1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015
An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients:
Looking at Diabetes Medications with a Cardiologists Eye
Part 11
Stan Schwartz MD,FACP
Affiliate, Main Line Health System
Emeritus, Clinical Associate Professor of Medicine,
U of Pa. 1

2. Incretin Effect, Normal and with Diabetes

3. Incretins
Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet b-cells
Stimulation of insulin secretion is glucose-dependent. Incretins only work when glucose levels are above basal levels- THUS , NO HYPOGLYCEMIA if not on secreatogogue or insulin
Two predominant incretins
glucagon-like peptide-1 (GLP-1)
glucose-dependent insulinotropic peptide ([GIP] also known as gastric inhibitory peptide)
Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s204; Meier JJ et al. Diabetes Metab Res Rev. 2005;21:

4. Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
mmol/L
15.0
250
12.5
Placebo
GLP-1
Glucose *
200
10.0
mg/dL
7.5
150
5.0
100
*P <0.05
Patients with type 2 diabetes (N=10)
2.5 50
250
When glucose levels
approach normal values,
insulin levels decreases. 40
Insulin
200
pmol/L 30 *
150
mU/L 20
100
Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
This slide shows results from a study that characterized changes in glucose, insulin, and glucagon levels in response to a pharmacologic infusion of GLP-1. Ten patients with uncontrolled type 2 diabetes mellitus being treated with diet and oral hypoglycemic agents received an intravenous infusion of GLP-1 over 240 minutes. During infusion, blood was drawn at 30-minute intervals to permit assay of glucose, insulin, and glucagon levels. One day later, the procedure was repeated with a placebo infusion.
Infusion of GLP-1 over 240 minutes lowered plasma glucose to normal basal levels in all patients, with significant mean reductions observed at all time points from 60 minutes onward (P<0.05 vs placebo). Initially, during GLP-1 infusion with a starting plasma glucose level of 12.7 mmol/L (228.6 mg/dL), plasma insulin increased and glucagon decreased. However, as plasma glucose approached normal basal levels, insulin and glucagon returned to baseline or near-baseline levels, thus demonstrating the glucose-dependent nature of the effects of GLP-1. 50 * 10 * 20 20
When glucose levels approach normal values, glucagon levels rebound.
Glucagon
pmol/L 15 15 *
pmol/L 10 10 5 5
Infusion
–30 60
120
180
240
Minutes
Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.
Reference:
Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia ;36:741–744.

5. Summary of Incretin Actions on Different Target Tissues
Insulin secretion
Glucagon secretion
Gastric emptying
Appetite
Cardioprotection
Cardiac output
Insulin biosynthesis
b cell proliferation
b cell apoptosis
Neuroprotection
Glucose production
Insulin sensitivity
Brain
Heart
GI tract
Liver
Muscle
Stomach
GLP-1
The two principal incretins, GIP and GLP-1, both act on the b-cell to stimulate glucose-dependent insulin secretion and in preclinical studies, both incretins stimulate b-cell proliferation and reduce b-cell apoptosis. GLP-1 also has multiple actions on other cell types, including reduction of glucagon secretion from the islet a-cell, inhibition of food intake and gastric emptying, and regulation of cardiovascular function and contractility. Although GLP-1 action on the liver and muscle is thought to be indirect, possibly via other hormones or through the nervous system, treatment of diabetic subjects with GLP-1R agonists has also been associated with increased insulin sensitivity in peripheral tissues such as muscle and liver.
Drucker D. J. Cell Metabolism 2006 5

6. CV Benefits of GLP-1

7. Cardioprotective Mechanisms for Incretin Therapy
? Any neg.
METABOLIC SYNDROME AND RELATED DISORDERS
Volume 12, Number 6, 2014
Mary Ann Liebert, Inc.
Pp. 303–310
DOI: /met

