As potent insulin sensitizers, the thiazolidinediones have significant effects on glucose metabolism that result in lower blood glucose levels in insulin-resistant patients with type 2 diabetes (Table 1). Several studies have documented the glucose-lowering effects of rosiglitazone and pioglitazone when used as monotherapy agents and in combination with sulfonylureas, metformin, and insulin.
In large, multicenter studies, rosiglitazone and pioglitazone significantly improve glycemic control. In a 26-week study with 408 type 2 diabetic patients (11), treatment with 15, 30, or 45 mg pioglitazone significantly decreased the HbA1c by 1.00% to 1.60%
TABLE 1 Relative Efficacy of Rosiglitazone and Pioglitazone
Reduction in fasting plasma glucose, Reduction in mean change from the control group HbA1c (%)
Rosiglitazone 4 mg 43-58 0.9-1.2
Rosiglitazone 8 mg 62-76 1.5
Pioglitazone 15 mg 39 1.0
Pioglitazone 30 mg 41-58 1.0-1.5
Pioglitazone 45 mg 65-68 1.5-1.6
Combination with sulfonylureas
Rosiglitazone 4 mg 39-47 0.9-1.13
Pioglitazone 15 mg 39 0.9
Pioglitazone 30 mg 58 1.3
Combination with metformin
Rosiglitazone 4 mg 40 1.0
Rosiglitazone 8 mg 53 1.5
Pioglitazone 30 mg 38 0.8
Combination with insulin
Rosiglitazone 4 mg 41 0.7
Rosiglitazone 8 mg 45 1.3
Pioglitazone 15 mg 35 1.0
Note: Since the above data was not obtained from simultaneous trials, the comparative data is only a rough approximation of the relative effectiveness as stage, severity of hyperglycemia and type of patients studied varied in the above studies. Source: From Refs. 11,12,15,16,19,20-25.
and fasting plasma glucose (FPG) 39 to 65mg/dL as compared to placebo. Decreases in FPG occurred as early as the second week of therapy with maximal decreases seen after 10 to 14 weeks and maintained until the end of therapy. In addition, in all pioglitazone groups, there were significant beneficial effects on lipids. Of interest, the subset of patients naive to oral antidiabetic therapy had greater improvements in HbA1c and FPG compared with previously treated patients. In a similar 26-week study with 493 patients (12), rosiglitazone 2 and 4mg twice daily reduced FPG concentrations relative to placebo by 58 and 76 mg/dL and mean HbA1c levels by 1.2% and 1.5%, respectively. In this study, there were also beneficial changes in measures of insulin sensitivity, p-cell function, and microalbuminuria. The overall adverse event profile of pioglitazone and rosiglitazone in these large studies was similar to that of placebo.
In the context of monotherapy, it is noteworthy that in the UKPDS, there was a progressive failure of all glucose-lowering therapies (metformin, sulfonylureas, and insulin) to maintain glycemic control (13). Since the thiazolidinediones increase insulin sensitivity and improve p-cell function, it is expected that glycemic control with these agents would be enduring. In the ADOPT study (A Diabetes Outcome Progression Trial), 4360 type 2 diabetic subjects were randomized to either rosiglitazone, metformin or glyburide as initial monotherapy and evaluated for monotherapy failure (defined as a confirmed FPG level of > 180 mg/dL) (14). After 5 years, the cumulative incidence of monotherapy failure in the rosiglitazone group was 15%, compared to 21% with metformin and 34% with glyburide. The annual rate of decline in p-cell function (after the first 6 months) was 6.1% in the glyburide group, 3.1% in the metformin group, and 2% in the rosiglitazone group. As expected, rosiglitazone was associated with more weight gain and edema than metformin or glyburide. Surprisingly, glyburide was associated with a lower risk of cardiovascular events [including congestive heart failure (CHF)] than was rosiglitazone (P < 0.05), and the risk associated with metformin was similar to that with rosiglitazone.
