1. GLP-1 Modulates Numerous Functions in Humans
GLP-1: Secreted upon the ingestion of food
Promotes satiety and reduces appetite
DISCUSSION POINTS:
Upon food ingestion, GLP-1 is secreted into the circulation from L cells of small intestine.
GLP-1 increases beta-cell response by enhancing glucose-dependent insulin secretion.
GLP-1 decreases beta-cell workload and hence the demand for insulin secretion by:
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (beta-cell workload)
Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon
Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
By decreasing beta-cell workload and improving beta-cell response, GLP-1 is an important regulator of glucose homeostasis.
SLIDE BACKGROUND:
Effect on Beta-cell: Drucker DJ. Diabetes. 1998; 47:
Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997; 160:
Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997; 160:
Effects on Stomach: Nauck MA, et al. Diabetologia. 1996; 39:
Effects on CNS: Flint A, et al. J Clin Invest. 1998; 101:
Alpha cells:
 Postprandial glucagon secretion
What Happens to the
Incretin Effect in Diabetes?
Liver:  Glucagon reduces hepatic glucose output
Beta cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

2. Leveraging the Therapeutic Potential of GLP-1
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Leveraging the Therapeutic Potential of GLP-1
GLP-1
Short half-life (2 minutes)
Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV)
DPP-IV inhibition
Could extend endogenous GLP-1 half-life
Incretin mimetics
Mimic many of the glucoregulatory effects of GLP-1
Resistant to DPP-IV
DISCUSSION POINTS:
The half-life of GLP-1 is less than 2 minutes – meaning a continuous infusion of exogenous GLP-1 would be necessary to overcome the enzymatic degradation of GLP-1 by DPP-IV.
Inhibition of DPP-IV, which would extend the half-life of endogenous GLP-1, is one avenue of research.
Incretin mimetics are compounds that mimic GLP-1’s glucoregulatory effects, but are resistant to DPP-IV degradation. Examples are:
Analogs of the natural GLP-1 molecule.
Exenatide, a naturally occurring incretin mimetic that mimics multiple glucoregulatory effects of GLP-1 and is resistant to DPP-IV enzymatic degradation, is the first FDA-approved incretin mimetic. The active ingredient is exenatide.
Adapted from Drucker DJ. Diabetes Care. 2003;26:

3. Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences
Properties/Effect
Exenatide1
DPP-4 Inhibitor1
Liraglutide, Exenatide-OW2,3
Glucose-dependent insulin secretion
Yes
Glucose-dependent glucagon
Slows gastric emptying No
Little or no
Effect on body weight
Weight loss
Weight neutral
Effect on A1c
~1%
<1%
>1%
Effect on fasting glucose
Modest
Good
Effect on postprandial glucose
Effect on CVD risk factors
Improve
(with weight loss)
No consistent change
Side effects
Nausea (pancre-atitis, CRF)
~ None observed
(pancreatitis)
Less nausea, skin, (?pancreatitis, CRF, MTC)
Administration
Subcutaneous
Twice daily
Oral
Once daily
Daily or weekly
1. Amori RE, et al. JAMA. 2007;298:
2. Exenatide LAR (once weekly): Drucker DJ, et al. Lancet. 2008;372:
3. Liraglutide: Buse JB, et al. Lancet. 2009;374:39-47.

4. If absorptive capacity exceeded = glucosuria
“Sodium Glucose Co-transporter 2” Mediates Glucose Reabsorption in S1/S2 Segments of Renal Proximal Tubule; SGLT1 in S3 Segment
SGLT1 also in GI
SGLT2 is “heavy lifter”
Normal GFR, reabsorption capacity ~300g/day, typical load average 180g/day
If absorptive capacity exceeded = glucosuria
Ferrannini, E. & Solini, A. Nat. Rev. Endocrinol .2010; EM Wright et al, Physiol Rev, 2010.

5. SGLT2 Inhibition Lowers Renal Threshold for Glucose Excretion (RTG)
Below RTG
Minimal Glucosuria Occurs
150
125
Above RTG
Glucosuria Occurs
Urinary
Glucose
Excretion
(g/d)
RTG
SGLT2i- Treated Healthy
SGLT2i- Treated T2DM
100
Untreated T2DM
Untreated Healthy 75
RTG 50 25 2 4 6 8 10 12 14
Plasma Glucose (mmol/l)
Increased UGE occurs only when Plasma Glucose Exceeds RTG
SGLT2 Inhibition Lowers RTG
UGE: Urinary Glucose Excretion.
Adapted from Sha S, et al. Diabetes Obes Metab 2011;13:669–672

6. Comparison of Selectivity of SGLT2 Inhibitors
Compound
Selectivity SGLT2/1
Method used (EC50s or IC50s)
Empagliflozin
~2500
IC50
Dapagliflozin
~1200
EC50
Canagliflozin
~160
Sotagliflozin*
~20
EC50, half maximal effective concentration; IC50, half maximal inhibitory concentration; SGLT, sodium–glucose co-transporter; Dual SGLT1 and SGLT2 inhibitor
1. Han S, et al. Diabetes 2008;57:1723–9; 2. Liang Y, et al. Poster presentation at ADA 2009, NewOrleans, LA: 534-p; 3. Grempler R, et al. Poster presentation at ADA 2009, New Orleans, LA: 521-p; 4. Zambrowicz B, et al. Clin Pharmacol Ther 2012;92:158–69

7. 1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93
Empagliflozin
Empagliflozin is a highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2) in the kidney
Glucose reduction occurs by reducing renal glucose reabsorption and thus increasing urinary glucose excretion
In patients with type 2 diabetes, empagliflozin leads to1:
Significant reductions in HbA1c
Weight loss
Reductions in blood pressure without increases in heart rate
Does it have an Impact on MACE and if so how???
1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93

8. Patients with event/analysed
CV death, MI and stroke
Patients with event/analysed
Empagliflozin
Placebo HR
(95% CI)
p-value
3-point MACE
490/4687
282/2333
0.86
(0.74, 0.99)*
0.0382
CV death
172/4687
137/2333
0.62
(0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333
0.87
(0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
1.24
(0.92, 1.67)
0.1638
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI
Favours empagliflozin
Favours placebo

9. EMPA-REG OUTCOME®: Therapeutic considerations
Empagliflozin, as used in this trial, for 3 years in 1,000 patients with type 2 diabetes at high CV risk:
25 lives saved (82 vs 57 deaths)
22 fewer CV deaths (59 vs 37)
14 fewer hospitalizations for heart failure (42 vs 28)
53 additional genital infections (22 vs 75)

10. Humalog/Novolog/Apidra
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Humalog/Novolog/Apidra
Regular
NPH / Lente
Another way to look at it, or to think about it, is that Humalog is very rapid acting, like a rocket.
It gets into the bloodstream quickly , then it is gone.
Regular, although, quick-acting, is not as fast as Humalog. It takes a little longer to peak, and to get into the blood stream.
NPH and Lente take even longer. They last for many hours into the day.
Ultralente is the slowest acting insulin and lasts for a very long time.
Lantus /Ultralente/Detimir