Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance

In the paper

“In one study, 9 the use of rosiglitazone decreased the risk of diabetes in adults with impaired glucose tolerance by 62%; given concerns about cardiovascular safety, 14 however, the Food and Drug Administration has restricted the use of rosig litazone therapy to patients in whom glycemic control cannot be achieved with other medications and who cannot take pioglitazone.”

What the sources say

• ?Could not verify

  The Results report increased odds of myocardial infarction with rosiglitazone, supporting the cardiovascular-safety concern immediately preceding citation 14. But the supplied claim concerns an FDA restriction: the Discussion describes FDA approval criteria, not a restriction limiting rosiglitazone to patients who cannot use other medications or pioglitazone. Searches for those eligibility conditions found no supporting passage in our copy. (LLM, conf=0.76)

  cites [14] sourceExperimental — accuracy not yet measured

In the paper

“The natural history of type 2 diabetes mellitus has been well defined, 4 starting with a genetic predisposition and progression from normal glucose tolerance with insulin resistance to impaired glucose tolerance and eventually type 2 diabetes mellitus with the superimposition of beta-cell failure.”

What the sources say

• Supported

  The “Natural History of Type 2 Diabetes” section describes inherited insulin resistance with initially normal glucose tolerance, progression from normal glucose tolerance to impaired glucose tolerance, and then overt diabetes as β-cell function declines. No page number is supplied in the passages. (LLM, conf=0.94)

  cites [4] source

In the paper

“Studies have shown that the rate of conversion of impaired glucose tolerance to type 2 diabetes mellitus is reduced with lifestyle modification 7 ; the use of metformin, 7 thiazolidinediones, [8][9][10][11] or acarbose 12 ; and bariatric surgery.13”

What the sources say

• ?Not checked — no full text of the sourcecites [7] source
• ?Not checked — no full text of the sourcecites [8] source
• ?Not checked — no full text of the sourcecites [9] source
• Partly supported

  This citation is attached to the thiazolidinediones clause, not the other interventions. The Discussion reports that troglitazone reduced diabetes incidence by 75% during treatment, but explicitly says whether other thiazolidinediones are effective remains to be determined. It therefore supports troglitazone, not the class-wide claim without qualification. (LLM, conf=0.86)

  cites [10] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [11] source
• ?Not checked — no full text of the sourcecites [12] source

In the paper

“The number of people who would need to be treated to prevent one case of diabetes was 8 for 2.2 years of the trial and 18 for 1 year.”

In the paper

“During a median follow-up period of 2.4 years (mean, 2.2), diabetes developed in 50 of the 299 patients in the placebo group (16.7%) and in 15 of the 303 patients in the pioglitazone group (5.0%).”

In the paper

“Protection from diabetes with pioglitazone was of similar magnitude (with no significant heterogeneity) in subgroups defined by sex, age, weight, race or ethnic group, and fasting glucose level, as well as in patients with both impaired glucose tolerance and impaired fasting glucose and those with isolated impaired glucose tolerance (Fig. 3).”

In the paper

“Neither pioglitazone nor placebo altered levels of low-density lipoprotein cholesterol.”

In the paper

“Nine fractures occurred in 8 of the patients receiving pioglitazone (3%) and eight fractures occurred in 7 of the patients receiving placebo (2.6%) (Table 4 in the Supplementary Appendix).All fractures were associated with trauma.”

• Also stated in: § Discussion · plain

  “Although an increased incidence of fractures has been reported with the use of thiazolidinediones, in this study, the incidence was similar in both groups, and all fractures were related to trauma.”

In the paper

“Events related to the cardiovascular system numbered 23 in the placebo group (7.7%) and 26 in the pioglitazone group (8.6%) (Table 3 in the Supplementary Appendix), with 1 case of congestive heart failure in each group (0.3%).”

• Also stated in: § Discussion · plain

  “Physician-reported congestive heart failure developed in only one patient in each group.”

• Also stated in: § Discussion · plain

  “For the comparison of placebo and pioglitazone regarding frequency of edema, cardiovascular events, and total events, P = 0.007, P = 0.80, and P = 0.03, respectively.”

In the paper

“The ratio of urinary microalbumin to creatinine was low at baseline; during the study it fell slightly and similarly in the two groups (1.85±0.2 to 1.53±0.2mg per gram in the pioglitazone group vs. 1.47±0.3 to 1.25±0.3mg per gram in the placebo group, P = 0.20).”

In the paper

“Although pioglitazone is a well-documented insulin sensitizer, insulin resistance was reduced according to the Matsuda index of insulin sensitivity measured during the oral glucose-tolerance test but not according to measurement of insulin sensitivity during the frequent-sampling intravenous glucose-tolerance test.”

• Also stated in: § Discussion · plain

  “Insulin sensitivity as determined with the use of an intravenous glucose-tolerance test with frequent sampling in a subgroup of 191 patients was not altered in either group.”

In the paper

“Pioglitazone was associated with lower diastolic blood pressure, higher levels of HDL cholesterol, and reduced rates of carotid intima-media thickening, as compared with placebo.”

• Also stated in: § Discussion · plain

  “Use of pioglitazone improved diastolic blood pressure, HDL cholesterol levels, and serum levels of alanine aminotranferase and aspartate aminotransferase, and it slowed progression of carotid intima-media thickening.”

In the paper

“One unexplained sudden death oc-curred in the placebo group, and three deaths occurred in the pioglitazone group (one unexplained sudden death, one death from biliary carcinoma, and one death from a carcinoid tumor).”

In the paper

“Edema and weight gain were greater with pioglitazone than with placebo, as reported previously, 8,40 and edema largely accounted for the increase in adverse events associated with pioglitazone.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] source
• ?Not checked — no full text of the sourcecites [40] source

In the paper

“We calculated that enrollment of approximately 600 patients was required to achieve 90% power, if treatment with pioglitazone decreased the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus by 50%.”

In the paper

“In one study, 9 the use of rosiglitazone decreased the risk of diabetes in adults with impaired glucose tolerance by 62%; given concerns about cardiovascular safety, 14 however, the Food and Drug Administration has restricted the use of rosig litazone therapy to patients in whom glycemic control cannot be achieved with other medications and who cannot take pioglitazone.”

What the sources say

• ?Not checked — no full text of the sourcecites [9] source

In the paper

“However, further glycemic separation between groups over time would presumably have a beneficial effect on microvascular disease.”

In the paper

“Since neither approach produced statistically significant evidence of bias due to missing data, the primary and secondary analyses were performed without data imputation.”

In the paper

“Takeda Pharmaceuticals provided financial support for the study but had no access to the data.”

In the paper

“All results were transmitted to the Data Coordinating Center in Phoenix, Arizona, where they were recorded and audited and then sent to the Data Analysis Center in San Antonio.”

In the paper

“The study was conducted in accordance with the protocol.”

In the paper

“Troglitazone was reported to be associated with a 55% decrease in the rate of conversion to diabetes among women with prior gestational diabetes, 11 but this agent is no longer available.”

What the sources say

• ?Not checked — no full text of the sourcecites [11] source

In the paper

“The small difference in levels of HbA 1c between the two groups is not surprising, given the low baseline level of HbA 1c in patients with impaired glucose tolerance.”

In the paper

“The rate of adherence to the study regimen, assessed by means of pill counts, was greater than 80% in both groups.”

In the paper

“However, if development of diabetic hyperglycemia can be delayed or prevented, it is plausible that the onset of microvascular complications might be slowed.”

In the paper

“It is not feasible to conduct studies of microvascular outcomes in patients with impaired glucose tolerance because of the large sample and long study duration required.”

In the paper

“Loss to follow-up was relatively high in both study groups (24% in the placebo group and 30% in the pioglitazone group, not a significant dif-ference).”

In the paper

“Microvascular and macrovascular complications are common in type 2 diabetes mellitus and are related to both the severity and the duration of hyperglycemia. 3”

What the sources say

• ?Not checked — no full text of the sourcecites [3] source

In the paper

“We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance.”

In the paper

“However, the greater the weight gain, the greater the improvements in betacell function and insulin sensitivity, and thus the greater the reduction in HbA 1c .26,35,36”

What the sources say

• ?Not checked — no full text of the sourcecites [26] source
• ?Not checked — no full text of the sourcecites [35] source
• ?Not checked — no full text of the sourcecites [36] source

In the paper

“Carotid intima-media thickening is highly correlated with cardiovascular events, and changes in this measure over time have predictive value beyond that of standard markers of risk.18,38”

What the sources say

• ?Not checked — no full text of the sourcecites [18] source
• ?Not checked — no full text of the sourcecites [38] source