1. NEW DIABETES TREATMENTS
Richard Sachson MD

2. Major Diabetes Milestones
1552 BC Diabetes in Egypt
1800 Scientific method
1921 Insulin discovered
1869 Langerhans identifies pancreatic cells
1922 Clinical success
1944 Standard syringe
1955 Oral agents
1970 Insulin pump
2005 Exubera,
Incretins
Pramlintide
1986 Insulin pen
1989
Insulin
analogues
Please see full prescribing information.

3. Current Treatment Goals for Glycemic Control
Slide ID: 12962
The ACE recommends a more rigorous HbA1c goal for all patients than the ADA’s general recommendation of <7.0%. Instead, ACE advocates a goal of 6.5%,1 based on the epidemiologic analysis of the UKPDS data, which showed that the risk for both microvascular and macrovascular complications of diabetes increased at HbA1c values 6.5%.2
It should be noted that guidelines may be modified for individual patients whose functional state or risk for other adverse treatment effects (eg, hypoglycemia) is thought to outweigh the benefits of optimal glucose control.1 In addition, ACE recommends treatment targets for FPG and 2-hour postprandial glucose (PPG) of <110 mg/dL and <140 mg/dL, respectively.1 These targets are based on the increased cardiovascular risk associated with plasma glucose values above these levels.3,4
1ACE. Endocr Pract. 2002;8(suppl):5-11.
2Stratton IM, et al. Br Med J. 2000;321:
3Goldberg RB, et al. Circulation. 1998;98:
4Shaw JE, et al. Diabetologia. 1999;42:
lllllllllllllllllll

4. New Diabetes Therapeutic Agents
Incretins
GLP1 analogues:Exenatide- Byetta
DPP4 Inhibitors:Sitagliptin- Januvia
Pramlintide-Symlin
Inhaled insulin-Exubera

5. INCRETINS

6. Major discussion point:
INtestine
SeCRETion
INsulin

7. GLP-1 and GIP Are Incretin Hormones
Is released from L cells in ileum and colon1,2
Is released from K cells in duodenum1,2
Stimulates insulin response from beta cells in a glucose-dependent manner1
Inhibits gastric emptying1,2
Has minimal effects on gastric emptying2
Reduces food intake and body weight2
Has no significant effects on satiety or body weight2
Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1
Deficient in type 2 diabetes
Does not appear to inhibit glucagon secretion from alpha cells1,2
Normal levels but decreased responsiveness in type 2 diabetes
GLP-1 and GIP Are Incretin Hormones
GLP-1 and GIP are the currently identified incretin hormones.
An incretin is a hormone with the following characteristics1:
It is released from the intestine in response to ingestion of food, particularly glucose.
The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin.
The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent).
GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1
In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3
GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner. GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide.
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
References:
1. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
2. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.
3. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199–E206.
4. Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

8. DPP-4 Degrades GLP-1
Slide ID: 12992
GLP-1 is released by intestinal L-cells in response to ingested food (upper left), GLP-1 is rapidly and extensively inactivated (lower right).1
The kinetics of the inactivation process were explored in 8 healthy subjects and 8 patients with type 2 diabetes, all of whom were administered—subcutaneously or intravenously—the active amide GLP-1 (7-36).2
In all instances, the active amide was rapidly cleaved at its N-terminal by dipeptidyl peptidase–4 (DPP-4), leaving the inactive metabolite GLP-1 (9-36) and giving the active amide a half-life of only 1 to 2 min.
DPP-4 is a ubiquitous enzyme that circulates freely in plasma, exists at the surface of endothelial cells, and rapidly inactivates several biologically active peptides.
1Kieffer TJ, et al. Endocrinology. 1995;136:
2Deacon CF, et al. Diabetes. 1995;44:

9. Inappropriate Insulin and Glucagon Responses to Glucose in Patients With T2DM
NGT
NGT
150
T2DM
160
T2DM
140
100
Insulin (μU/mL)
Glucagon (pg/mL)
120 50
Hormone levels were tracked in persons with normal glucose tolerance (green curves) and in T2DM patients (orange curves) before and after a carbohydrate challenge.1
For insulin (left graph), the normal response was a steep rise. Diabetic patients showed only a blunted response.
For glucagon (right graph), the normal response was an acute fall. Among patients with diabetes, findings reveal that glucagon is not suppressed and may experience an inappropriate increase, revealing inherent dysfunction of the pancreatic α-cell.
1. Muller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med. 1970;283:
100 80
–60 60
120
180
240
–60 60
120
180
240
Time (min)
Muller WA, et al. N Engl J Med. 1970;283:

10. Glucose-Dependent Effects of GLP-1
Not Required
DISCUSSION POINTS:
--A continuous infusion of GLP-1 resulted in significant decrease in plasma glucose over a 4-hour period, compared to placebo.
--Compared to placebo, GLP-1 initially enhanced insulin secretion, but as plasma glucose approached normal concentrations, insulin secretion subsided despite the continuing GLP-1 infusion – demonstrating glucose-dependent insulin secretion.
--GLP-1 suppresses glucagon concentrations in the presence of hyperglycemia. However, glucagon levels return to baseline as plasma glucose approaches normal, despite continued infusion of GLP-1 – demonstrating that GLP-1 does not suppress glucagon during euglycemia or hypoglycemia.
--Glucose dependency is demonstrated by a return of plasma insulin and glucagon to pretreatment concentrations as plasma glucose approaches the normal range.
SLIDE BACKGROUND:
--Ten subjects with type 2 diabetes – all on diet/SFU and some on metformin or acarbose. All antidiabetic medications were withheld at the start of the study.
--IV GLP-1 (7-36 amide) was infused for 4 hours at 1.2 pmol/kg/min. * * *

11. EXENATIDE

12. The Beginning Not Required DISCUSSION POINTS:
--Exenatide, which was discovered in the salivary secretions of the Gila monster, has 53% amino acid sequence identity with mammalian GLP-1.
--Exenatide binds in vitro to the known human GLP-1 receptors on beta cells and mimics multiple glucoregulatory effects of GLP-1.
--The amino acid at position 2, the site of DPP-IV inactivation on the GLP-1 molecule, is different in exenatide – making BYETTA resistant to DPP-IV enzymatic degradation.
--After a single SC injection, BYETTA can be measured in the plasma for up to 10 hours.
SLIDE BACKGROUND:
--Following BYETTA SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours.
--The mean terminal half-life of exenatide is 2.4 hours. Pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.