9. Mechanism of Incretins
12, 12.2
Mechanism of Incretins
Incretin Mimetic
Glucose dependent
 Insulin
(GLP-1and GIP)
 Glucose uptake by peripheral tissue
Ingestion of food
Pancreas
Release of
active incretins
GLP-1 and GIP
Beta cells
Alpha cells
GI tract
 Blood glucose in fasting and postprandial states
DPP-4 inhibitor X
DPP-4 enzyme
Glucose-
dependent
Mechanism of Action of Sitagliptin
This illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate).
The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.
When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced.
In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells.
Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states.
The effects of GLP-1 and GIP are glucose dependent.
The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones.
Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.
 Hepatic glucose production
 Glucagon
(GLP-1)
Inactive
GLP-1
Inactive
GIP
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a meal.
Incretin Mimetics are resistant to DPP-4 inactivation
Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones.
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

10. ? Pancreatitis, ? C-cell tumors ? pancreatitis

11. Acutely Improving Beta-Cell Response BYETTA Reduced Hyperglycemia in Fasting Patients
exenatide
exenatide
Required
DISCUSSION POINTS:
--When a single subcutaneous dose of BYETTA (0.05 mcg/kg and 0.10 mcg/kg) was given to hyperglycemic, fasting patients with type 2 diabetes:
--Plasma glucose concentrations were significantly lowered compared with placebo
--Plasma insulin concentrations were significantly increased compared with placebo
--As plasma glucose concentrations approached euglycemia (normal levels) for the BYETTA treatment groups (~3 hours), insulin secretion subsided to near-basal level, which demonstrated the glucose-dependent property of BYETTA.
SLIDE BACKGROUND:
--Subjects with type 2 diabetes (n = 12) injected with single SC exenatide dose after an overnight fast (subjects remained fasting during the subsequent 8 hours).
NO HYPO- can use NPO

12. Not correlated to nausea
exenatide
REQUIRED
DISCUSSION POINTS:
Weight: 25% of the patients lost on average 26.2 lbs (11.4% of baseline body weight)
Overall, 81% of patients had reductions in body weight
SLIDE BACKGROUND:
Patients in this analysis received either 5 or 10 mcg BYETTA BID in the 30-week placebo- controlled trials, followed by 5 mcg BID for 4 weeks and 10 mcg BID thereafter
All patients continued any pre-existing treatment regimens of MET and/or SFU throughout the trials
The 82-week completer cohort (n = 314) consisted of those patients who were treated with BYETTA for 82 weeks by the time of this analysis
Weight-change quartiles consisted of 4 subgroups with approximately equal numbers of patients (n = 78 or 79) for each treatment arm, with Quartile 1 consisting of the 25% of patients with the greatest weight reductions, Quartile 4 consisting of the 25% of patients with the smallest weight reductions (or weight gains), and Quartiles 2 and 3 consisting of those with intermediate weight changes
Baseline weights: Quartile 1: lbs, Quartile 2: lbs, Quartile 3: lbs, Quartile 4: lbs
WEEK WEIGHT Dec.-
Not correlated to nausea 12

13. Changes in Glycemia and Weight in 3 Studies of Exenatide vs Insulin
Heine
et al1
Barnett et al2
Nauck
et al3
Heine
et al1
Barnett et al2
Nauck
et al3 10 9
Change in A1C, % 8
ADA GOAL 7
-1.1%
-1.4%
-0.9%
-1.1%
-1.4%
-1.0% 6
Glargine, Once Daily
Insulin Aspart, 70/30
Exenatide 4 3 2
In all the exenatide versus insulin studies, exenatide was as effective as insulin in lowering A1C levels. However, the use of insulin consistently resulted in weight gain, whereas exenatide consistently resulted in weight loss.1-3 1
Change in Weight, kg
+1.8 kg
+2.3 kg
+2.9 kg -1 -2 -3
-2.3 kg
-2.2 lb
-2.5 kg
1. Heine R, et al. Ann Intern Med. 2005;143:
2. Barnett AH, et al. Clin Ther. 2007;29:
3. Nauck MA, et al. Diabetologia. 2007;50:
Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:
Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:
Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50: