1. New therapies in diabetes mellitus
4/21/2017 1:06 AM
New therapies in diabetes mellitus
(or how to keep your friendly diabetologist busy)
Melissa Meredith, M.D.
Mar. 7, 2007

2. New Available Therapies
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New Available Therapies
Incretin agents
Incretin agonists
Exenatide (Byetta)
DPP-IV inhibitors
Sitagliptin (Januvia)
Vildagliptin (Galvus)
Insulin
Insulin detemir (Levemir)
Inhaled insulin- Exubera
Pramlintide (Amylin)

3. Patterns of Glucose, Insulin, and Glucagon in Type 2 Diabetes
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Patterns of Glucose, Insulin, and Glucagon in Type 2 Diabetes
400
Glucose
Postprandial hyperglycemia
Type 2 diabetes
300
Normal
mg/dL
200
100
Glucagon
High and not suppressed
360
Insulin
Delayed and reduced 60
240
pmol/L
fmol/L 45
120 30
-60 60
120
180
240
300
-60 60
120
180
240
300
Minutes
Minutes
Mitrakou A et al. Diabetes. 1990;39:

4. The Incretin Effect in Subjects Without and With Type 2 Diabetes
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The Incretin Effect in Subjects Without and With Type 2 Diabetes
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
0.6
0.5
0.4
0.3
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1 80 60 40 20 80 60 40 20
The incretin effect is diminished
in type 2 diabetes.
Incretin Effect
nmol / L
nmol/L
IR Insulin, mU/L
IR Insulin, mU/L
The Incretin Effect in Subjects Without and With Type 2 Diabetes
Speaker notes
In 1964, it was demonstrated that the insulin secretory response was greater when glucose was administered orally through the GI tract than when glucose was delivered via IV infusion. The term incretin effect was coined to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion.1,2
The incretin effect implies that nutrient ingestion causes the gut to release substances that enhance insulin secretion beyond the release caused by the rise in glucose secondary to absorption of digested nutrients.1
Studies in humans and animals have shown that the incretin hormones GLP-1 and GIP account for almost all of the incretin effect,3 stimulating insulin release when glucose levels are elevated.4,5
Although the incretin effect is detectable in both healthy subjects and in those with diabetes, it is abnormal in those with diabetes, as demonstrated by the study shown on the slide.6
In this study, patients with type 2 diabetes and weight-matched, metabolically healthy control subjects were given glucose either orally or IV to achieve an isoglycemic load.6
In those without diabetes (shown on the left), the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect)—that is, the pancreatic beta cells secreted much more insulin when the glucose load was administered through the GI tract.6
In patients with type 2 diabetes (shown on the right), the same effect was observed but was diminished in magnitude.6
The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone.7,8
Purpose:
To introduce the concept of the incretin effect in healthy individuals and the abnormality
in patients with type 2 diabetes.
Takeaway:
Gastrointestinal ingestion of glucose stimulates a greater insulin response than that seen from
IV glucose infusion. This effect is significantly decreased in patients with type 2 diabetes. The response is largely attributed to the effect of incretins. 60
120
180 60
120
180
Time, min
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Permission pending.
References
1. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75–85.
2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
3. Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659.
4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544.
5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
6. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.
7. Creutzfeldt W. The entero-insular axis in type 2 diabetes—incretins as therapeutic agents. Exp Clin Endocrinol Diabetes. 2001;109 (suppl 2):S288–S303.
8. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

5. GLP-1 Effects in Humans Understanding the Natural Role of Incretins
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GLP-1 Effects in Humans Understanding the Natural Role of Incretins
 Beta-cell
workload
GLP-1 secreted upon the ingestion of food
Promotes satiety and reduces appetite
Alpha cells:
 Postprandial glucagon secretion
Not Required
DISCUSSION POINTS:
GLP-1: key incretin with characteristics that make it an appealing target for therapy in type 2 diabetes.
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:
 Beta-cell
response
Liver:  Glucagon reduces hepatic glucose output
Beta cells: Enhances glucose-dependent insulin secretion
Decreased apoptosis
Beta cell regeneration
Stomach: Helps regulate gastric emptying
GLP-1 levels are decreased in DM 2
Adapted from Flint A, et al. J Clin Invest. 1998;101: Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: Adapted from Nauck MA, et al. Diabetologia. 1996;39: Adapted from Drucker DJ. Diabetes. 1998;47:

