TZD Class Review, rosiglitazon
[ Pobierz całość w formacie PDF ]Drug Class
Review:
Thiazolidinediones
Generic Name
Brand Name
Manufacturer
Pioglitazone
Actos
Takeda Pharmaceuticals; Eli Lilly
Rosiglitazone
Avandia
GlaxoSmithKline
I. FDA Indications
Pioglitazone and rosiglitazone are indicated for monotherapy or for use in combination with a sulfonylurea,
metformin, or insulin in patients with type 2 diabetes mellitus.
1,2
II. Pharmacology
Pioglitazone and rosiglitazone are thiazolidinediones (TZDs) that act primarily by decreasing insulin resistance.
Their mechanism of action for improving insulin sensitivity is not yet fully understood. They are selective
agonists for peroxisome proliferator-activated receptor-gamma (PPARγ). Activation of PPARγ receptors results
in increased glucose transport into cells in adipose tissue, skeletal muscle, and liver.
1,2
III. Pharmacokinetics
Pioglitazone and rosiglitazone are highly protein bound (>99%), primarily to serum albumin. Both are
extensively metabolized in the liver through cytochrome P450 isoenzymes 2C8 (pioglitazone, rosiglitazone), 2C9
(rosiglitazone), and 3A4 (pioglitazone). Both have pharmacologically active metabolites. Pioglitazone is
eliminated primarily in the feces, and rosiglitzone is eliminated primarily in the urine. The pharmacokinetics of
pioglitazone and rosiglitazone are not influenced by age or ethnicity.
1,2
IV. Clinical Efficacy
Monotherapy
Pioglitazone and rosiglitazone produced statistically significant improvements in fasting plasma glucose (FPG)
and hemoglobin A1c (A1c) compared to baseline. Clinical studies showed that the mean absolute change in A1c
from baseline ranged from 0% to -0.7% for rosiglitazone and +0.2% to –1.4% for pioglitazone. Limited data are
published comparing rosiglitazone or pioglitazone monotherapy with other anti-diabetic monotherapy regimens.
Based on the available data, the reduction in A1c level with rosiglitazone and pioglitazone appears to be less than
that with sulfonylurea or metformin. However, these differences were not found to be statistically significant.
3-8
(Table 1)
Add-on therapy
When pioglitazone or rosiglitazone is added to another glycemic lowering agent in patients with type-2 diabetes
not well controlled on monotherapy, both drugs produced a significantly greater reduction on A1c and FPG than
continuing monotherapy with the other agent. These findings are consistent with other clinical studies that
showed combination of glycemic lowering agents provides greater effect than using one alone.
2,9-13
(Table 2)
Other clinical outcomes studies
Due to the unique mechanism of action of TZDs, there are some data that showed these drugs may preserve
pancreatic beta-cell function, and it has been suggested that they should therefore be used early in the disease
process.
14,15
Troglitazone was the first TZDs introduced, but subsequently removed from the market due to rare
cases of idiosyncratic hepatocellular injury leading to death or liver transplant during post-marketing clinical use.
Prior to its removal from the market, in The Troglitazone in Prevention of Diabetes (TRIPOD) study, it was
shown that treatment with troglitazone reduced endogenous insulin requirements, preserved beta-cell function
and prevented type-2 diabetes in Hispanic women with prior gestational diabetes.
16,17
The Pioglitazone in
Prevention of Diabetes (PIPOD) study is currently ongoing and testing whether the stability of glycemia and
beta-cell function observed in subjects during TRIPOD can be maintained with pioglitazone. An interim report
of this 4-year open-label study indicated that from 117 of 143 eligible women enrolled in PIPOD, 102 had their
first annual oral glucose tolerance test after first year treatment with pioglitazone, 1 (1.3%) developed diabetes.
25
Thiazolidinediones
For 26 women who entered PIPOD with mild diabetes, 9 (35%) of them still had glucose levels in the diabetic
range at the end of year 1. This interim report concludes that the protection from diabetes observed during
TRIPOD persisted during the first year of pioglitazone treatment in PIPOD.
17
Prevention of progressive islet beta-cell failure or long-term deterioration in glycemia is currently being
investigated in clinical trials. A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind,
multicenter study that evaluates the long term efficacy of monotherapy with rosiglitazone on glycemic control
and on the progression of pathophysiological abnormalities associated with type-2 diabetes as compared with
metformin or glyburide monotherapy in patients recently diagnosed with type-2 diabetes (<3 years).
18
While sulfonylurea, metformin, and insulin products have been shown in clinical trials to reduce microvascular
and macrovascular complications associated with diabetes, currently there are no data on long term effects on
morbidity and mortality related to diabetes and cardiovascular disease for TZDs.
19
Long-term clinical outcomes
studies are currently ongoing for pioglitazone and rosiglitazone.
20,21
V. Adverse Effects
Generally, TZDs are well tolerated. The adverse effect profiles are similar between pioglitazone and
rosiglitazone. With the exception of weight gain and peripheral edema, the incidence of adverse events with
TZDs was similar to placebo in clinical trials. Common adverse events reported with TZDs were upper
respiratory infection, injury, headache. As monotherapy, neither drug caused hypoglycemia, but in combination
therapy, hypoglycemia risk is increased, and dose reduction in concomitant agent may be necessary.
1,2
Dose-dependent weight gain of 0.7 kg to 5.3 kg has been reported in the clinical studies and seems to be a class
effect. The larger mean increase was noted with add-on therapy with insulin while the least weight gain was seen
when used in combination with metformin. The mechanism of weight gain with TZDs is unclear. It is likely
multifactorial and may be related to fluid retention or fat accumulation.
1,2,22
TZDs can cause fluid retention, which may exacerbate or lead to heart failure. The incidence of edema is about
3%-5% with TZDs monotherapy; however, when combined with insulin therapy, the incidence of edema can
increase to 13%-16%, compared with 5%-7% in patients receiving insulin plus placebo. In clinical trials and
post-marketing experience, combining pioglitazone or rosiglitazone with insulin resulted in the development of
peripheral edema in approximately 16% of patients. Three of 10 patients who developed cardiac failure on
rosiglitazone/insulin combination had no known prior evidence of heart failure, or pre-existing cardiac condition.
In a clinical study comparing pioglitazone/insulin combination versus insulin monotherapy, four patients
receiving the combination therapy developed heart failure compared to none receiving insulin monotherapy. All
four cases had previous histories of cardiovascular conditions including coronary artery disease, previous CABG
procedures, and myocardial infarction. Patients with New York Heart Association (NYHA) Class III and IV
heart failure were not included in clinical trials. Pioglitazone and rosiglitazone are not indicated in patients with
NYHA Class III or IV heart failure.
1,2,22,23
Pre-marketing and post-marketing clinical studies have shown that rosiglitazone and pioglitazone do not cause
hepatoxicity any more than placebo or active comparators. However, the manufacturers of rosiglitazone and
pioglitazone have recommended that liver function tests should be evaluated prior to the initiation of therapy in
all patients, every two months for the first year of therapy, and then periodically thereafter. Furthermore,
pioglitazone or rosiglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease
or the alanine aminotransferase (ALT) levels exceed 2.5 times the upper limit of normal. If ALT levels exceeds 3
times the upper limit of normal or if the patient is jaundiced, pioglitazone or rosiglitazone therapy should be
discontinued.
1,2,22
26
Thiazolidinediones
Compared to other anti-diabetic agents, pioglitazone and rosiglitazone have shown different effects on lipid
profile in clinical studies. For total and LDL levels, rosiglitazone caused significantly larger increase while
pioglitazone produced no statistically significant differences compared with baseline and controls. Both TZDs
caused a statistically significant increase from baseline in HDL levels. For triglyceride level, pioglitazone caused
a statistically significant decrease from baseline and rosiglitazone produced no statistically significant
differences.
22
VI. Drug-Drug Interactions
Pioglitazone is metabolized by CYP2C8 and 3A4. Pharmacokinetic interaction studies have not been conducted
with pioglitazone and other drugs metabolized by CYP3A4. In vitro, ketoconazole appears to significantly
inhibit the metabolism of pioglitazone. Patients receiving ketoconazole concomitantly with pioglitazone might
need more frequent evaluation with respect to glycemic control.
1
Rosiglitazone is primarily metabolized by CYP2C8, and to a lesser extent by 2C9. In vitro drug metabolism
studies suggest that rosiglitazone does not inhibit any of the major CYP 450 enzymes at clinically relevant
concentrations.
2
VII. Pregnancy
Pregnancy Category C for both products.
1,2
Therapy with TZDs may result in ovulation in some premenopausal anovulatory women. As a result, these
patients may be at an increased risk for pregnancy while taking pioglitazone or rosiglitazone.
1,2
VIII. Dosing
Pioglitazone is taken once daily without regard to meals. Dose can be initiated at 15 mg daily, and titrated up to
45 mg daily.
1
Rosiglitazone is taken either as a single daily dose or divided dosing without regard to meals. The usual starting
dose is 4 mg daily. The maximum recommended dose is 8 mg daily.
