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Core Defects of Type 2 Diabetes
Targeting Mechanisms for a
Comprehensive Approach
Part 4 of 4
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JANUMET™ (sitagliptin/metformin HCl) Label Data:
Sitagliptin Plus Metformin Provided Significant Improvements
in Glycemic Control Beyond Metformin Alone*
24-week placebo-adjusted results†
A1C
FPG
2-Hour PPG
Mean Baseline A1C: 8.0%
P <0.001*
Mean Baseline: 170 mg/dL
P <0.001*
Mean Baseline: 275 mg/dL
P <0.001*
–0.25
–0.50
–1.00
–0.7%‡
(95% CI: –0.8, –0.5)
n=454
–10
–20
–30
–25‡
–40
–50
–60
Mean Change in PPG, mg/dL §
n=453
–0.75
0
0
Mean Change in FPG, mg/dL §
Mean Change in A1C, % §
0.00
(95% CI: –31, –20)
*Compared with placebo plus metformin.
†In patients inadequately controlled on metformin monotherapy.
‡Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value.
§Difference from placebo.
n=387
–10
–20
–30
–40
–50
–60
–51‡
(95% CI: –61, –41)
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JANUMET™ (sitagliptin/metformin HCl) Label Data:
Percentage of Patients Achieving A1C <7.0% With the
Combination of Sitagliptin and Metformin
24-Week Study
P<0.001
47%
Percentage of patients
50
n=453
40
30
20
18%
n=224
10
0
Placebo
+
Placebo
metformin
Sitagliptin
JANUVIA+
metformin
A total of 41 (of 224) patients on placebo plus metformin and 213 (of 453) patients on sitagliptin plus
metformin achieved A1C <7.0%.
Intent-to-treat population using last observation on study before pioglitzone rescue therapy.
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JANUMET™ (sitagliptin/metformin HCl) Label Data:
Weight Change and Hypoglycemia Incidence in Patients
Treated With the Combination of Sitagliptin and Metformin
24-Week Add-On Therapy to Metformin Study
Weight Change
Hypoglycemia
Placebo + metformin (n=169)
Placebo + metformin (n=169)
10
1
8
Patients, %
Mean Change in Body Weight
From Baseline, lb
Sitagliptin + metformin (n=399)
2
0
–1
–2
–3
–1.3
–1.5
Sitagliptin + metformin (n=399)
6
4
2.1%
2
1.3%
0
Patients with at least 1 episode of
hypoglycemia over 24 weeks
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JANUMET™ (sitagliptin/metformin HCl) Label Data:
Overall Incidence of Selected Adverse Reactions in Patients
Treated With the Combination of Sitagliptin and Metformin
Overall:
• The incidence of side effects and discontinuation rates with sitagliptin and
metformin were similar to those with placebo and metformin.
• The incidence of hypoglycemia in patients treated with sitagliptin and
metformin was similar to that in patients treated with placebo and metformin
(1.3% vs 2.1%).
• The incidence of gastrointestinal disturbances in patients treated with
sitagliptin and metformin was similar to that in patients treated with placebo
and metformin (11.6% vs 9.7%).
• The most common adverse experience in sitagliptin monotherapy reported
regardless of investigator assessment of causality in ≥5% of patients and
more commonly than in patients given placebo was nasopharyngitis.
• The most common (>5%) established adverse reactions due to initiation of
metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal
discomfort, indigestion, asthenia, and headache.
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JANUMET™ (sitagliptin/metformin HCl) Label Data:
Incidence of Selected Gastrointestinal Adverse Reactions in
Patients Treated With Sitagliptin and Metformin
Incidence in Patients With Sitagliptin or Placebo Added to
a Twice-Daily Metformin Regimen
Sitagliptin and Metformin,
%
Placebo and Metformin,
%
Nausea
1.3
0.8
Vomiting
1.1
0.8
Abdominal Pain
2.2
3.8
Diarrhea
2.4
2.5
Other AEs
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JANUMET™ (sitagliptin/metformin HCl):
Contraindications
• JANUMET is contraindicated in patients with:
– Renal disease or renal dysfunction, eg, as suggested
by serum creatinine levels ≥1.5 mg/dL (males),
≥1.4 mg/dL (females) or abnormal creatinine clearance
– Acute or chronic metabolic acidosis, including diabetic
ketoacidosis, with or without coma
• JANUMET should be temporarily discontinued in patients
undergoing radiologic studies involving intravascular
administration of iodinated contrast materials, because
use of such products may result in acute alteration of
renal function.
