Transcript Core Defects of Type 2 Diabetes

Core Defects of Type 2 Diabetes
Targeting Mechanisms for a
Comprehensive Approach
Part 3 of 4
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JANUVIA™ (sitagliptin):
Adverse Reactions
Overall:
• Adverse reactions and discontinuation rates were similar to
placebo (both as monotherapy and as combination therapy)
• Incidence of hypoglycemia with JANUVIA was similar
to placebo (1.2% vs 0.9%)
• The adverse reactions, reported regardless of investigator
assessment of causality in ≥5% of patients treated with
JANUVIA 100 mg daily as monotherapy or in combination with
pioglitazone and more commonly than in patients treated with
placebo, were upper respiratory tract infection, nasopharyngitis,
and headache.
• Incidence of selected GI adverse reactions in patients treated
with JANUVIA vs placebo was as follows:
– Abdominal pain (2.3%, 2.1%)
– Nausea (1.4%, 0.6%)
– Diarrhea (3.0%, 2.3%)
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JANUVIA™ (sitagliptin): Once-Daily Dosing—
Proven 24-Hour Glycemic Control
Usual Dosing for JANUVIA*
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*,†
A dosage adjustment is recommended in patients with moderate or severe
renal insufficiency and in patients with end-stage renal disease requiring
hemodialysis or peritoneal dialysis.
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
(~Serum Cr levels [mg/dL]
Men: >3.0; Women: >2.5)
Assessment of renal function is recommended prior to JANUVIA
initiation 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.
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JANUVIA™ (sitagliptin):
Contraindications/Warnings and Precautions
• Contraindications
– None
• Warnings and Precautions
– Use in patients with renal insufficiency:
A dosage adjustment is recommended in patients with moderate
or severe renal insufficiency and in patients with ESRD requiring
hemodialysis or peritoneal dialysis.
– Use with medications known to cause hypoglycemia:
As monotherapy and as part of combination therapy with
metformin or pioglitazone, rates of hypoglycemia were similar to
rates in patients taking placebo.
The use of JANUVIA in combination with medications known to
cause hypoglycemia, such as sulfonylureas or insulin, has not
been adequately studied.
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Summary of JANUVIA™ (sitagliptin)
• JANUVIA is an oral, selective inhibitor of the DPP-4 enzyme
• Indication:
– Indicated as monotherapy and in combination with metformin
or TZDs
– Usual recommended dose is 100 mg once daily
• In clinical studies:
– JANUVIA significantly improved A1C, FPG, and PPG
– Mean A1C response with JANUVIA appears to be related to
baseline A1C level
• Overall:
– Incidence of adverse reactions was similar to that with placebo
 Overall incidence of hypoglycemia similar to that with placebo
 A neutral effect on weight relative to that with placebo
• Before prescribing JANUVIA, please read the full Prescribing
Information, available at this presentation.
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Complementary Mechanisms of Action
Combining Sitagliptin and Metformin
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Metformin Lowers Plasma Glucose by Lowering Hepatic
Glucose Production and by Improving Insulin Sensitivity
Liver
↓ Gluconeogenesis
↓ Glycogenolysis
↑ Glycogen synthesis
Metformin
Blood glucose
Muscle
Adipose
tissue
Liver
1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 2. Setter SM et al. Clin Ther. 2003;25:2991–3026.
3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626.
5. Bailey CJ et al. N Engl J Med. 1996;334:574–579.
↑Glucose
uptake in
muscle and
fat by
increasing
insulin
sensitivity5
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The Combination of Sitagliptin and Metformin
Addresses
the 3Reduces
Core Defects
of Type 2 Diabetes
Sitagliptin
Hyperglycemia
Metformin
in a Complementary Manner
Sitagliptin improves
beta-cell function and
increases insulin
Beta-Cell
synthesis and
Dysfunction
release.
Hepatic Glucose
Sitagliptin reduces HGO
through suppression of glucagon Overproduction
(HGO)
from alpha cells.
*Please see corresponding speaker note for references.
Metformin has insulinsensitizing properties.
Insulin
Resistance
Metformin decreases HGO by
targeting the liver to decrease
gluconeogenesis and
glycogenolysis.
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JANUMET™ (sitagliptin/metformin HCl):
Indications and Usage
• Indication
– JANUMET is indicated as an adjunct to diet and
exercise to improve glycemic control in adult patients
with type 2 diabetes mellitus who are not adequately
controlled on metformin or sitagliptin alone or in
patients already being treated with the combination of
sitagliptin and metformin.
• Important limitations of use
– JANUMET should not be used in patients with type 1
diabetes or for the treatment of diabetic ketoacidosis.
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JANUMET™ (sitagliptin/metformin HCl):
Boxed Warning: Lactic Acidosis
• The labeling for JANUMET contains a boxed warning for lactic
acidosis, a rare,* but serious, metabolic complication that can occur
due to metformin accumulation during treatment with JANUMET.
• The risk of lactic acidosis increases with conditions such as sepsis,
dehydration, excess alcohol intake, hepatic insufficiency, renal
impairment, and acute congestive heart failure.
• The onset is often subtle, accompanied only by nonspecific symptoms
such as malaise, myalgias, respiratory distress, increasing
somnolence, and nonspecific abdominal distress.
• Laboratory abnormalities include low pH, increased anion gap, and
elevated blood lactate.
• If acidosis is suspected, JANUMET should be discontinued and the
patient hospitalized immediately.
See the full Prescribing Information for the complete Boxed Warning.
*The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low
(approximately 0.03 cases/1,000 patient-years, with approximately 0.015 fatal cases/1,000 patient-years). When
lactic acidosis occurs, it is fatal in approximately 50% of cases.
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JANUMET™ (sitagliptin/metformin HCl):
Pharmacokinetics
• Bioequivalence: A clinical bioequivalence study has
demonstrated that JANUMET is bioequivalent to
corresponding doses of sitagliptin plus metformin as
individual tablets
• Bioavailability:
– Sitagliptin ~87%
– Metformin ~50–60%
• Metabolism: both sitagliptin and metformin are
predominantly excreted unchanged in the urine
• Pharmacokinetics: no meaningful changes in either
sitagliptin or metformin with co-administration
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