13. Exenatide Mimics Many Properties of GLP-1
Required
DISCUSSION POINTS:
--Exenatide, like GLP-1:
--Enhances glucose-dependent insulin secretion
--Decreases postprandial glucagon secretion, thus decreasing hepatic glucose output
--Regulates gastric emptying, decreasing the rate of peak nutrient absorption from meals
--Decreases food intake
--Acutely decreases plasma glucose to near-normal concentrations
--BUT, one important difference – exenatide is resistant to enzymatic degradation by DPP-IV – thus, extending exenatide’s presence in plasma following a SC injection (measurable for up to 10 hours).
SLIDE BACKGROUND:
--Following BYETTA SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours.
--The mean terminal half-life of exenatide is 2.4 hours. Pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.
--GLP-1 data: Drucker DJ. Diabetes Care. 2003; 26:
--Exenatide data: Nielsen LL, et al. Regul Pept. 2004; 17:77-88
--Exenatide duration: Parkes D, et al. Drug Dev Res. 2001; 53: 
Long

14. Reducing Workload BYETTA Reduced Postprandial Glucose and Glucagon
Required
DISCUSSION POINTS:
--When a single dose of subcutaneous BYETTA was administered to patients with type 2 diabetes 15 minutes prior to a standard meal test (liquid meal), BYETTA:
--Eliminated the abnormal rise postprandial plasma glucose
--Suppressed postprandial glucagon concentrations, an important contributor to postprandial glucose surge

15. BYETTA Lowered Postprandial Glucose and Augmented Beta-Cell Response
Not Required
DISCUSSION POINTS:
--In the BYETTA 10-mcg arm, by Week 30, the postprandial glucose rise was nearly eliminated, and the postprandial glucose AUC( min) was reduced (P<0.005 vs placebo).
--Similar results were seen with the BYETTA 5-mcg arm (data not shown to simplify graphs).
--Despite the lower glucose stimulus in the 10-mcg BYETTA arm (vs placebo), there was an increased early insulin secretory response (vs placebo).
SLIDE BACKGROUND:
--Metformin (MET) Study: 30-week placebo-controlled, double-blind, Phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 mcg BYETTA BID with MET; ITT, N = 336.
--The Last Observation Carried Forward (LOCF) method was applied to the data.
--A subgroup of patients in the placebo and BYETTA 10 mcg treatment groups had meal tolerance tests at Week 30.
--Meal size calculated individually at baseline to provide 20% of subject’s total daily calories (macronutrient composition: 55% carbohydrate/15% protein/30% fat), and the standardized breakfast was given 15 minutes after injection of BYETTA 10 mcg.
--Placebo BID (n = 13), BYETTA 10 mcg BID (n = 16).

16. Open-Label Extension – Combined BYETTA Sustained A1C Reductions
Required
DISCUSSION POINTS:
--87% of the subjects who completed the 30-week placebo-controlled, double-blind, Phase 3 studies chose to continue in open-label extension (OLE) studies.
--All subjects were given 5 mcg BYETTA for the first 4 weeks of the OLE (overall, Weeks 30 to 34), after which they received 10 mcg BYETTA for the remainder of their participation in the OLE.
--Shown is 82-week data (30 weeks from placebo-controlled, double-blind study and 52 weeks from OLE) for 393 patients.
--Of the 1446 subjects randomized to the three 30 week, blinded, placebo-controlled trials, 1125 completed and were eligible for enrollment into the open label extension studies (OLE).
--Of the 1125 subjects, 977 (87%) enrolled into the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks and 393 had completed treatment through 82 weeks.
--Using the intent-to-treat (ITT) and Last Observation Carried Forward (LOCF) analysis method, the 977 ITT population had A1C and weight reductions at 82 weeks consistent with the 82-week completer population shown here.
--Placebo cohort upon receiving BYETTA showed an immediate decrease of A1C similar to that observed with BYETTA treatment in the first 30 weeks.
--Mean A1C reductions from baseline were very similar at 82 weeks (at least -1.1%) for all three original study treatment groups.
--For patients receiving 10 mcg BYETTA for 82 weeks, 51% achieved an A1C of 7% at 82 weeks.
SLIDE BACKGROUND:
--The slight upward trend seen for both the placebo and BYETTA treatment groups from Weeks 18 to 30 likely represents an initial study effect that disappears over time, and is similar in magnitude to the decrease in A1C during the 4-week placebo lead-in period.