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JANUMET™ (sitagliptin/metformin HCl):
Selected Warnings and Precautions
• Metformin and sitagliptin are known to be substantially
excreted by the kidney. The risk of metformin accumulation
and lactic acidosis increases with the degree of impairment of
renal function. Thus, patients with serum creatinine levels
above the upper limit of normal for their age should not
receive JANUMET.
• Before initiation of therapy with JANUMET and at least
annually thereafter, renal function should be assessed and
verified as normal.
• Concomitant medication(s) that may affect renal function or
result in significant hemodynamic change or may interfere with
the disposition of metformin, such as cationic drugs that are
eliminated by renal tubular secretion [see Drug Interactions
(7.1)], should be used with caution.
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JANUMET™ (sitagliptin/metformin HCl):
Selected Warnings and Precautions
• Cardiovascular collapse (shock) from whatever cause, acute
congestive heart failure, acute myocardial infarction and other
conditions characterized by hypoxemia have been associated with
lactic acidosis and may also cause prerenal azotemia. When such
events occur in patients on JANUMET therapy, the drug should be
promptly discontinued.
• Use of JANUMET should be temporarily suspended for periods of
stress, trauma, infection, or any surgical procedure (except minor
procedures not associated with restricted intake of food and fluids)
and should not be restarted until the patient's oral intake has
resumed and renal function has been evaluated as normal.
• Patients should be warned against excessive alcohol intake, acute or
chronic, while receiving JANUMET.
• JANUMET should generally be avoided in patients with clinical or
laboratory evidence of hepatic disease.
• Hematologic parameters should be measured annually.
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JANUMET™ (sitagliptin/metformin HCl):
Drug Interactions
• Drug Interactions
– Pharmacokinetic drug interaction studies with JANUMET
have not been performed; however, such studies have been
conducted with the individual components of JANUMET
(sitagliptin and metformin hydrochloride).
– Use cationic drugs with caution.
– There are no known clinically meaningful drug interactions
for sitagliptin.
• Use of Metformin With Other Drugs
– When drugs that tend to produce hyperglycemia are
administered to a patient receiving JANUMET, the
patient should be closely monitored to maintain adequate
glycemic control.
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JANUMET™ (sitagliptin/metformin HCl):
Recommended Dosing
• In general: twice daily with meals, with gradual dose escalation, to
reduce the gastrointestinal side effects due to metformin
• Starting dose based on patient’s current regimen
• Available dosage forms:
– 50 mg sitagliptin/500 mg metformin
– 50 mg sitagliptin/1,000 mg metformin
Tablets not shown at actual size.
• Patients inadequately controlled on metformin:
– Starting dose equal to 100 mg sitagliptin daily plus current
metformin dose
• Patients inadequately controlled on sitagliptin:
– Starting dose 50 mg sitagliptin/500 mg metformin twice daily
– Titrated up to 50 mg sitagliptin/1,000 mg metformin twice daily
• Patients switching from sitagliptin coadministered with
metformin:
– Initiate at current doses of sitagliptin and metformin
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Case Study: Caroline D.
9.0%
8.8%
8.6%
A1C, %
8.4%
Patient History:
45-year-old woman,
bus driver
BMI = 31 kg/m2
Borderline hypertension
Type 2 diabetes diagnosed
Lab Results:
A1C = 7.6%
FPG = 150 mg/dL
Serum creatinine = 0.9 mg/dL
(CrCl = 104 mL/min)
Treatment:
Diet and exercise
recommended
8.2%
Lab Results:
A1C = 8.0%
FPG = 170 mg/dL
Serum creatinine = 1.0 mg/dL
(CrCl = 100 mL/min)
Treatment:
Metformin up-titrated to
2,000 mg/day
Considerations for next
treatment decision:
• Mechanism of action
• Efficacy
• Tolerability
Current Lab Results:
A1C = 7.7%
FPG = 150 mg/dL
Treatment:
Metformin initiated
8.0%
7.8%
7.6%
7.4%
7.2%
7.0%
2005
2006
2007
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Overall Summary
• A majority of patients with type 2 diabetes may fail to attain A1C
goal with the conventional treatment paradigm
• The components of JANUMET™ (sitagliptin/metformin HCl)
have complementary MOAs and comprehensively address
3 core pathophysiologic defects of type 2 diabetes.
• Coadministration of sitagliptin and metformin results in:
– Significant reductions in A1C, FPG, and PPG compared with
metformin alone
– Weight loss comparable to metformin alone
– Low incidence of hypoglycemia comparable to metformin alone
– Similar overall incidence of side effects to metformin alone
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