6. results in lowering glucose levels in patients with type 2 diabetes.
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Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
15.0
250
12.5
Placebo
GLP-1
Glucose
mmol/L *
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 decrease. 40
Insulin
200
pmol/L 30
150 *
mU/L 20
100
Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
Speaker notes
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 IV 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 *
Purpose:
To show the glucose-dependent effect of GLP-1 infusion on insulin and glucagon release in patients with type 2 diabetes.
Takeaway:
GLP-1 stimulates insulin secretion and suppresses glucagon release only when glucose
levels are elevated (glucose dependent) and that the combination of both these effects
results in lowering glucose levels in patients with type 2 diabetes. 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 from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag. Permission pending
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.

7. Effect of Exenatide on A1C
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Effect of Exenatide on A1C
MET
SFU
MET + SFU
0.5
0.2
A1C
(%)
0.1
0.1
-0.5 * *
-0.9
-0.6 * *
-0.8
REQUIRED
DISCUSSION POINTS:
Significant A1C reductions were seen with the 5-mcg and 10-mcg BYETTA treatment arms in all three studies (P<0.005 vs placebo).
The A1C lowering in the 10-mcg arm was greater than in the 5-mcg arm (P<0.05).
Baseline A1C: placebo group = 8.5%; 5-mcg BYETTA BID treatment arm = 8.4%; 10-mcg BYETTA BID treatment arm = 8.5%.
BYETTA is associated with reduced A1C no matter the background oral therapy (MET and/or SFU), and disease duration (SFU + MET study patients had longer disease duration).
SLIDE BACKGROUND:
Three 30-week, placebo-controlled, double-blind, Phase 3 studies; subjects with type 2 diabetes randomized to placebo or 5 mcg or 10 mcg BYETTA BID with MET and/or SFU, N = 1446.
Combined pivotals: MET, SFU, MET + SFU; 30-week, double-blind, Phase 3 studies; ITT subjects with type 2 diabetes were randomized to placebo (n = 483), 5 mcg BYETTA BID (n = 480) or 10 mcg BYETTA BID (n = 483). The Last Observation Carried Forward (LOCF) method was applied to the data.
Individual pivotals:
MET (placebo [n = 113 and baseline A1C = 8.2], 5 mcg BYETTA BID [n = 110 and baseline A1C = 8.3], 10 mcg BYETTA BID [n = 113 and baseline A1C=8.2])
SFU (placebo [n = 123 and baseline A1C = 8.7], 5 mcg BYETTA BID [n = 125 and baseline A1C = 8.5], 10 mcg BYETTA BID [n = 129 and baseline A1C = 8.6])
MET + SFU (placebo [n = 247 and baseline A1C = 8.5], 5 mcg BYETTA BID [n = 245 and baseline A1C = 8.5], 10 mcg BYETTA BID [n = 241 and baseline A1C=8.5])
-0.5
-0.4 *
- 0.8 -1 * n
Baseline
Placebo BID
Exenatide 5 mcg BID
Exenatide 10 mcg BID
See Important Safety Information included in this presentation Mean (SE); *P<0.005 Data from DeFronzo RA, et al. Diabetes Care. 2005;28: Data from Buse JB, et al. Diabetes Care. 2004;27: Data from Kendall DM, et al. Diabetes Care. 2005;28:

8. Exenatide Sustained A1C Reduction 2-Year Completers
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Exenatide Sustained A1C Reduction 2-Year Completers
DISCUSSION
Treatment with exenatide resulted in improvements in glycemic control:
There was a sustained reduction in A1C at 30 weeks and 2 years of -1.1 ± 0.1% (95% CI: ‑1.3 to ‑1.0%, P<0.05 at 2 years)
50% of subjects completing 2 years of exenatide treatment achieved A1C ≤7%
31% of subjects completing 2 years of exenatide treatment achieved A1C ≤6.5%
Reduction in A1C from baseline in the 2-year eligible ITT population was -0.8 ± 0.1%
SLIDE BACKGROUND
Patients with T2DM treated with MET and/or SFU were randomized to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomized trials and received exenatide in the subsequent open-label extensions
At the time of this analysis, all patients (N=283) had received 2 years of exposure to exenatide
Sustained reduction in FPG concentration after 2 years of -25 ± 3 mg/dL (95% CI: ‑30.8 to ‑19.7 mg/dL, P<0.05)
This data is from Cohorts 1 and 2:
Cohort 1: PBO-controlled and open-label uncontrolled extension studies
Cohort 2: Open-label uncontrolled extension trial (104 weeks in duration)
N = 283; Mean (± SE); P<0.05.
Henry R, et al. Diabetes 2006; 55:A116.

9. Exenatide Continued to Reduce Weight 2-Year Completers
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Exenatide Continued to Reduce Weight 2-Year Completers
DISCUSSION
Exenatide treatment resulted in progressive reductions in body weight of -2.4 kg at 30 weeks and ± 0.3 kg at 2 years (mean ± SE, 95% CI: ‑5.4 to ‑4.0 kg, P <0.05 from baseline)
Reduction in body weight from baseline in the 2-year, eligible ITT population was -3.6 ± 0.2 kg
SLIDE BACKGROUND
Patients with T2DM treated with MET and/or SFU were randomized to receive placebo or exenatide in the original placebo-controlled, double blind, Phase 3, randomized trials and received exenatide in the subsequent open-label extensions
At the time of this analysis, all patients (N=283) had received 2 years of exposure to exenatide
This data is from Cohorts 1 and 2:
Cohort 1: PBO-controlled and open-label uncontrolled extension studies
Cohort 2: Open-label uncontrolled extension trial (104 weeks in duration)
No diet and exercise regimen was provided.
N = 283; Mean (± SE); P<0.05.
Henry R, et al. Diabetes 2006; 55:A116.

10. GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
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GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal GIP and GLP-1 release
DPP-4
Enzyme
GIP-(1–42)
GLP-1(7–36)
Intact
GIP-(3–42)
GLP-1(9–36)
Metabolites
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
GLP-1 and GIP have short biological half-lives; they are rapidly degraded by DPP-4.1–3
DPP-4 is a widely expressed enzyme present on cells in many tissues, including the kidney, GI tract, biliary tract and liver, placenta, uterus, prostate, skin, lymphocytes, and endothelial cells (which may be involved in the inactivation of circulating peptides).4
Rapid Inactivation
Half-life*
GLP-1 ~ 2 minutes
GIP ~ 5 minutes
GIP and GLP-1 Actions
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
References:
1. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131.
2. Kieffer TJ, McIntosh CHS, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology ;136:3585–3596.
3. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80:952–957.
4. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100.

11. S e c t i o n
14.1
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A1C, FPG, and 2-Hour PPG Placebo-Adjusted Results in a 24-Week Study of Sitagliptin Phosphate(Januvia) † ‡
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)
Sitagliptin 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.

12. S e c t i o n
14.1
Monotherapy Studies: Mean Response of A1c to Sitagliptin Appears to Be Related to the Degree of A1C Elevation at Baseline
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Reduction of A1C Overall and Stratified by Baseline A1C in a Prespecified Pooled Analysis of 2 Monotherapy Studies of sitagliptin
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 sitagliptin or placebo

13. Comparison of incretin agents
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Comparison of incretin agents
Exenatide
DPP-IV inhibitor
FDA indications
Combo with SU, metformin or TZD
Mono; combo with metformin or TZD
Mode of administration
Injected BID
Oral; once daily
Weight effects
Average loss 10#
Weight neutral
Side effects
30% nausea
Virtually none
Renal insufficiency
Not recommended
Dose adjustment necessary