17. Open-Label Extension – Combined BYETTA Continued to Reduce Weight
Required
DISCUSSION POINTS:
--87% of the subjects who completed the 30-week placebo-controlled, double-blind, Phase 3 studies chose to continue in open-label extension (OLE) studies.
--All subjects were given 5 mcg BYETTA for the first 4 weeks of the OLE (overall, Weeks 30 to 34), after which they received 10 mcg BYETTA for the remainder of their participation in the OLE.
--Shown is 82-week data (30 weeks from placebo-controlled, double-blind study and 52 weeks from OLE) for 393 patients.
--Of the 1446 subjects randomized to the three 30-week, blinded, placebo-controlled trials, 1125 completed and were eligible for enrollment into the OLE.
--Of the 1125 subjects, 977 (87%) enrolled into the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks and 393 had completed treatment through 82 weeks.
--Using the intent-to-treat (ITT) and Last Observation Carried Forward (LOCF) analysis method, the 977 ITT population had A1C and weight reductions at 82 weeks consistent with the 82-week completer population shown here.
--Placebo cohort upon receiving BYETTA showed an immediate decrease of weight similar to that observed with BYETTA treatment in the first 30 weeks.
--Mean body weight reductions mediated by BYETTA during the first 30 weeks were sustained and appeared to be progressive through 82 weeks.
SLIDE BACKGROUND:
--Diet and exercise counseling were not provided during the study.

18. Large Phase 3 Clinical Studies – Combined (ITT) Other Adverse Events
Required
DISCUSSION POINTS:
--In addition to hypoglycemia seen in the presence of an SFU, the adverse events (AEs) shown here were reported more frequently in the BYETTA treatment groups than in the placebo groups and had an overall incidence greater than 5%.
--AEs were mostly gastrointestinal in nature
--Nausea, the most common AE, was mostly mild to moderate in intensity
--Incidence of severe nausea low (placebo 1%, BYETTA 4%)
--Few “dropouts” due to nausea (placebo <1%, BYETTA 3%)
--Vomiting and diarrhea were reported much less frequently than nausea.
SLIDE BACKGROUND:
--Combined Phase 3 Studies: three 30-week, placebo-controlled, double-blind studies.
--Subjects with type 2 diabetes treated with MET, SFU, or MET + SFU
--Randomized to placebo (n = 483), 5 mcg BID (n = 480), or 10 mcg BID (n = 483)

19. General Prescribing Considerations Simple Dosing
Required
DISCUSSION POINTS:
--A typical treatment initiation of BYETTA includes:
--Consideration of whether any SFU dose should be reduced to minimize the risk of hypoglycemia, adjust based on blood glucose results
--No adjustment of metformin dose
--SC BID injection of BYETTA anytime within 60 minutes before the morning and evening meals with the prefilled pen that delivers fixed 5-mcg doses
--After 1 month of 5 mcg BYETTA:
--If BYETTA has been well-tolerated and if glycemic control is inadequate, then after 1 month may increase dose to 10 mcg BID, again SC anytime within 60 minutes before the morning and evening meals, with the prefilled pen that delivers fixed 10 mcg doses
--If BYETTA has not been well tolerated (e.g., due to nausea), continue the 5 mcg dosing BID, and reevaluate in the future

20. Byetta Prescribing Considerations
Adjunctive therapy to improve glycemic control in type 2 diabetic patients who are taking
Metformin
SFU
TZD

21. SIDAGLIPTIN- JANUVIA

22. More Than 50% of Secreted GLP-1 Is Degraded Before Plasma Absorption
GLP-1 (green) released into intestinal capillaries is immediately exposed to DPP-4 (red)1
> 50% of secreted GLP-1 is already degraded before it reaches the general circulation2
> 40% of circulating GLP-1 is already degraded before it reaches β-cells2
The transience of endogenous GLP-1 is dramatically illustrated in this micrograph of human ileum, in which immunohistochemical double staining displays L cells positive for GLP-1 in green surrounded by capillaries with endothelium positive for DPP-4, stained red.1 The image establishes that GLP-1 is stored almost entirely as the active amide, but is degraded by DPP-4 as soon as it enters the blood stream, circulating chiefly in an inactivated form.1
References
1. Hansen L, Deacon C, Ørskov C, et al. Glucagon-like peptide–1-(7-36)amide is transformed to glucagon-like peptide–1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology. 1999;140:5356–5363.
1. Hansen L, et al. Endocrinology. 1999;140:5356–5363; 2. Deacon CF, et al. Am J Physiol. 1996; 271(3 pt 1):E458–E464.
Histochemistry by C. Ørskov, Panum Institute, Copenhagen. Copyright © 1999, The Endocrine Society.

23. Mechanism of Action of Sitagliptin
12, 12.2
Mechanism of Action of Sitagliptin
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
JANUVIA
(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.
Concentrations of the active intact hormones are increased by JANUVIA™ (sitagliptin phosphate), thereby increasing and prolonging the actions of these hormones.
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

24. S e c t i o n
14.1
A1C, FPG, and 2-Hour PPG Placebo-Adjusted Results in a 24-Week Study of JANUVIA™ (sitagliptin phosphate) † ‡
A1C † ‡
FPG
(95% CI: –24, –10)
n=234 † ‡
2-hr PPG
(95% CI: –59, –34)
n=201
n=229
A1C, FPG, and 2-Hour PPG Placebo-Adjusted Results in a 24-Week Study of JANUVIA™ (sitagliptin phosphate)
In the 24-week study, 741 patients with type 2 diabetes were randomized to evaluate the efficacy and safety of JANUVIA.
This slide shows A1C (shown on the left), FPG (shown in the middle), and 2-hour PPG (shown on the right) results in the 24-week study.
A1C results shown are in a population with mildly to moderately elevated mean baseline A1C group of ~8%. Treatment with JANUVIA 100 mg daily provided significant improvement in A1C: The adjusted mean difference from placebo was 0.8% at 24 weeks (P<0.001). The improvement in A1C was not affected by gender, age, race, or baseline BMI.
Treatment with JANUVIA 100 mg daily provided a significant improvement in FPG compared with placebo. The adjusted mean difference from placebo was –17 mg/dL at 24 weeks (P<0.001).
The graph on the right shows the 2-hour PPG results. In addition to effects on FPG, treatment with JANUVIA 100 mg daily provided a significant improvement in PPG compared with placebo. The adjusted mean difference from placebo was –47 mg/dL at 24 weeks (P<0.001).
The results of this study indicate that JANUVIA lowers A1C levels and has effects on both FPG and PPG.
As is typical for trials of agents to treat type 2 diabetes, the mean response to JANUVIA in A1C lowering appears to be related to the degree of A1C elevation at baseline.
The percentage of patients achieving A1C goal (<7%) in monotherapy studies with JANUVIA compared with placebo was greater than 2-fold (41% vs 17%, respectively).
(95% CI: –1.0, –0.6)
JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared with placebo.
A1C lowering appears to be related to the degree of A1C baseline level.
*Compared with placebo.
†Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
‡Difference from placebo.

25. S e c t i o n
14.1
Monotherapy Studies: As Is Typical in Trials of Agents to Treat Type 2 Diabetes, Mean Response to JANUVIA™ (sitagliptin phosphate) in A1C Lowering Appears to Be Related to the Degree of A1C Elevation at Baseline
Reduction of A1C Overall and Stratified by Baseline A1C in a Prespecified Pooled Analysis of 2 Monotherapy Studies of JANUVIA
Inclusion Criteria: 7%–10%
Pooled Analysis*
Baseline A1C (%)
Overall < ≥8–< ≥9
0.0
-0.2
-0.4
n=411+
Monotherapy Studies: As Is Typical in Trials of Agents to Treat Type 2 Diabetes, Mean Response to JANUVIA™ (sitagliptin phosphate) in A1C Lowering Appears to Be Related to the Degree of A1C Elevation at Baseline
In a pooled analysis of the 2 monotherapy studies (placebo-controlled studies of 24 weeks [n=473] and 18 weeks [n=296] in patients with mild to moderate baseline A1C levels, mean 8.0%; enrollment range 7.0% to 10.0%), the overall patient population demonstrated a 0.7% drop in mean placebo-subtracted A1C.
In a prespecified subgroup analysis, the study showed that when patients were grouped by baseline A1C into those with mildly elevated A1C levels (<8%, n=411), moderately elevated A1C levels (≥8% to <9%, n=239), and the highest elevated A1C levels (≥9%, n=119), mean placebo-subtracted reductions in A1C after 18 weeks were –0.6%, –0.7%, and –1.4%, respectively (P<0.001 overall and for treatment by subgroup interactions).
The magnitude of A1C lowering by strata varied by study.
-0.6
n=769+
n=239+
-0.8
–0.6
–0.7
Change in A1C, %
–0.7
-1.0
-1.2
n=119+
-1.4
–1.4
-1.6
-1.8
The magnitude of A1C lowering by strata varied by study.
Reductions are placebo-subtracted.
* P<0.001 overall and for treatment by subgroup interactions.
+ Combined number of patients on JANUVIA or placebo

26. JANUVIA™ (sitagliptin phosphate) Effect on Body Weight
14.1, 14.2
JANUVIA™ (sitagliptin phosphate) Effect on Body Weight
Monotherapy studies
No increase in body weight from baseline with JANUVIA compared with a small decrease in the placebo group
Add-on to metformin
A similar decrease in body weight for both treatment groups
Add-on to pioglitazone
No significant difference in body weight between treatment groups
JANUVIA™ (sitagliptin phosphate): Effect on Body Weight
Body weight did not increase from baseline with JANUVIA in either the 18-week or 24-week monotherapy study compared with a small reduction in the body weight of patients given placebo.
A slight but similar decrease in body weight of patients was observed in both treatment groups of the add-on study with metformin.
There was no significant difference between JANUVIA and placebo in body weight change in the add-on study with pioglitazone.
Overall, JANUVIA appeared to have a neutral effect on body weight.

27. Dose-Adjusted (to 50 mg) AUC, μM/h Creatinine Clearance, mL/min
JANUVIA™ (sitagliptin) AUC0–inf Increased With Decreasing Creatinine Clearance
Dose-Adjusted (to 50 mg) AUC, μM/h 4 8 12 16 20 24 28
Creatinine Clearance, mL/min 10 30 50 70 90
110
130
150
170
190
210
230
AUC GMR increase <2-fold
when CrCl >50 mL/min
Dose adjustments
<30 mL/min: ¼ dose
30–50 mL/min: ½ dose
>50 mL/min: full dose
JANUVIA™ (sitagliptin) in Patients With Renal Insufficiency
This slide summarizes the rationale for dose adjustments in patients with moderate to severe renal insufficiency. A single-dose, open-label study evaluated the pharmacokinetics of JANUVIA (50 mg dose) in patients with varying degrees of chronic renal insufficiency compared with healthy subjects. In addition, the effects of renal insufficiency on JANUVIA pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed using population pharmacokinetic analyses.
Patients with mild renal insufficiency (creatinine clearance [CrCl]: 50 to <80 mL/min) did not have a clinically relevant increase in the plasma concentration of JANUVIA compared with normal healthy control individuals. An approximately 2-fold increase in the plasma area under the curve (AUC) of JANUVIA was observed in patients with moderate renal insufficiency (CrCl: 30 to <50 mL/min), and an approximately 4-fold increase was observed in patients with severe renal insufficiency (CrCl: <30 mL/min) and in patients with end-stage renal disease (ESRD) on hemodialysis compared with normal healthy control subjects.
To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in patients with ESRD requiring hemodialysis or peritoneal dialysis.
Note: A dosage adjustment is recommended based on the pharmacokinetic profile of JANUVIA, to ensure that patients receive the appropriate levels of drug required to achieve the efficacy of JANUVIA.

28. Dosage and Administrationc t i o n 2
Dosage and Administration
Usual Dosing for JANUVIA™ (sitagliptin phosphate)*
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPAR agonist.
Patients With Renal Insufficiency*,†
50 mg once daily
25 mg once daily
Moderate
Severe and ESRD‡
CrCl 30 to <50 mL/min
(~Serum Cr levels [mg/dL]
Men: >1.7–≤3.0; Women: >1.5–≤2.5)
CrCl <30 mL/min
Men: >3.0; Women: >2.5)
Dosage and Administration
This slide shows the recommended dosage and administration of JANUVIA™ (sitagliptin phosphate) in patients with type 2 diabetes.
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPR agonist such as a thiazolidinedione.
JANUVIA can be taken with or without food.
For patients with mild renal insufficiency (CrCl 50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage adjustment of JANUVIA is required.
For patients with moderate renal insufficiency (CrCl 30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women), the dosage of JANUVIA is 50 mg once daily.
For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with ESRD requiring hemodialysis or peritoneal dialysis, the dosage of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.
Because there is a need for dosage adjustment based on renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.
Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula.
Assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.
*JANUVIA can be taken with or without food. †Patients with mild renal insufficiency—100 mg once daily.
‡ESRD = end-stage renal disease requiring hemodialysis or peritoneal dialysis.

29. PRAMLINTIDE ACETATE- SYMLIN

30. Amylin the Hormone Reported in 1987 37-amino acid peptide
Co-located and co-secreted with insulin from pancreatic β-cells
Neuroendocrine hormone
Deficient in diabetes
Optional
DISCUSSION POINTS:
Amylin, a neuroendocrine hormone that is co-located and co-secreted from beta cells, plays a critical role in the appearance of glucose in the circulation after a meal. It is deficient in patients with diabetes. Y T N S G V A L I K C Q R F H
Amide A S S
Adapted from Unger RH, Foster DW. Williams Textbook of Endo (8th edition) 1992;

31. Amylin is Co-Secreted With Insulin
Meal
Meal
Meal 30
600 25
Optional
DISCUSSION POINTS:
24-hour plasma profile of insulin and amylin in healthy subjects without diabetes.
Both peptides are co-secreted by beta cells in response to nutrient intake.
In the peripheral circulation, the insulin-to-amylin molar ratio is approximately 20:1.
When secreted by the pancreas, the insulin:amylin molar ratio is approximately 50:1. This higher ratio is seen in the portal circulation but falls to approximately 20:1 in the peripheral circulation since insulin, not amylin, is extracted by the liver.
SLIDE BACKGROUND:
Data presented are mean values. 20
400
Plasma Amylin (pM)
Plasma Insulin (pM) 15
200 10 5
7 AM
Noon
5 PM
Midnight
Time (24 h)
Healthy subjects, n = 6; Mean
Data from Kruger D, et al. Diabetes Educ 1999; 25:

32. Amylin is Deficient in Diabetes
Meal 20 15
Without Diabetes
Optional
DISCUSSION POINTS:
Amylin is deficient in patients with type 1 and type 2 diabetes.
The graph illustrates postprandial amylin concentrations in subjects without diabetes, insulin-using type 2 diabetes, and type 1 diabetes.
Diabetes manifests with beta-cell failure, which results in absolute or relative deficiency of both insulin and amylin.
Type 1 diabetes: Beta-cell destruction resulting in absolute insulin and amylin deficiency.
Type 2 diabetes: Insulin and amylin secretory capacity depends on where the patient is in the natural history of his/her disease with regards to beta-cell function. Though insulin-using patients in this study had normal fasting amylin concentrations, postprandial amylin secretion was clearly abnormal.
SLIDE BACKGROUND:
Data presented are mean + SEM.
Sustacal is a registered trademark of Mead Johnson.
Plasma Amylin (pM) 10
Insulin-Using Type 2 5
Type 1
-30 30 60 90
120
150
180
Time After Sustacal® Meal (min)
Without diabetes, n = 27
Insulin-using type 2, n = 12
Type 1, n = 190; Mean data
Data from Kruger D, et al. Diabetes Educ 1999; 25:

33. Amylin Regulates Postprandial Glucose Appearance
Mechanisms of Action
Amylin*
Inhibits inappropriately high postprandial
glucagon secretion 
Optional
DISCUSSION POINTS:
Extensive preclinical studies have demonstrated that amylin’s mechanism of action include inhibition of inappropriately high postprandial glucagon secretion, slowing of gastric emptying, and the promotion of satiety and reduced caloric intake.
Slows gastric emptying
Promotes satiety and reduces caloric intake
*All amylin studies were performed in animals
SYMLIN Prescribing Information, 2005

34. Pramlintide- Symlin
Synthetic analog of amylin that overcomes the tendency of human amylin to:
Aggregate, form insoluble particles
Adhere to surfaces
Pharmacokinetic and pharmacodynamic properties similar to human amylin
Active ingredient of SYMLIN
Optional
DISCUSSION POINTS:
Pramlintide is a synthetic analog of human amylin, a naturally occurring beta-cell hormone, and is the active ingredient in SYMLIN (pramlintide acetate) injection.
Human amylin has a tendency to aggregate and adhere to surfaces, characteristics that make it unsuitable for pharmacological preparation.
Pramlintide was specifically engineered with three proline substitutions at the indicated sites (amino acids 25, 28, and 29) to overcome this tendency to self-aggregate.
The pharmacokinetic and pharmacodynamic properties of pramlintide, as measured by receptor binding and studying a spectrum of biological actions in rats in vivo, are either similar to or indistinguishable from those of human amylin.
Pramlintide is the active ingredient in SYMLIN (pramlintide acetate) injection.
Human amylin
Pramlintide (synthetic analog of amylin)
Amide S A Y T N G V L I K C Q R F H P
Adapted from Young A, et al. Drug Dev Res 1996; 37:
Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87:
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information
11/11/ :04:52 PM