2
Dose adjustment in patients with renal insufficiency is not recommended for pioglitazone or rosiglitazone. There
are no data on the use of pioglitazone or rosiglitazone in patients under 18 years of age; therefore, use of these
products in pediatric patients is not recommended.
1,2
Pioglitazone is available in 15mg, 30mg, and 45mg tablets.
1
Rosiglitazone is available in 2mg, 4mg, and 8mg tablets.
2
VIX. Summary
The TZDs offers a unique mechanism of action for the management of type-2 diabetes by targeting insulin
resistance. Current available clinical data suggests that they are effective in the treatment of type-2 diabetes as
monotherapy or in combination with other anti-diabetic agents. However, evidence to show that the TZDs are
superior to other anti-diabetic agents in glycemic control is lacking. Furthermore, long-term safety and effects on
diabetes-related complication reduction are still pending at this time. More clinical data is warranted to better
assess the role of TZDs in the management of type-2 diabetes.
27
Thiazolidinediones
Table 1. Clinical studies: monotherapy
Study Design
Treatment Arms
Mean duration of
diabetes / Mean baseline
A1c / Prior Treatment
Efficacy
(mean change from baseline at the end of the
study)
A1c (%)
FPG (mg/dL)
Grunberger et al
3
RCT, DB, MC
26 weeks
Type 2 diabetes
N=959
RSG 4mg qd
RSG 2mg bid
RSG 8mg qd
RSG 4mg bid
PLB
5-6 years;
8.9%-9%;
Diet/exercise or oral
diabetes agent (agents not
specified)
- 25% drug-naïve
- 60% monotherapy
- 15% combination
RSG 4mg qd: 0*
RSG 2mg bid: -0.1*
RSG 8mg qd: -0.3*
RSG 4mg bid:-0.7*
PLB: +0.8
*p<0.0001 vs. PLB
RSG 4mg qd: -25
RSG 2mg bid: -35
RSG 8mg qd: -42
RSG 4mg bid: -55
PLB: +8
Significance not
reported
Lebovitz et al
4
RCT, DB, MC
26 weeks
Type 2 diabetes
N=533
RSG 2mg bid
RSG 4mg bid
PLB
5 years;
8.8%-9%;
Diet/exercise or oral
diabetes agent
(agents not specified)
- 27% drug-naive
- 66% monotherapy
- 7% combination
RSG 2mg bid: -0.3*
RSG 4mg bid: -0.6*
PLB: +0.9
*p<0.0001 vs. PLB
RSG 2mg bid: -38*
RSG 4mg bid: -54*
PLB: +19
*p<0.0001 vs. PLB
Charbonnel et al
5
RCT, DB
52 weeks
Type 2 diabetes
N=587
RSG 2 mg bid
RSG 4 mg bid
GLB 2.5mg-15 mg qd
(median titrated dose 7.5
mg qd)
Not reported;
8%
Diet/exercise or oral
diabetes agent
(agents not specified)
- 39% drug-naive
- 51% monotherapy
- 10% combination
RSG 2mg bid: -0.27
RSG 4mg bid: -0.53*
GLB: -0.72
*Difference not
statistically
significant vs. GLB
(p value not reported)
RSG 2mg bid: -25.4*
RSG 4mg bid: -40.8**
GLB: -30
*p=0.21 vs. GLB
**p=0.033 vs. GLB
Aronoff et al
6
RCT, DB, MC
26 weeks
Type 2 diabetes
N=408
PIG 7.5 mg qd
PIG 15 mg qd
PIG 30mg qd
PIG 45 mg qd
PLB
Not reported;
10%;
Diet/exercise or diabetes
agent
(agents not specified)
- 31% drug-naive
- 56% monotherapy
- 13% combination
PIG 7.5 mg qd: +0.2
PIG 15 mg qd: -0.3*
PIG 30 mg qd: -0.3*
PIG 45 mg qd: -0.9*
PLB: +0.7
*p≤0.05 vs. PLB
PIG 7.5 mg qd: -18.1*
PIG 15 mg qd: -29.6*
PIG 30 mg qd: -31.8*
PIG 45 mg qd: -53.9*
PLB: +9.4
*p≤0.05 vs. PLB
Schernthaner et
al
7
RCT, MC
52 weeks
Type 2 diabetes
N=1199
PIG up to 45 mg qd
MET up to 850 mg tid
Not reported;
8.6%;
Diet/exercise
PIG: -1.42
MET: -1.5
Difference not
statistically
significant between
groups (p value not
reported)
PIG: -45
MET: -37.8
p=0.016 between
groups
Pavo et al
8
RCT, DB, MC
32 weeks
Type 2 diabetes
N=205
PIG up to 45 mg qd
(mean dose 41.5 mg qd)
MET up to 850 mg tid
(mean dose 2292 mg qd)
5-6 years;
8.6%;
Not reported
PIG: -1.3*
MET: -1.5
p=0.28 vs. MET
PIG: -54*
MET: -50.4
p=0.628 vs. MET
RCT=randomized controlled trial, DB=double-blind, MC=multicenter, RSG=rosiglitazone, PIG=pioglitazone, MET=metformin,
GLB=glyburide, FPG=fasting plasma glucose
28
Thiazolidinediones
Table 2. Clinical studies: add-on therapy
Study Design
Treatment Arms
Mean duration of
diabetes / Mean
baseline A1c / Prior
Treatment
Efficacy
(mean change from baseline at the end of
the study)
A1c (%)
FPG (mg/dL)
Fonseca et al
9
RCT, DB, MC
26 weeks
Type 2 diabetes
N=348
RSG 4 mg qd + MET 2.5 g qd
RSG 8 mg qd + MET 2.5 g qd
PLB + MET 2.5 g qd
7-8 years;
8.6%-8.9%;
MET 2.5 g qd only x
4-7 weeks prior to
randomization
RSG 4 /MET: -0.56*
RSG 8/MET: -0.78*
PLB/MET: +0.45
*p<0.001 vs.
PLB/MET
RSG 4/MET: -32.4*
RSG 8/MET: -48.6*
PLB/MET: +5.94
*p<0.001 vs.
PLB/MET
Product
Information
2
RCT, DB
26 weeks
Type 2 diabetes
N=375
RSG 2 mg bid + SUL
PLB + SUL
Not reported;
9.2%;
SUL (specific agent
or dose not reported)
RSG/SUL: -0.9*
PLB/SUL: +0.2
*p≤0.0001 vs.
PLB/SUL
RSG/SUL: -38*
PLB/SUL: +6
*p≤0.0001 vs.
PLB/SUL
Raskin et al
10
RCT, DB, MC
26 weeks
Type 2 diabetes
N=319
RSG 2 mg bid + INS
RSG 4 mg bid + INS
PLB + INS
11-12 years;
9%;
Insulin bid (total
daily dose ≥ 30 units)
x 8 weeks prior to
randomization
RSG 2/INS: -0.6*
RSG 4/INS: -1.2*
PLB/INS: +0.1
*p<0.0001 vs.
PLB/INS
RSG 2/INS: -42*
RSG 4/INS: -44*
PLB/INS: +10.8
*p<0.0001 vs.
PLB/INS
Kipnes et al
11
RCT, DB, MC
16 weeks
Type 2 diabetes
N=560
PIG 15 mg qd + SUL*
PIG 30 mg qd + SUL*
PLB + SUL*
*SUL=GLB or GLP
Not reported;
10%;
Sulfonylurea
monotherapy x 2-4
weeks prior to
randomization
PIG 15/SUL: -0.8*
PIG/SUL: -1.2*
PLB/SUL: +0.1
*p≤0.05 vs.
PLB/SUL
PIG 15/SUL: -33.8*
PIG 30/SUL: -52.3*
PLB/SUL: +5.6
*p≤0.05 vs.
PLB/SUL
Einhorn et al
12
RCT, DB, MC
16 weeks
Type 2 diabetes
N=328
PIG 30 mg qd + MET*
PLB + MET*
*dose not adjusted unless in
response to hypoglycemia
Not reported;
9.8%;
Metformin
monotherapy x 4
weeks prior to
randomization
PIG/MET: -0.64*
PLB/MET: +0.19
*p≤0.05 vs.
PLB/MET
PIG/MET: -42.8*
PLB/MET: -5.2
*p≤0.05 vs.
PLB/MET
Rosenstock et
al
13
RCT, DB, MC
16 weeks
Type 2 diabetes
N=566
PIG 15 mg qd + INS
PIG 30 mg qd + INS
PLB + INS
Not reported;
9.8%;
Insulin ≥30 units/day
PIG 15/INS: -0.99*
PIG 30/INS: -1.26*
PLB/INS: -0.26
*p≤0.05 vs. PLB/INS
PIG 15/INS: -34.5*
PIG 30/INS: -48*
PLB/INS: +0.6
*p≤0.05 vs. PLB/INS
RCT=randomized controlled trial, DB=double-blind, MC=multicenter, RSG=rosiglitazone, PIG=pioglitazone, MET=metformin,
GLB=glyburide, GLP=glipizide, SUL=sulfonylurea, INS=insulin, FPG=fasting plasma glucose
29
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