Reduction in Diabetes, Book Chapter
“Diabetes: An Old Disease, a New Insight,” edited by Dr. Ahmad., Landes
Bioscience, 2011
Summary
•
•
•
•
•
Epidemiology and Economics of obesity/diabetes-costly
Perspectives on Obesity- culture
Consequences of Obesity, Prediabetes, Obesity
Obesity/ Diabetes Risk Factors,
Obesity/ Diabetes Onset can be Prevented or Delayed – Early Risk
Identification and Intervention.
• Medical Benefits to Weight Loss
• Treatment-CDC’s diabetes prevention program and other EvidenceBased Interventions– Basics, Next Lecture in Series
We can do Better, We must do better
I’ll show you how next time 