35. SYMLIN Indications and Boxed Warning
SYMLIN is given at mealtimes and is indicated for:
Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin.
Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.
REQUIRED
Key Concept:
SYMLIN is indicated as an adjunct to mealtime insulin in patients with type 2 and patients with type 1 diabetes.
Risk of severe hypoglycemia, which is greater in patients with type 1 diabetes, can be reduced with appropriate patient selection, careful patient instructions, and insulin dose adjustments.
DISCUSSION POINTS:
SYMLIN is indicated as an adjunct to mealtime insulin in patients with type 2 and patients with type 1 diabetes who have failed to achieve desired glucose control despite optimal insulin therapy.
In patients with type 2 diabetes, the labeled indication extends to mealtime insulin-using patients who are also treated with a sulfonylurea and/or metformin.
The SYMLIN label has a boxed warning describing the increased risk of insulin-induced hypoglycemia associated with SYMIN use as an adjunct to mealtime insulin, particularly in patients with type 1 diabetes.
It is important to note that appropriate patient selection, careful patient instructions, and insulin dose adjustments (proactive reduction in mealtime insulin dose upon SYMLIN initiation) are important for reducing the risk of hypoglycemia.
WARNING SYMLIN is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is seen within 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk.
SYMLIN Prescribing Information, 2005
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

36. SYMLIN Reduces Postprandial Glucagon
Placebo
Symlin
Type 2, Insulin-Using
Type 1
Insulin
Insulin 60
Sustacal®
100
Sustacal
Optional
DISCUSSION POINTS:
An important mechanism of action of SYMLIN is a reduction in the paradoxical rise in plasma glucagon that often occurs in patients with diabetes during the postprandial period.
Abnormally elevated postprandial glucagon contributes to postprandial hyperglycemia in patients with diabetes.
SYMLIN reduces postprandial plasma glucagon in patients with insulin-using type 2 diabetes (left figure) and type 1 (right figure) diabetes.
SLIDE BACKGROUND:
Left figure: Crossover design trial; insulin-treated patients with type 2 diabetes (n = 12) were infused with either SYMLIN (100 mcg/h) or placebo for 5 h during a Sustacal® meal challenge test.
Right figure: Crossover trial design; patients with type 1 diabetes (n = 9) infused with SYMLIN (25 mcg/h) or placebo for 5 h during a Sustacal meal challenge test.
In both trials, SYMLIN or placebo was infused at t = 0 min, regular insulin injected at t = 30 min, and Sustacal meal ingested at t = 60 min.
Data presented are mean (±SE) plasma glucagon (pg/mL).
A similar trial, conducted in non-insulin-using patients with type 2 diabetes, yielded similar results.
Sustacal is a registered trademark of Mead Johnson. 50 80
Plasma Glucagon (pg/mL)
Plasma Glucagon (pg/mL) 40 60 30 40 1 2 3 4 5 1 2 3 4 5
Time (h)
Time (h)
Type 2, N = 12: AUC1-4 h: P = 0.005; Type 1, N = 9: AUC1-5 h: P <0.001; Mean (SE) Adapted from Fineman M, et al. Metabolism 2002; 51: ; Data from Fineman M, et al. Horm Metab Res 2002; 34: See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

37. SYMLIN Improves Postprandial Glucose
Type 2
Type 1
Placebo + Insulin Lispro
SYMLIN 120 mcg + Insulin Lispro
Placebo + Insulin Lispro
SYMLIN 60 mcg + Insulin Lispro
260
260
220
220
Optional
DISCUSSION POINTS:
The 3 key mechanisms of action of SYMLIN (inhibits inappropriately high postprandial glucagon secretion; slows gastric emptying; promotes satiety, reducing caloric intake) limit postprandial appearance of glucose in the circulation, resulting in postprandial glucose excursions.
The effect of pramlintide to reduce postprandial plasma glucose is demonstrated in two separate trials involving patients with insulin-using type 2 diabetes (left figure) and type 1 diabetes (right figure).
When insulin lispro was administered with placebo (white line) mean postprandial glucose excursions were excessive (up to 80 mg/dL) resulting in very high postprandial glucose concentrations.
The administration of SYMLIN as an adjunct to the mealtime insulin (yellow line) resulted in significant reductions in postprandial glucose concentrations.
SLIDE BACKGROUND:
These trials used a randomized, single-blind, placebo-controlled, crossover trial design.
Left figure: Patients with type 2 diabetes (n = 19) were administered placebo or 120 mcg pramlintide and insulin lispro immediately prior to a standardized meal.
Right figure: Patients with type 1 diabetes (n = 21) were administered placebo or 60 mcg pramlintide with insulin lispro immediately prior to a standardized meal.
Insulin lispro doses were adjusted for the content of the standardized meal and the anticipated effects of pramlintide. Mean insulin lispro dose (±SE) in patients with type 1 diabetes was 6.2 ± 1 U, and in patients with type 2 diabetes was 18.1 ± 2.7 U.
Plasma glucose concentration (mg/dL) was measured at regular intervals for 4 hours following the standardized meal.
Plasma Glucose (mg/dL)
Plasma Glucose (mg/dL)
180
180
140
140
100
100 1 2 3 4 1 2 3 4
Time Relative to Meal and SYMLIN (h)
Time Relative to Meal and SYMLIN (h)
Evaluable; Type 2, n = 19; Type 1, n = 21; Mean (SE)
Data from: Maggs DG, et al. Diabetes Metab Res Rev 2004; 20:55-60; Weyer C, et al. Diabetes Care 2003; 26:
SYMLIN Prescribing Information, 2005; Data on file, Amylin Pharmaceutical, Inc.
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

38. SYMLIN Slows Gastric Emptying
Insulin + Placebo
Insulin + SYMLIN 25 20 15
Optional
DISCUSSION POINTS:
One of the key mechanisms of action of SYMLIN is the regulation of gastric emptying (GE), which is an important determinant of postprandial glucose concentrations.
In patients with type 1 diabetes, a single pre-prandial dose of SYMLIN (60 mcg) significantly slowed GE of a standardized breakfast compared with administration of placebo.
The effect of SYMLIN on GE did not extend to a second meal eaten 4 hours later.
Pramlintide has also been shown to slow GE in patients with type 2 diabetes.
SLIDE BACKGROUND:
These data are from a double-blind, randomized, crossover trial in 11 males with type 1 diabetes.
Participants self-injected their usual dose of insulin at time = -30 minutes, and 15 min later they self-injected either placebo, 30 mcg SYMLIN, or 60 mcg SYMLIN.
At time = 0, a standardized breakfast (a radio-labeled pancake and milkshake) was eaten.
Radio images of the stomach were obtained for the next 8 h.
At time = 240 minutes, a second standardized radio-labeled meal was eaten (no SYMLIN was administered).
Data presented are mean, derived from t1/2 emptying of the solid component of the meal.
Similar results were observed with SYMLIN at a 30 mcg dose.
% Emptied Per Hour
After Breakfast 10 5
Placebo
60 mcg
SYMLIN
Type 1; N = 11 (crossover); Mean Adapted from Kong MF, et al. Diabetologia 1998; 41:
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

39. SYMLIN Reduces Caloric Intake
-202 kcal
(-23%)
P <0.01
1000
750
Optional
DISCUSSION POINTS:
SYMLIN increases satiety, resulting in decreased caloric intake, and may lead to weight loss in SYMLIN-treated patients.
SYMLIN reduced mean caloric intake by approximately 25% during a buffet trial in subjects with type 2 diabetes without affecting meal duration.
While total caloric intake was reduced, the proportion of carbohydrate, protein, and fat content in the meal was unchanged.
SLIDE BACKROUND:
In a randomized, double-blind, placebo-controlled, crossover trial, subjects underwent an ad-libitum buffet meal test on two occasions.
After an overnight fast, subjects received a single SC injection of SYMLIN (120 mcg) or placebo immediately followed by a standardized preload meal. After 1 h, subjects were offered an ad-libitum buffet meal. Total caloric intake and meal duration were measured.
Similar results were observed in obese patients without diabetes treated with SYMLIN (120 mcg).
CHO
Ad-Libitum
Caloric Intake (kcal)
500
CHO
Fat
Fat
250
Protein
Protein
Placebo
120 mcg
SYMLIN
Type 2, n = 11 (crossover); Mean
Adapted from Chapman I, et al. Diabetologia 2005; 48:
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

40. SYMLIN Clinical Effects TYPE 2 CLINICAL PRACTICE TRIAL
120 mcg SYMLIN + Insulin
 A1C (%)
 Weight (lbs)
 Insulin Use (%)
REQUIRED
DISCUSSION POINTS:
In patients with type 2 diabetes, SYMLIN as an adjunct to insulin resulted in significant reductions in A1C (-0.6 ± 0.1%, n = 59) and weight (-6.2 ± 0.7lb, n = 125) with significantly less mealtime (-10.3 ± 4.8%, n = 104) and total insulin (-6.4 ± 2.7%, n = 124) used compared to baseline.
SLIDE BACKGROUND:
The SYMLIN clinical practice trial was an open-label trial in patients with type 2 (n = 166) and type 1 (n = 265) diabetes incorporating insulin dose reduction during initiation, frequent self-blood glucose monitoring, diabetes education, and investigators who were skilled in the use of insulin and who selected patients from their practices.
Insulin-using patients with type 2 diabetes initiated SYMLIN at 120 mcg with a concomitant 30% to 50% reduction of mealtime insulin; during the maintenance phase of the trial, SYMLIN dose was kept at 120 mcg and insulin doses were optimized to achieve glycemic goals. This protocol for SYMLIN initiation is different from the SYMLIN Prescribing Information, which recommends initiation at 60 mcg followed by escalation to a final dose of 120 mcg as tolerated.
This data analysis includes the 26 week (6-month) observed cases endpoint data from patients with type 2 diabetes receiving the indicated dose of 120 mcg.
-0.0
Mealtime
Basal
Total
-0.6% *
-6.2 lbs *
-10.3%
-4.2%
-6.4% *
-0.2 -2 -4
-0.4 -4 -8
-0.6 -6
-12
-0.8 -8
-16
Initial insulin reduction
n = 166 at baseline; 6 month data; Mean (SE); *P <0.05 compared to baseline
Data on file, Amylin Pharmaceuticals, Inc.
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