Thiazolidinedione and Sulfonylurea Combination Therapy
The thiazolidinediones are useful glucose lowering agents when used in combination therapy in patients with type 2 diabetes failing existing sulfonylurea therapy (15,16). In a large international, 26-week, open-label study, 348 patients with type 2 diabetes were randomized to receive 2 mg b.i.d. rosiglitazone or placebo daily, in addition to existing sulfonylurea therapy (15). After 26 weeks, the addition of rosiglitazone to existing sulfonylurea therapy significantly reduced the mean HbA1c from 9.1% to 7.9% as compared to no change in the control group. Although adverse events were similar in both groups, more patients in the rosiglitazone + sulfonylurea group reported mild hypoglycemia. Similar glycemic benefits have been reported when pioglitazone is used in combination with sulfonylureas (17). Results from these studies highlight the fact that combination thiazolidinedione + sulfonylurea treatment improves glycemic control and is well-tolerated in patients with type 2 diabetes from across the world.
In studies so far, there does not appear to be any differences between rosiglitazone and pioglitazone in terms of their glucose-lowering and insulin-sensitizing properties. This was confirmed in a double-blind study in which 87 type 2 diabetic patients with the metabolic syndrome were randomized to the addition of pioglitazone 15mg/day or rosiglitazone 4mg/day along with glimepiride, 4mg/day (18). After 12 months, there were similar decreases in HbA1c in both the thiazolidinedione groups (from 7.8% to 6.7% in the rosiglitazone + glimepiride group and from 7.9% to 6.8% in the pioglitazone + glimepiride group). In both treatment groups there was an improvement in insulin sensitivity as measured by the homeostasis model assessment index (HOMA). Of note, triglycerides decreased significantly in the pioglitazone + glimepiride group as compared to a significant increase in triglycerides in the rosiglitazone + glimepiride group. These possible lipid differences between the thiazolidinediones are discussed later in the lipids section.
In obese type 2 diabetic patients inadequately controlled on metformin alone, the addition of a thiazolidinedione further improves insulin sensitivity, glucose control and P-cell function. In a large, U.S. multicenter, double-blind study, 348 patients [mean body mass index (BMI) 30.1 kg/m2, FPG 216 mg/dL and HbA1c level 8.8%], were randomized to receive 2.5g/day of metformin plus either placebo, 4 or 8mg of rosiglitazone (19). After 26 weeks, metformin-rosiglitazone therapy significantly improved glucose control, insulin sensitivity, and P-cell function significantly in a dose-dependent manner. The mean levels of HbA1c significantly decreased by 1.0% and 1.2% in the 4 and 8mg metformin-rosiglitazone groups, respectively, as compared with the metformin-placebo group. Interestingly, in this study, while those in the control group experienced a mean decrease in weight of 1.2 kg from baseline, those in the rosiglitazone groups experienced a significant mean increase of 0.7 kg in the 4-mg and 1.9 kg in the 8-mg rosiglitazone groups. There were no significant differences in waist-to-hip ratios among groups.
Like rosiglitazone, pioglitazone also improves insulin sensitivity and glucose control when added to metformin. In a 16-week study (followed by a 1.5-year open-label extension), 328 patients with type 2 diabetes who had suboptimal control on maximum doses of metformin (20) were randomized to either pioglitazone + metformin or placebo + metformin and 249 subjects completed the study. After 16 weeks, patients receiving pioglitazone 30 mg + metformin had significant decreases in FPG levels by 38 mg/dL and HbA1c by 0.83% compared with the placebo + metformin group. In the 72-week open-label extension of this study, 154 patients received open-label pioglitazone 30 mg + metformin and this resulted in a sustained mean decrease from baseline of 1.36% in HbA1c and 63 mg/dL in FPG.
Of note, in an analysis of 550 patients of varying BMI, the improvement in glycemia, insulin sensitivity (HOMA) and P-cell function resulting from the addition of rosiglitazone to maximum dose metformin was most pronounced in the more obese patients (21).
Thiazolidinedione treatment is also effective when used late in the course of type 2 diabetes and a thiazolidinedione is added to a failing regimen of a sulfonylurea and metformin—triple oral agent combination therapy. In a prospective observational study, 35 patients with type 2 diabetes were followed after the addition of pioglitazone or rosiglitazone to a failing regimen of a sulfonylurea and metformin (22). At a mean follow-up of 72 months, 51% of patients remained well controlled on triple oral therapy (mean HbA1c 6.9%). In the remaining patients, triple oral therapy failed (mean HbA1c 8%) and the use of insulin was necessary after a mean duration of 38 months. Of note, stimulated C-peptide levels increased significantly in the triple therapy group and did not increase or decrease non-significantly at the time of insulin initiation in the insulin-requiring group. Thus even when used late in the course of type 2 diabetes, thiazolidinediones result in improved and enduring glycemic control which persists for up to 6 years and is dependent on preserved or improved P-cell function.
In the United States, both pioglitazone and rosiglitazone are approved for use in combination with insulin. However, since thiazolidinedione and insulin combination therapy is associated with an increased incidence of edema and a potentially greater propensity for patients to develop CHF, the thiazolidinediones should be used prudently in patients with pre-existing edema, especially in those who have evidence of milder degrees of heart failure (NYHA Class 1 and 2). In patients with NYHA Class 3 and 4 cardiac status, treatment with rosiglitazone or pioglitazone is currently not recommended.
Two large, multicenter studies have evaluated the efficacy and safety of the thiazolidinediones in insulin-treated patients with type 2 diabetes (23,24). In one 26-week study, 319 type 2 diabetic patients (mean HbA1c > 7.5%) on twice-daily insulin therapy (total daily dose > 30 U) (23) were randomized to rosiglitazone 4 or 8 mg daily or placebo. In an intent-to-treat analysis, rosiglitazone plus insulin treatment resulted in a significant mean reduction in HbA1c from baseline of 0.6% and 1.2% in the 4 and 8mg groups, respectively, despite a 6% and 12% mean reduction of insulin dosage in the two groups. The most common adverse event was symptoms consistent with hypoglycemia and edema. However, no case of edema was considered to be a serious and no patients were withdrawn from the study due to edema.
In the other large, double-blind, placebo-controlled, randomized, multicenter study, 566 patients with type 2 diabetes on stable insulin regimens for > 30 days and HbA1c > 8.0% (24) received either 15 or 30 mg pioglitazone, or placebo. After 16 weeks, pioglitazone 15 and 30 mg significantly decreased the mean HbA1c from baseline by 1.0% and 1.3%, respectively. As in the study with rosiglitazone and insulin, the incidence of weight increase, hypoglycemia and edema were higher among patients receiving insulin plus pioglitazone.
Since thiazolidinedione treatment is associated with variable amounts of weight gain, it would be expected that when these agents are used in morbidly obese patients with type 2 diabetes, there would be excessive weight gain, especially since these patients require large quantities of insulin to maintain glucose control. In one study (25), eight morbidly obese patients (median BMI 42 kg/m ) with type 2 diabetes on large doses of insulin (median daily dose 204 U) and poor glycemic control (median HbA1c 8.1%) were treated with combination insulin and maximum doses of rosiglitazone. At 24 weeks, there was a median weight gain of 3 kg, a fall in median HbA1c from 8.1% to 6.7% and a reduction in median insulin dose from 204 to 159U/day (23% reduction from baseline). Peripheral edema was the only significant side-effect seen in five of the eight patients. Thus, the combination of insulin and rosiglitazone is effective in morbidly obese patients with type 2 diabetes without excessive weight gain but with a high incidence of peripheral edema.
At the outset, it should be noted that insulin is the mainstay of treatment in type 1 diabetes and thiazolidinediones are not approved for use in these patients. However, it is being increasingly recognized that although insulin resistance is common in type 2 diabetes, overweight and normal-weight adults with type 1 diabetes can have peripheral and hepatic insulin resistance. Type 1 diabetic subjects with a family history of type 2 diabetes who undergone intensive insulin therapy have a greater tendency toward expressing the markers of insulin resistance, such as weight gain, increased insulin requirements, and dyslipidemia (26).
In a recent randomized, double-blind study in 50 adult type 1 diabetic subjects with BMI > 27 kg/m , rosiglitazone 4 mg b.i.d. in combination with insulin improved glycemic control and blood pressure (BP) without an increase in insulin requirements, compared with the insulin- and placebo-treated subjects, whose improved glycemic control required an 11% increase in insulin dose. Weight gain and hypoglycemia were similar in both groups. The greatest effect of rosiglitazone occurred in subjects with more pronounced markers of insulin resistance. Clearly, there is need for more investigation into the long-term effects of the thiazolidinediones on glycemic control and cardiovascular risk factors in type 1 diabetic individuals with features of insulin resistance (27).
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