14. Summary- incretin agents
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Summary- incretin agents
Incretin agonists and DPP-4 inhibitors appear to have similar ability to lower blood glucose and A1c
Both agents are most suitable for patients with diabetes for <10 years duration (need to be able to secrete adequate insulin)
Consider when patient has reasonable FPG, but post-prandial hyperglycemia
Both agents are costly ($ /month range)
ADA recommends metformin as first-line agent for virtually all patients with DM 2 (unless contraindicated or not tolerated) and these agents currently are best suited for second or third line therapy
Summary
JANUVIA™ (sitagliptin phosphate) is:
Orally active and a selective inhibitor for the DPP-4 enzyme
Indicated as an adjunct to diet and exercise to improve glycemic control
Recommended dose is 100 mg once daily
In clinical studies
JANUVIA significantly improved A1C, FPG, and PPG compared with placebo
Mean response with JANUVIA on A1C lowering appears to be related to the baseline A1C level
Overall:
Incidence of adverse reactions with JANUVIA was similar to placebo
JANUVIA showed
Overall incidence of hypoglycemia similar to placebo
A neutral effect on weight relative to placebo .

15. Strategies for engineering basal insulins
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Strategies for engineering basal insulins
Modification of isoelectric point - precipitation at pH 7.4
Insulin glargine
Strengthening of hexamer association, e.g.,
Co(III)-hexamer (substituting Zn ions with Cobalt at high insulin concentration)
Acylation with hydrophobic residues, e.g.,
Insulin detemir
Three principle strategies have been adopted to engineer basal insulin analogs with protracted action profiles.
One strategy has been to modify the isoelectric point such that the insulin is soluble during injection (when in a suitable medium), but crystallizes into a slowly-absorbed precipitate depot in the neutral pH of the subcutaneous environment. This method has been used with some success with insulin glargine, which has a very protracted action, but variability may still be a problem – perhaps as a result of physical variation in the nature of precipitation from one injection to another. The redissolution rate of any precipitated agent shows some variation from injection to injection.
Another method has been to attempt to strengthen the hexamer association of insulin at high concentrations by substituting Zn ions with Cobalt. However, while hexamers of Co(III)-insulin are chemically cleaved in the circulation, the time-action profile has not shown advantages over NPH insulin.
The most recent strategy has been to acylate the insulin molecule with fatty acid residues, encouraging hexamer formation and enabling the resulting analog to bind to albumin. This approach has met with success in the development of insulin detemir.

16. Insulin detemir: Mode of protraction
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Insulin detemir: Mode of protraction
Self-association (hexameric)
Fatty acid side chains bind to albumin in injection depot
Albumin binding in circulation
Protracted absorption
‘Buffering’ effect and minor contribution to protraction
A series of physico-chemical experiments have clarified the mechanism of protraction of insulin detemir actions.
Insulin detemir forms a relatively stable hexamer, and the fatty-acid side chains enable weak hexamer-hexamer contacts to be made at high concentration. Osmolarity and elution experiments have suggested that insulin detemir forms a hexamer-dihexamer equilibrium in the injection depot, which increases the depot residence time as associated insulin is slower to penetrate the capillary wall than monomeric insulin detemir.
This delay in absorption provides the opportunity for albumin binding to occur in the depot and this further protracts the absorption process. This has been shown in elution and subcutaneous disappearance rate studies using radio-labeled insulin analog/albumin in pigs. Thus, most of the protraction of the time-action profile of insulin detemir is due to protracted absorption.
Once absorbed into the circulation, monomeric insulin detemir will bind to albumin in blood (about 98% is albumin-bound), but this is a dynamic reversible interaction. This process accounts for some further protraction of actions, but is not as important as delayed absorption.
When insulin detemir leaves the circulation and reaches the interstitial fluid in target tissues, albumin binding will again take place. The contribution of this albumin binding to protraction is negligible, however, as insulin detemir has a much greater affinity for insulin receptors.

17. PD profiles in patients with type 1 DM
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PD profiles in patients with type 1 DM
GIR: Glucose infusion rate
6.0
Pharmacodynamic Parameters for LEVEMIR and NPH
LEVEMIR
NPH
0.2 U/kg
0.4 U/kg
0.3 U/kg
AUCGIR (mg/kg)
419
1184
743
GIRmax (mg/kg/min)
1.1
1.7
1.6
5.0
4.0
3.0
GIR (mg/kg/min)
2.0
1.0
Study 1338, Plank et al. 2005
The time-action profile of insulin detemir has been shown to be dose-dependent, protracted and relatively low and smooth. This slide shows pharmacodynamic data from a comparative study involving several doses of Levemir and 0.3 U/kg NPH insulin administered during a glucose clamp procedure. In such procedures, the glucose infusion rate (GIR) at any given time point is a measure of the magnitude of insulin actions at that time. The mean duration of action of Levemir was up to 24 hours depending upon dose administered, and this profile of Levemir is appropriate for once- or twice-daily administration. 4 8 12 16 20 24
Time since Injection (hrs)
Levemir 0.2 U/kg
Levemir 0.4 U/kg
NPH 0.3U/kg
Plank et al. Diabetes Car.e. 2005;28(5):

18. PD profiles in patients with type 2 DM
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PD profiles in patients with type 2 DM
Mean GIR profiles (smoothed with a local regression technique) for 0.4 and 0.8 U/kg Levemir and glargine*
Levemir
glargine 2 4 6 8 10 12 14 16 18 20 22 24
0.5
1.0
1.5
2.0
2.5
3.0
Glucose infusion rate
(mg/kg/min)
Time (h)
0.4 U/kg
0.8 U/kg
This is the first head-to-head comparison of the pharmacodynamic (PD) and pharmacokinetic (PK) properties of insulin detemir (IDet) and insulin glargine (IGlar) in subjects with type 2 diabetes (T2D). Twenty-seven insulin-treated male subjects with T2D (BMI 30.8 ± 2.6 kg/m2 (mean ± SD), HbA1c 7.6 ± 1.1%) were enrolled in this randomized, double-blind, parallel trial and received 0.4, 0.8, and 1.4 U/kg of IDet or IGlar under glucose clamp conditions; target blood glucose (BG) 90 mg/dL, iv insulin infusion (rate 0.3 mU/kg/min 3h–0.5h before dosing), clamp duration 24h or until BG>200 mg/dL. The mean glucose infusion rate (GIR) profiles for IDet and IGlar were similar in shape/flatness (figure) and showed increasing effect with increasing dose. The dose-response relationship (log-effect versus log-dose) was similar for the insulin preparations in intercept and slope
(p-values: slope=0.23, intercept=0.84). Within-subject variability was lower for IDet than for IGlar (p-values: within-subject<0.0001, between-subject=0.38). The duration of action (time from dosing to GIR<0.5 mg/kg/min) increased with rising doses for both IDet and IGlar without major difference between the two preparations for the clinically relevant doses 0.4 and 0.8 U/kg (IDet 719 ± 512, 1007 ± 408; IGlar: 613 ± 443, 1162 ± 413 min) and was >24h in most subjects with the highest dose (1328 ± 154 vs ± 0 min). In conclusion, this first head-to-head comparison of the PD/PK-properties of IDet and IGlar in subjects with T2D confirmed lower within-subject variability for IDet and showed no substantial differences in the shape of the profiles, duration of action and dose-response relationship between both analogues.
*An additional dose of 1.4 U/kg was tested. No significant difference in pharmacodynamics was observed.
Klein et al. Diabetes. 2006;55(suppl 1):A76, 325-OR

19. Individual GIR profiles
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Individual GIR profiles 6 3
Levemir
GIR (mg/kg/min) 6 3 8 16 24 8 16 24 8 16 24 6 3
NPH-insulin
GIR (mg/kg/min) 6 3 8 16 24 8 16 24 8 16 24
Each panel represents 4 injections of the indicated insulin formulation in an individual study subject of Study 1450. 6 3
Insulin glargine
GIR (mg/kg/min) 6 3 8 16 24 8 16 24 8 16 24
Elapsed Time (hours)
Each panel = 4 injections of the indicated formulation in an individual study subject.
Heise et al. Diabetes. 2004;53:

20. Summary- insulin detemir
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Summary- insulin detemir
Protracted time-action profile similar to insulin glargine
Comparable glycemic results as NPH insulin and insulin glargine
Lower risk of nocturnal hypoglycemia as compared with NPH-insulin
Less weight gain than NPH insulin and insulin glargine
Best results with BID (AM and HS)
Cost similar to glargine

21. Pfizer / Aventis / Nektar Exubera® Pulmonary Insulin Delivery System
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Pfizer / Aventis / Nektar Exubera® Pulmonary Insulin Delivery System

22. Mean Glucose Infusion Rate
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INH Absorbed More Rapidly than SC Regular; as Rapidly as SC Lispro - Study 017
100
INH 6 mg
Insulin lispro 18 U
Regular insulin 18 U 80 60
Mean Glucose Infusion Rate
(% of Maximum) 40 20 60
120
180
240
300
360
420
480
540
600
Time (min)
Diabetologia 2000;43(Suppl 1):A46.

23. Summary of INH therapy in Type 1DM
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Summary of INH therapy in Type 1DM
Similar level of glycemic control over week time periods as SC NPH/regular insulin regimens
Short-term decreases in DLCO and increases in insulin antibody binding noted without apparent clinical consequences
Studies comparing to insulin analogs and real efficacy studies are on-going
Pts on INH therapy still require at least 1 SC injection/day of basal insulin

24. Summary of INH Therapy in DM2
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Summary of INH Therapy in DM2
Achieves similar glycemic control compared to SC NPH/regular insulin regimens over weeks
Achieves better glycemic control than failing OHA regimens over weeks
Patient satisfaction scores and quality of life scores higher with inhaled insulin
Patients report higher likelihood of using insulin if able to use inhaled insulin

25. Safety of inhaled insulin
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Safety of inhaled insulin
Adverse events: increased cough; no increased SAEs or deaths
Hypoglycemia- similar rates of hypoglycemia (vs. Regular); no difference in severe hypoglycemia
Pulmonary safety
Small decreases in FEV1 and DLCO were observed
Changes were not progressive or apparently clinically significant, but did resolve with discontinuation
Insulin antibodies
Increased production of IgG antibodies, esp in DM 1 (30%)
Clinical significance unknown

26. 4/21/2017 1:06 AM
Using Exubera
Available in 1 mg (approx. 3 units) and 3 mg (approx. 8 units) blisters
Initial pre-meal dosing determined by weight
Take no more than 10 minutes before the meal
Take in one breath and hold for 5 seconds
Clean the inhaler weekly
Replace release unit every 2 weeks
Store insulin at room temperature

27. 4/21/2017 1:06 AM
Using Exubera
Get baseline spirometry (FEV1) and recheck in 6 months and then yearly
Do not use in smokers (need to have quit for 6 months prior to using)
Not recommended for people with COPD or asthma
Probably safe to use with upper respiratory illness; unclear with pneumonia

28. Conclusions- inhaled insulin
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Conclusions- inhaled insulin
Inhaled insulin generally well-tolerated and as efficacious as Regular insulin in controlling blood glucose
Best use will probably be in adding to oral agents in type 2 patients
Studies comparing to insulin analogs are underway
Need longer duration studies for safety
Cost is about 30% higher than current insulins

29. 4/21/2017 1:06 AM
Pramlintide (Symlin)
Analog of a beta-cell protein named amylin (islet-associated polypeptide)
Physiologic actions
Delayed gastric emptying
Reduced post-prandial glucose excursion
Neuroendocrine effects on appetite and satiety
FDA approved for use in type 1 and type 2 diabetes who are not controlled on insulin therapy
Injected with each meal
Trend to weight loss (or no gain with improved A1c)

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32. 4/21/2017 1:06 AM
Pramlintide (Symlin)
Is injected with each meal containing at least 30 gms of carbohydrate
Cannot mix with insulin
Should not be used in patients who are non-compliant, have an A1c>9.0%, gastroparesis, severe hypoglycemia, children
Start with low dose to minimize GI effects
Need to decrease bolus insulin dose
Strongly encourage using this medication with a diabetes educator who is experienced in insulin dose adjustment