41. Adverse Events SYMLIN TYPE 1 TRIALS
Phase 3 Clinical Trials
Clinical Practice Trial
Adverse Event
Placebo (%)
SYMLIN (%)
SYMLIN (%)
(N = 538)
(N = 716)
(N = 265)
Nausea 17 48 37
REQUIRED
DISCUSSION POINTS:
In patients with type 1 diabetes, SYMLIN was generally well tolerated and not associated with hepatic or renal toxicity, changes in clinical laboratory values or ECGs.
In patients with type 1 diabetes, the most common adverse events in the Phase 3 clinical trials and the clinical practice trial, excluding hypoglycemia, were primarily gastrointestinal in nature.
Nausea, the most common adverse event, was primarily mild to moderate in intensity, generally occurred early in the course of therapy and dissipated with time.
SLIDE BACKGROUND:
SYMLIN Phase 3 clinical trials were long-term (26 or 52 weeks), randomized, double-blind, placebo-controlled trials in which both SYMLIN and insulin doses were fixed (no SYMLIN dose titration and no proactive mealtime insulin dose reduction).
Patients in the type 1 SYMLIN Phase 3 clinical trials (placebo, n = 538, SYMLIN, n = 716) had a mean baseline A1C of 8.9 to 9.0.
This pooled data analysis of the type 1 Phase 3 clinical trials includes only the 26 week (6-month) endpoint data from patients with type 1 diabetes receiving the indicated doses of 30/60 mcg.
The SYMLIN clinical practice trial was an open-label trial in patients with type 2 (n = 166) and type 1 (n = 265) diabetes incorporating insulin dose reduction during initiation, frequent self-blood glucose monitoring, diabetes education, and investigators who were skilled in the use of insulin and who selected patients from their practices.
This data analysis of the patients with type 1 diabetes in the clinical practice trial includes the 26 week (6-month) endpoint data from patients receiving any SYMLIN dose.
Anorexia 2 17
Inflicted Injury 10 14 8
Vomiting 7 11 7 5
Arthralgia 7 2
Fatigue 4 7 5
Allergic Reaction 5 6
<1
Dizziness 4 5 2
Frequency 5%; excluding hypoglycemia; ITT; Indicated dose
SYMLIN Prescribing Information, 2005
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

42. SYMLIN Indications SYMLIN is given at mealtimes and is indicated for:
Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin.
Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.
REQUIRED
Key Concept:
SYMLIN is indicated as an adjunct to mealtime insulin in patients with type 2 and patients with type 1 diabetes.
DISCUSSION POINTS:
SYMLIN is indicated as an adjunct to mealtime insulin in patients with type 2 and patients with type 1 diabetes who have failed to achieve desired glucose control despite optimal insulin therapy.
In patients with type 2 diabetes, the labeled indication extends to mealtime insulin using patients who are also treated with a sulfonylurea and/or metformin.
SYMLIN Prescribing Information, 2005
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

43. SYMLIN Initiation Type 2: Type 1: Immediately before major meal/snack
Initially reduce mealtime insulin 50%
Advance SYMLIN to next dose if no significant nausea for 3-7 days
If nausea occurs and persists, reduce to previous dose
Type 2:
Type 1:
Maintenance Dose
45 mcg
60 mcg
30 mcg
Alternate Maintenance
Dose
15 mcg
REQUIRED
DISCUSSION POINTS:
SYMLIN should be administered immediately before major meals or snacks.
It is recommended that mealtime insulin dose be initially reduced by 50% upon SYMLIN initiation.
SYMLIN should be initiated at a dose of 60 mcg (10 U) in patients with type 2 diabetes and 15 mcg (2.5 U) in patients with type 1 diabetes.
The dose of SYMLIN should then be increased every 3 to 7 days (as tolerated based on nausea) until the maintenance dose is reached. Patients with type 2 diabetes require one SYMLIN dose titration to reach a maintenance dose of 120 mcg with major meals. Patients with type 1 diabetes require 3 SYMLIN dose titrations (in 15 mcg increments) to reach a maintenance dose of 60 mcg with major meals.
If nausea occurs and persists at a given dose, SYMLIN should be reduced to the previous dose.
Importantly, once a maintenance dose of SYMLIN is reached, insulin dose adjustments based on self-monitoring of blood glucose should be made based on the individual patient’s treatment goals.
120 mcg
60 mcg
Maintenance Dose
Initiation
Initiation
Adjust insulin based on self-monitoring of blood glucose
SYMLIN Prescribing Information, 2005
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

44. SYMLIN + Insulin: General Considerations
SC injection into abdomen or thigh
Do not mix with insulin
SYMLIN and insulin should always be given as separate injections and at separate sites at least 2 inches apart
Administer using U-100 insulin syringe
Inject before each major meal (and snack 250 kcal or 30 g CHO)
Administration:
20 U
120 mcg
10 U
60 mcg
7½ U
45 mcg
5 U
30 mcg
2½ U
15 mcg
Units
Dose
REQUIRED
DISCUSSION POINTS:
SYMLIN should be injected into the abdomen or thigh
SYMLIN should not be mixed with insulin and should be administered at separate injection sites.
Long-term insulin mixing trials have not been conducted. The pH of SYMLIN is approximately 4, thus mixing with insulin (most preparations pH of approximately 7) may alter solubility of insulin and/or SYMLIN and therefore may alter the pharmacokinetic properties of insulin and/or SYMLIN.
SYMLIN should be administered using a standard U-100 insulin syringe.
Since the concentration of SYMLIN is 0.6 mg (600 mcg) per mL (100 U), a 60 mcg SYMLIN dose is 10 U in an insulin syringe.
SYMLIN Prescribing Information, 2005
See safety information with Boxed Warning in this presentation and the accompanying Prescribing Information

45. EXUBERA

46. Respiratory Tract Surface Area

54. Metabolic Management of Type 2 Diabetes
Figure 1. Metabolic Management of Type 2 Diabetes.
Practitioners should reinforce lifestyle interventions with patients at every visit. Glycated hemoglobin levels should be checked every 3 months until the level is under 7%; after that, levels should be checked at least every 6 months. Although three oral drugs can be used, initiation and intensification of insulin therapy are preferred on the basis of effectiveness and expense. The algorithm is adapted from Nathan et al.7 No indicates that no change in pharmacologic intervention is indicated.
Nathan D. N Engl J Med 2006;355: