CV Risk Reduction, Diabetes Prevention, and TZDs

1. CV Risk Reduction, Diabetes Prevention, and TZDs

2. UKPDS 34: Intensive glucose control andCV protection The United Kingdom Prospective Diabetes Study 34 (UKPDS 34) randomized overweight (>120% ideal bodyweight) patients with newly-diagnosed type 2 diabetes to metformin (n = 342) or other intensive glycemic control medication (chlorpropamide, glibenclamide, or insulin; n = 951), or usual care (n = 411). The target fasting glucose was 108 mg/dL. The median duration was 10.7 years. Metformin was associated with a 36% relative risk reduction (RRR) in all-cause mortality vs usual care as opposed to an 8% RRR for intensive treatment vs usual care (P = 0.02 for metformin vs intensive therapy). There was no difference between the two intensive-treatment groups in the relative risk reduction in MI, although the trend was in favor of metformin. These data suggest that insulin-sensitizing therapy may be associated with greater reductions in CV outcomes than other glucose-lowering therapies.The United Kingdom Prospective Diabetes Study 34 (UKPDS 34) randomized overweight (>120% ideal bodyweight) patients with newly-diagnosed type 2 diabetes to metformin (n = 342) or other intensive glycemic control medication (chlorpropamide, glibenclamide, or insulin; n = 951), or usual care (n = 411). The target fasting glucose was 108 mg/dL. The median duration was 10.7 years. Metformin was associated with a 36% relative risk reduction (RRR) in all-cause mortality vs usual care as opposed to an 8% RRR for intensive treatment vs usual care (P = 0.02 for metformin vs intensive therapy). There was no difference between the two intensive-treatment groups in the relative risk reduction in MI, although the trend was in favor of metformin. These data suggest that insulin-sensitizing therapy may be associated with greater reductions in CV outcomes than other glucose-lowering therapies.

3. DCCT/EDIC: Lower glucose = lower long-term CV risk The Diabetes Control and Complications Trial (DCCT) compared the effect of intensive diabetes therapy vs conventional therapy on the long-term incidence of CV disease events in 1441 patients with type 1 diabetes (aged 13 to 40 years). At 6.5 years, the A1C levels were 7.4% in the intensive treatment group vs 9.1% in the conventional treatment group (P < 0.01). Although intensive glucose control was associated with fewer CV events, the small number of events precluded a determination of whether intensive diabetes therapy affected CV risk. Subsequently, 97% of the DCCT subjects agreed to join the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study, in which they were followed for an additional 11 years (until 2005). The primary outcome was the time to the first CV event, including nonfatal MI or stroke, death due to CV disease, confirmed angina, or the need for revascularization. The Diabetes Control and Complications Trial (DCCT) compared the effect of intensive diabetes therapy vs conventional therapy on the long-term incidence of CV disease events in 1441 patients with type 1 diabetes (aged 13 to 40 years). At 6.5 years, the A1C levels were 7.4% in the intensive treatment group vs 9.1% in the conventional treatment group (P < 0.01). Although intensive glucose control was associated with fewer CV events, the small number of events precluded a determination of whether intensive diabetes therapy affected CV risk. Subsequently, 97% of the DCCT subjects agreed to join the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study, in which they were followed for an additional 11 years (until 2005). The primary outcome was the time to the first CV event, including nonfatal MI or stroke, death due to CV disease, confirmed angina, or the need for revascularization.

4. DCCT/EDIC: Intensive glucose control reduces long-term CV risk Intensive treatment was associated with a 42% reduction in the cumulative incidence of a first CV event compared with conventional treatment. The risk of the first occurrence of nonfatal MI, stroke or death from CV disease was reduced 57% with intensive treatment. These benefits reinforce the original DCCT message that intensive therapy should be implemented as early as possible in persons with type 1 diabetes.Intensive treatment was associated with a 42% reduction in the cumulative incidence of a first CV event compared with conventional treatment. The risk of the first occurrence of nonfatal MI, stroke or death from CV disease was reduced 57% with intensive treatment. These benefits reinforce the original DCCT message that intensive therapy should be implemented as early as possible in persons with type 1 diabetes.

5. DCCT/EDIC: Intensive treatment slows renal changes Microalbuminuria has become a prognostic marker for CV risk in diabetic and nondiabetic subjects.1 DCCT/EDIC results showed that the incidence of microalbuminuria or albuminuria was significantly lower among patients receiving intensive compared with conventional therapy. Microalbuminuria and albuminuria were each strongly associated with an increased risk of CV disease in the study, and each explained some, but not all, of the benefit of intensive glucose lowering. Microalbuminuria has become a prognostic marker for CV risk in diabetic and nondiabetic subjects.1 DCCT/EDIC results showed that the incidence of microalbuminuria or albuminuria was significantly lower among patients receiving intensive compared with conventional therapy. Microalbuminuria and albuminuria were each strongly associated with an increased risk of CV disease in the study, and each explained some, but not all, of the benefit of intensive glucose lowering.

6. Vascular effects of thiazolidinediones (TZDs) Examining the clinical impact of TZDs TZDs have vascular and nonglycemic benefits beyond glucose lowering. TZDs have vascular and nonglycemic benefits beyond glucose lowering.

7. TZDs impact carotid IMT TZD treatment reduces carotid IMT, a surrogate of atherosclerotic disease progression, in subjects with type 2 diabetes or CAD. Minamikawa et al showed that troglitazone (400 mg daily) vs usual care (sulfonylureas or diet alone) significantly reduced IMT within 3 months in 135 Japanese subjects with type 2 diabetes (P < 0.001). Results were maintained through 6 months. Koshiyama et al demonstrated significant IMT reductions at 6 months with pioglitazone (30 mg/day) vs usual care (sulfonylureas or diet alone) in 106 Japanese patients with type 2 diabetes (P < 0.001). Sidhu et al demonstrated IMT reductions with rosiglitazone (daily doses of 4 mg for 8 weeks uptitrated to 8 mg for 40 weeks) in 92 patients with CAD without diabetes at48 weeks (P = 0.03). Langenfeld et al demonstrated that treatment with pioglitazone (45 mg each morning) substantially reduced IMT vs glimepiride (1 to 6 mg/day titrated for optimal glycemic control) at 12 weeks in 173 patients with type 2 diabetes (P < 0.0001), despite similar metabolic improvements. Improvement of IMT with pioglitazone at 12 and 24 weeks was independent of its effects on glucose control. Thus, TZDs have been consistently demonstrated to reduce a surrogate of atherosclerotic disease progression.TZD treatment reduces carotid IMT, a surrogate of atherosclerotic disease progression, in subjects with type 2 diabetes or CAD. Minamikawa et al showed that troglitazone (400 mg daily) vs usual care (sulfonylureas or diet alone) significantly reduced IMT within 3 months in 135 Japanese subjects with type 2 diabetes (P < 0.001). Results were maintained through 6 months. Koshiyama et al demonstrated significant IMT reductions at 6 months with pioglitazone (30 mg/day) vs usual care (sulfonylureas or diet alone) in 106 Japanese patients with type 2 diabetes (P < 0.001). Sidhu et al demonstrated IMT reductions with rosiglitazone (daily doses of 4 mg for 8 weeks uptitrated to 8 mg for 40 weeks) in 92 patients with CAD without diabetes at48 weeks (P = 0.03). Langenfeld et al demonstrated that treatment with pioglitazone (45 mg each morning) substantially reduced IMT vs glimepiride (1 to 6 mg/day titrated for optimal glycemic control) at 12 weeks in 173 patients with type 2 diabetes (P < 0.0001), despite similar metabolic improvements. Improvement of IMT with pioglitazone at 12 and 24 weeks was independent of its effects on glucose control. Thus, TZDs have been consistently demonstrated to reduce a surrogate of atherosclerotic disease progression.

8. TZD impact on restenosis in type 2 diabetes Restenosis in stented arteries is largely related to neointimal hyperplasia1. The pathobiology of restenosis differs from atherosclerosis and is a much more accelerated process that occurs over ~6 months to 1 year. Impaired insulin sensitivity is an important marker in the development of restenosis after coronary stenting. Recent studies have also shown the inflammatory response is important not only in atherosclerosis, but also in restenosis after stent implantation.1 Choi et al assessed reductions in restenosis with rosiglitazone 8 mg before catheterization and 4 mg/day post-stenting, added to conventional diabetes therapy for 6 months in 95 patients with diabetes and CHD. Rosiglitazone significantly reduced the rate of restenosis, which was 17.6% in the rosiglitazone group vs 38% in the control group. Concomitant reductions in CRP were also observed with rosiglitazone (data not shown). The rosiglitazone group also had a lower degree of diameter stenosis (23%) compared with the control group (40.4%) (P = 0.004).Restenosis in stented arteries is largely related to neointimal hyperplasia1. The pathobiology of restenosis differs from atherosclerosis and is a much more accelerated process that occurs over ~6 months to 1 year. Impaired insulin sensitivity is an important marker in the development of restenosis after coronary stenting. Recent studies have also shown the inflammatory response is important not only in atherosclerosis, but also in restenosis after stent implantation.1 Choi et al assessed reductions in restenosis with rosiglitazone 8 mg before catheterization and 4 mg/day post-stenting, added to conventional diabetes therapy for 6 months in 95 patients with diabetes and CHD. Rosiglitazone significantly reduced the rate of restenosis, which was 17.6% in the rosiglitazone group vs 38% in the control group. Concomitant reductions in CRP were also observed with rosiglitazone (data not shown). The rosiglitazone group also had a lower degree of diameter stenosis (23%) compared with the control group (40.4%) (P = 0.004).

9. TZDs consistently reduce restenosis after coronary stenting in patients with diabetes A series of studies by Takagi et al showed that TZDs consistently and significantly reduced restenosis in stented patients with type 2 diabetes at 6 months. Neointimal area reductions included: 43% decrease with troglitazone 400 mg/day vs diet alone (N = 52; 2.0 mm2 vs 3.5 mm2, respectively). 50% decrease with troglitazone 400 mg/day added to conventional diabetes therapy vs other anti-diabetes therapy (N = 157 patients receiving small stents; 1.4 mm2 vs2.8 mm2, respectively). 39% decrease with pioglitazone 30 mg/day added to conventional diabetes therapy vs other anti-diabetes therapy (N = 44; 1.7 mm2 vs 2.8 mm2, respectively). Choi et al observed a 54% reduction in restenosis with rosiglitazone added to conventional diabetes therapy vs other diabetes therapies.A series of studies by Takagi et al showed that TZDs consistently and significantly reduced restenosis in stented patients with type 2 diabetes at 6 months. Neointimal area reductions included: 43% decrease with troglitazone 400 mg/day vs diet alone (N = 52; 2.0 mm2 vs 3.5 mm2, respectively). 50% decrease with troglitazone 400 mg/day added to conventional diabetes therapy vs other anti-diabetes therapy (N = 157 patients receiving small stents; 1.4 mm2 vs2.8 mm2, respectively). 39% decrease with pioglitazone 30 mg/day added to conventional diabetes therapy vs other anti-diabetes therapy (N = 44; 1.7 mm2 vs 2.8 mm2, respectively). Choi et al observed a 54% reduction in restenosis with rosiglitazone added to conventional diabetes therapy vs other diabetes therapies.

10. Surrogate outcome results driving major TZD trials Surrogate outcome studies with TZDs provide indirect evidence for CV event reduction. CV risk factor reductions observed with TZD treatment may also reduce CV morbidity and mortality.Surrogate outcome studies with TZDs provide indirect evidence for CV event reduction. CV risk factor reductions observed with TZD treatment may also reduce CV morbidity and mortality.

11. Major TZD outcome trials Large, multicenter trials in progress are assessing the effects of TZDs in the reduction of complications from type 2 diabetes (DM2) and insulin resistance. PROactive, published in 2005, and ADOPT, CHICAGO, and DREAM, anticipated in 2006, are discussed in detail in this curriculum. Trials emerging in 2007 and 2008. Results for ACCORD,3 BARI-2D,3,4 and ORIGIN2 are anticipated for 2009.Large, multicenter trials in progress are assessing the effects of TZDs in the reduction of complications from type 2 diabetes (DM2) and insulin resistance. PROactive, published in 2005, and ADOPT, CHICAGO, and DREAM, anticipated in 2006, are discussed in detail in this curriculum. Trials emerging in 2007 and 2008. Results for ACCORD,3 BARI-2D,3,4 and ORIGIN2 are anticipated for 2009.

12. Major TZD outcome trials

13. PROactive: Study design PROactive assessed whether pioglitazone treatment could reduce CV morbidity and mortality in patients (mean age 62 years) with type 2 diabetes and evidence of coronary, cerebrovascular, or peripheral vascular disease. Inclusion criteria required an A1C >6.5% despite treatment with diet alone or oral glucose-lowering agents, with or without insulin. Patients treated with insulin alone, or who had planned coronary or peripheral revascularization, or New York Heart Association (NYHA) classes II�IV HF were excluded. Patients were randomized to oral pioglitazone (n = 2605) or placebo (n = 2633) in addition to their existing medications. At 1 month, the 15-mg starting dose of pioglitazone was titrated to 30 mg for the second month, and to 45 mg (or maximum tolerated dose) thereafter.PROactive assessed whether pioglitazone treatment could reduce CV morbidity and mortality in patients (mean age 62 years) with type 2 diabetes and evidence of coronary, cerebrovascular, or peripheral vascular disease. Inclusion criteria required an A1C >6.5% despite treatment with diet alone or oral glucose-lowering agents, with or without insulin. Patients treated with insulin alone, or who had planned coronary or peripheral revascularization, or New York Heart Association (NYHA) classes II�IV HF were excluded. Patients were randomized to oral pioglitazone (n = 2605) or placebo (n = 2633) in addition to their existing medications. At 1 month, the 15-mg starting dose of pioglitazone was titrated to 30 mg for the second month, and to 45 mg (or maximum tolerated dose) thereafter.

14. PROactive: CV history at baseline The high-risk status of study subjects is demonstrated by the high prevalence of concomitant CV morbidity. Most participants were male (66%), white (99%), and had a history of hypertension (75%); the mean BMI was 31 kg/m2.The high-risk status of study subjects is demonstrated by the high prevalence of concomitant CV morbidity. Most participants were male (66%), white (99%), and had a history of hypertension (75%); the mean BMI was 31 kg/m2.

15. PROactive: CV medications at baseline The majority of subjects were taking pharmacologic agents to reduce CV risk at baseline, in addition to diabetes medications as needed: Metformin, sulphonylurea, or both: ~55% Insulin plus metformin, sulphonylurea or both: ~30% Another combination of glucose-lowering medications: ~12% Only 4% of participants controlled their blood glucose with diet alone. The majority of subjects were taking pharmacologic agents to reduce CV risk at baseline, in addition to diabetes medications as needed: Metformin, sulphonylurea, or both: ~55% Insulin plus metformin, sulphonylurea or both: ~30% Another combination of glucose-lowering medications: ~12% Only 4% of participants controlled their blood glucose with diet alone.

16. PROactive: Nonsignificant reduction in primary outcome The primary outcome (death, nonfatal MI [including silent MI], stroke, acute coronary syndromes [ACS], leg amputation, coronary or peripheral revascularization) was reduced by 10% (nonsignificant) over 36 months with pioglitazone vs placebo. However, the confirmed survival curve divergence suggests that a greater risk reduction might have been achieved with longer treatment duration.The primary outcome (death, nonfatal MI [including silent MI], stroke, acute coronary syndromes [ACS], leg amputation, coronary or peripheral revascularization) was reduced by 10% (nonsignificant) over 36 months with pioglitazone vs placebo. However, the confirmed survival curve divergence suggests that a greater risk reduction might have been achieved with longer treatment duration.

17. PROactive: Significant reduction in secondary outcome The main secondary outcome (death, first occurrence of nonfatal MI [excluding silent MI] or stroke) was significantly reduced by 16% with pioglitazone vs placebo. Analysis indicated that when 48 patients were treated with pioglitazone, a first major CV event could be prevented in 3 years. All three secondary outcome components were improved with pioglitazone vs control. The treatment benefit occurred in patients already receiving comprehensive medical therapy (diabetes, antiplatelet, antihypertensive, and lipid-altering agents).The main secondary outcome (death, first occurrence of nonfatal MI [excluding silent MI] or stroke) was significantly reduced by 16% with pioglitazone vs placebo. Analysis indicated that when 48 patients were treated with pioglitazone, a first major CV event could be prevented in 3 years. All three secondary outcome components were improved with pioglitazone vs control. The treatment benefit occurred in patients already receiving comprehensive medical therapy (diabetes, antiplatelet, antihypertensive, and lipid-altering agents).

18. PROactive: Subgroup analysis�Previous MI Pioglitazone reduced risk of CV events, including: Fatal/nonfatal MI* by 28% (P = 0.045) ACS by 37% (P = 0.035) Over 3 years, pioglitazone added to medication in 1000 patients could prevent: 22 recurrent MIs 23 ACS events Future studies are needed to further elucidate the underlying mechanism(s) of these clinical results This prespecified subgroup analysis included the 46% of patients who had a previous MI (6 or more months prior to randomization) and were, therefore, considered at high risk for a subsequent macrovascular event. Pioglitazone treatment significantly reduced the risk of ACS by 37% and recurrent MI by 28%. Adding pioglitazone to the medication of 1000 patients would prevent approximately 22 recurrent MIs and 23 ACS events over 3 years.This prespecified subgroup analysis included the 46% of patients who had a previous MI (6 or more months prior to randomization) and were, therefore, considered at high risk for a subsequent macrovascular event. Pioglitazone treatment significantly reduced the risk of ACS by 37% and recurrent MI by 28%. Adding pioglitazone to the medication of 1000 patients would prevent approximately 22 recurrent MIs and 23 ACS events over 3 years.

19. PROactive: HF hospitalization and mortality Although significantly higher HF rates were reported in the pioglitazone vs control group (11% vs 8%, respectively; P < 0.0001), HF death frequency was similar between groups (~1% for both; P = 0.634). The investigators attribute the higher incidence of HF, which was not centrally adjudicated, to a possible diagnostic bias in the pioglitazone group due to the increase in TZD-related edema. TZDs do not appear to have any direct adverse effects on myocytes.Although significantly higher HF rates were reported in the pioglitazone vs control group (11% vs 8%, respectively; P < 0.0001), HF death frequency was similar between groups (~1% for both; P = 0.634). The investigators attribute the higher incidence of HF, which was not centrally adjudicated, to a possible diagnostic bias in the pioglitazone group due to the increase in TZD-related edema. TZDs do not appear to have any direct adverse effects on myocytes.

20. PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes The cardioprotective benefits demonstrated with pioglitazone in PROactive by study end (3 years) were similar to the benefits observed in subgroups of patients with diabetes at the end of other landmark clinical trials. Comparing the benefits of year 3 in each trial, observed benefits are greater in PROactive. Separation of the curves occurred prior to 1 year in PROactive, earlier than either CARE or HPS. CV risk reduction at study end (active vs placebo groups): HPS (Heart Protection Study): At a mean 4.8 year follow-up, simvastatin 40 mg daily reduced CV death, MI, stroke, or revascularization by 22% in 5963 participants with diabetes. CARE (Cholesterol and Recurrent Events): At a median 5 year follow-up, pravastatin 40 mg/day reduced CHD death or MI 20% in 586 patients with a previous MI. MICRO-HOPE (MIcroalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation): After 4.5 years, ramipril 10 mg once daily reduced CV death, MI, and stroke by 25% in 3577 high-risk patients with diabetes. PROactive: In the subgroup of patients with prior MI, at the 3 year follow-up, pioglitazone 15�45 mg/day reduced cardiac death, nonfatal MI, coronary revascularization, and ACS by 19%. A longer follow-up would be expected to further improve these benefits. Slide citations: HPS: Collins R et al. Lancet. 2003;361:2005-2016. CARE: Goldberg RB et al. Circulation. 1998;98:2513-2519. MICRO-HOPE: HOPE Study Investigators. Lancet. 2000;355:253-259. PROactive: Erdmann E et al. www.proactive-results.com.The cardioprotective benefits demonstrated with pioglitazone in PROactive by study end (3 years) were similar to the benefits observed in subgroups of patients with diabetes at the end of other landmark clinical trials. Comparing the benefits of year 3 in each trial, observed benefits are greater in PROactive. Separation of the curves occurred prior to 1 year in PROactive, earlier than either CARE or HPS. CV risk reduction at study end (active vs placebo groups): HPS (Heart Protection Study): At a mean 4.8 year follow-up, simvastatin 40 mg daily reduced CV death, MI, stroke, or revascularization by 22% in 5963 participants with diabetes. CARE (Cholesterol and Recurrent Events): At a median 5 year follow-up, pravastatin 40 mg/day reduced CHD death or MI 20% in 586 patients with a previous MI. MICRO-HOPE (MIcroalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation): After 4.5 years, ramipril 10 mg once daily reduced CV death, MI, and stroke by 25% in 3577 high-risk patients with diabetes. PROactive: In the subgroup of patients with prior MI, at the 3 year follow-up, pioglitazone 15�45 mg/day reduced cardiac death, nonfatal MI, coronary revascularization, and ACS by 19%. A longer follow-up would be expected to further improve these benefits. Slide citations: HPS: Collins R et al. Lancet. 2003;361:2005-2016. CARE: Goldberg RB et al. Circulation. 1998;98:2513-2519. MICRO-HOPE: HOPE Study Investigators. Lancet. 2000;355:253-259. PROactive: Erdmann E et al. www.proactive-results.com.

21. PROactive in perspective Significant 16% reduction in secondary outcome(MI, stroke, or death) despite nonsignificant 10% reduction in primary outcome HF hospitalizations increased vs placebo, though HF deaths were similar TZD effect on plaque stability and inflammation might contribute to CV benefits 3-year trial may be too short to definitively evaluate CV treatment effect; event curves did not begin to separate until 18 months Pioglitazone reduced CV events in high-risk patients with diabetes when added to baseline medications for glycemic control and CV risk reduction. Pioglitazone provided additional glycemic control, which reduced the need for insulin therapy.Pioglitazone reduced CV events in high-risk patients with diabetes when added to baseline medications for glycemic control and CV risk reduction. Pioglitazone provided additional glycemic control, which reduced the need for insulin therapy.

22. Fluid retention after TZD use tends to be peripheral In a retrospective chart review, TZD-associated edema was assessed in patients with type 2 diabetes plus chronic systolic HF and LVEF =45%. TZD-users (n = 111) were charted for 12 months after TZD initiation. Fluid retention was compared with diabetic non-TZD users with chronic HF and edema(n = 80 age/gender-matched controls). Nineteen of 111 (17%) TZD users exhibited edema (weight gain >10 lbs at any time over 12 months). TZD-associated edema most frequently manifested as peripheral edema. Pulmonary edema typically associated with myocardial depression was infrequently observed in the TZD- vs non-TZD-treated HF patients with edema. Additional data from the same study indicated that edema development in the TZD-treated patients did not correlate with HF severity.In a retrospective chart review, TZD-associated edema was assessed in patients with type 2 diabetes plus chronic systolic HF and LVEF =45%. TZD-users (n = 111) were charted for 12 months after TZD initiation. Fluid retention was compared with diabetic non-TZD users with chronic HF and edema(n = 80 age/gender-matched controls). Nineteen of 111 (17%) TZD users exhibited edema (weight gain >10 lbs at any time over 12 months). TZD-associated edema most frequently manifested as peripheral edema. Pulmonary edema typically associated with myocardial depression was infrequently observed in the TZD- vs non-TZD-treated HF patients with edema. Additional data from the same study indicated that edema development in the TZD-treated patients did not correlate with HF severity.

23. Managing TZD-related fluid retention Karalliedde et al assessed edema management strategies in 381 TZD-treated patients with type 2 diabetes. Patients initially treated with rosiglitazone 4 mg twice daily gained a mean of 4 lbs; mean hematocrit (Hct) levels fell 2.9% (SD 1.9%) after 12 weeks. Of the 381 patients receiving treatment, 260 patients had an Hct reduction =0.5% after12 weeks. In this subset of patients, edema management was assessed with rosiglitazone/diuretic, rosiglitazone alone, and rosiglitazone discontinuation. Although all diuretic treatments limited rosiglitazone treatment-associated edema, spironolactone 50 mg/day was most effective.Karalliedde et al assessed edema management strategies in 381 TZD-treated patients with type 2 diabetes. Patients initially treated with rosiglitazone 4 mg twice daily gained a mean of 4 lbs; mean hematocrit (Hct) levels fell 2.9% (SD 1.9%) after 12 weeks. Of the 381 patients receiving treatment, 260 patients had an Hct reduction =0.5% after12 weeks. In this subset of patients, edema management was assessed with rosiglitazone/diuretic, rosiglitazone alone, and rosiglitazone discontinuation. Although all diuretic treatments limited rosiglitazone treatment-associated edema, spironolactone 50 mg/day was most effective.

24. Collecting duct (CD) PPAR?: Potential mechanism for volume expansion Within the kidney, PPARg expression is largely restricted to the inner medulla and the inner medullary collecting duct. Zhang et al found that in mice with collecting duct-specific deletion of the PPARg receptor, plasma volume increased ~20% less with rosiglitazone than the control group. Therefore, mice with CD-specific knockout of the PPARg receptor were apparently resistant to rosiglitazone-induced increases in body weight and plasma volume expansion found in the control mice expressing PPARg. Rosiglitazone reduced urinary sodium excretion in the control group, but not in the knockout mice. These results demonstrate a PPARg-dependent pathway in regulating sodium transport in the collecting duct that underlies TZD-induced fluid retention.Within the kidney, PPARg expression is largely restricted to the inner medulla and the inner medullary collecting duct. Zhang et al found that in mice with collecting duct-specific deletion of the PPARg receptor, plasma volume increased ~20% less with rosiglitazone than the control group. Therefore, mice with CD-specific knockout of the PPARg receptor were apparently resistant to rosiglitazone-induced increases in body weight and plasma volume expansion found in the control mice expressing PPARg. Rosiglitazone reduced urinary sodium excretion in the control group, but not in the knockout mice. These results demonstrate a PPARg-dependent pathway in regulating sodium transport in the collecting duct that underlies TZD-induced fluid retention.

25. TZDs associated with lower mortality In a retrospective cohort study of 16,417 Medicare beneficiaries with diabetes discharged after hospitalization for HF, Masoudi et al showed that TZDs were associated with reduced mortality. As shown, mortality among those receiving TZD therapy (mean age 75.9 years, n = 2226) was significantly lower than in patients receiving no insulin-sensitizing therapy (mean age 77 years, n = 12,069). The adjusted hazard ratio (HR) was 0.87 (95% CI, 0.80�0.94). In a retrospective cohort study of 16,417 Medicare beneficiaries with diabetes discharged after hospitalization for HF, Masoudi et al showed that TZDs were associated with reduced mortality. As shown, mortality among those receiving TZD therapy (mean age 75.9 years, n = 2226) was significantly lower than in patients receiving no insulin-sensitizing therapy (mean age 77 years, n = 12,069). The adjusted hazard ratio (HR) was 0.87 (95% CI, 0.80�0.94).

26. TZDs in type 2 diabetes and HF Class I�II Use cautiously Initiate treatment at lowest dose Escalate dose gradually Allow more time than usual to achieve A1C target Class III�IV TZDs should not be used at this time Because of the potential for fluid retention with TZD therapy, the American Heart Association (AHA) and ADA jointly issued a 2003 consensus statement advising caution with these agents in patients with diabetes and coexisting HF. The AHA/ADA consensus statement recommended the following guidelines for the use of TZDs in HF patients: NYHA class I�II: TZDs may be used cautiously, with treatment at the lowest dose and gradual dose escalation. NYHA class III�IV: TZDs should not be used.Because of the potential for fluid retention with TZD therapy, the American Heart Association (AHA) and ADA jointly issued a 2003 consensus statement advising caution with these agents in patients with diabetes and coexisting HF. The AHA/ADA consensus statement recommended the following guidelines for the use of TZDs in HF patients: NYHA class I�II: TZDs may be used cautiously, with treatment at the lowest dose and gradual dose escalation. NYHA class III�IV: TZDs should not be used.

27. Major TZD outcome trials The following slides discuss new trials with TZDs; the data are anticipated in 2006. ADOPT = A Diabetes Outcome Progression TrialCHICAGO = Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone studyDREAM = Diabetes REduction Assessment with ramipril and rosiglitazone MedicationThe following slides discuss new trials with TZDs; the data are anticipated in 2006. ADOPT = A Diabetes Outcome Progression TrialCHICAGO = Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone studyDREAM = Diabetes REduction Assessment with ramipril and rosiglitazone Medication

28. DREAM: Background and study objective Previous studies have shown evidence for ?new-onset diabetes with RAAS and PPAR agonists Does treatment with ramipril and/or rosiglitazone prevent or delay the development of diabetes in persons with IGT or IFG and no diabetes? The angiotensin-converting enzyme (ACE) inhibitor ramipril is known to reduce CV and renal disease in high-risk subjects with diabetes and in patients with vascular disease but without diabetes. In addition, rosiglitazone has beneficial effects on metabolic and CV risk factors. The DREAM trial will assess whether rosiglitazone or ramipril, alone or in combination, can prevent or delay new-onset diabetes in high-risk individuals (N = 5269). The Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR) substudy will assess treatment effects on carotid atherosclerosis as measured by ultrasound.The angiotensin-converting enzyme (ACE) inhibitor ramipril is known to reduce CV and renal disease in high-risk subjects with diabetes and in patients with vascular disease but without diabetes. In addition, rosiglitazone has beneficial effects on metabolic and CV risk factors. The DREAM trial will assess whether rosiglitazone or ramipril, alone or in combination, can prevent or delay new-onset diabetes in high-risk individuals (N = 5269). The Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR) substudy will assess treatment effects on carotid atherosclerosis as measured by ultrasound.

29. RAAS modulation reduces new-onset diabetes Recently, the results of large randomized clinical trials have suggested a difference in the incidence of new diabetes according to CV medication use. As seen in this slide, a consistent reduction in new-onset diabetes was demonstrated in randomized trials of agents that block the renin-angiotensin-aldosterone system (RAAS). Treatment with ACE inhibitors and angiotensin-receptor blockers (ARBs) yielded a lower incidence of diabetes development than beta-blockers and diuretics. Whereas treatment with ACE inhibitors or ARBs appears to improve insulin sensitivity and glucose metabolism, certain agents�notably thiazide diuretics and beta-blockers�are associated with metabolic disturbances that may result in increased insulin resistance. These results should be taken into account, at least in patients with a risk of developing diabetes. Recently, the results of large randomized clinical trials have suggested a difference in the incidence of new diabetes according to CV medication use. As seen in this slide, a consistent reduction in new-onset diabetes was demonstrated in randomized trials of agents that block the renin-angiotensin-aldosterone system (RAAS). Treatment with ACE inhibitors and angiotensin-receptor blockers (ARBs) yielded a lower incidence of diabetes development than beta-blockers and diuretics. Whereas treatment with ACE inhibitors or ARBs appears to improve insulin sensitivity and glucose metabolism, certain agents�notably thiazide diuretics and beta-blockers�are associated with metabolic disturbances that may result in increased insulin resistance. These results should be taken into account, at least in patients with a risk of developing diabetes.

30. TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes The role of insulin resistance in pancreatic beta-cell failure and type 2 diabetes was tested directly in the Troglitazone in Prevention of Diabetes (TRIPOD) study. Young (mean age ~34) Hispanic women from Los Angeles County Women and Children�s Hospital with a history of gestational diabetes in the previous 4 years received troglitazone 400 mg/day or placebo. During a median follow-up of 30 months, average annual incidence rates of diabetes were 12.1% vs 5.4% in placebo and troglitazone groups, respectively, which translates to a 55% reduction in the risk of diabetes. The protective effect persisted for at least 8 months after study medication cessation, and was associated with preserved beta-cell function, suggesting that TZD treatment had fundamentally altered the underlying biology leading to type 2 diabetes.The role of insulin resistance in pancreatic beta-cell failure and type 2 diabetes was tested directly in the Troglitazone in Prevention of Diabetes (TRIPOD) study. Young (mean age ~34) Hispanic women from Los Angeles County Women and Children�s Hospital with a history of gestational diabetes in the previous 4 years received troglitazone 400 mg/day or placebo. During a median follow-up of 30 months, average annual incidence rates of diabetes were 12.1% vs 5.4% in placebo and troglitazone groups, respectively, which translates to a 55% reduction in the risk of diabetes. The protective effect persisted for at least 8 months after study medication cessation, and was associated with preserved beta-cell function, suggesting that TZD treatment had fundamentally altered the underlying biology leading to type 2 diabetes.

31. TZDs blunt diabetes progression The Diabetes Prevention Program (DPP) assessed four treatments to prevent diabetes in individuals at high risk, as indicated by elevated fasting and postload glucose concentrations. Subjects (N = 2343) were randomized to troglitazone 400 mg/day, metformin 850 mg twice daily, placebo, or aggressive lifestyle modification. The slide summarizes the cumulative incidence of diabetes by subgroup for the 1.5 years before early termination of the troglitazone arm (withdrawn from the study); agent was withdrawn from the US market in 2000. Compared with placebo, troglitazone reduced the development of diabetes by 75%, lifestyle intervention by 58%, and metformin by 44%. At the study end, diabetes incidence for the troglitazone group was 3 cases/100 person-years vs 12, 6.7, and 5.1 cases/100 person-years for placebo, metformin, and lifestyle modification, respectively. These differences reached significance for troglitazone vs metformin (P = 0.02) and placebo (P < 0.001).The Diabetes Prevention Program (DPP) assessed four treatments to prevent diabetes in individuals at high risk, as indicated by elevated fasting and postload glucose concentrations. Subjects (N = 2343) were randomized to troglitazone 400 mg/day, metformin 850 mg twice daily, placebo, or aggressive lifestyle modification. The slide summarizes the cumulative incidence of diabetes by subgroup for the 1.5 years before early termination of the troglitazone arm (withdrawn from the study); agent was withdrawn from the US market in 2000. Compared with placebo, troglitazone reduced the development of diabetes by 75%, lifestyle intervention by 58%, and metformin by 44%. At the study end, diabetes incidence for the troglitazone group was 3 cases/100 person-years vs 12, 6.7, and 5.1 cases/100 person-years for placebo, metformin, and lifestyle modification, respectively. These differences reached significance for troglitazone vs metformin (P = 0.02) and placebo (P < 0.001).

32. DREAM: Study design DREAM assessed treatment with rosiglitazone and/or ramipril in 5269 multi-ethnic adult patients (ages =30 years) with IGT and/or IFG in a 2 x 2 factorial trial design. Follow-up was 3 to 5 years. The primary outcome was new-onset diabetes or all-cause mortality. The secondary outcome was a composite: CV events: MI, stroke, CV death, revascularization, HF, angina, or ventricular arrhythmia requiring resuscitation Renal events: progression of normo- or microalbuminuria to micro- or macroalbuminuria, or a 30% decrease in creatinine clearance Subsequent to the outcome assessments, there was a washout period during which placebo was assigned to all groups, allowing investigators to distinguish transitory glucose lowering from a more fundamental effect on diabetes development. At this time, FPG and A1C levels were assessed, and a final OGTT was performed on participants with no diabetes.DREAM assessed treatment with rosiglitazone and/or ramipril in 5269 multi-ethnic adult patients (ages =30 years) with IGT and/or IFG in a 2 x 2 factorial trial design. Follow-up was 3 to 5 years. The primary outcome was new-onset diabetes or all-cause mortality. The secondary outcome was a composite: CV events: MI, stroke, CV death, revascularization, HF, angina, or ventricular arrhythmia requiring resuscitation Renal events: progression of normo- or microalbuminuria to micro- or macroalbuminuria, or a 30% decrease in creatinine clearance Subsequent to the outcome assessments, there was a washout period during which placebo was assigned to all groups, allowing investigators to distinguish transitory glucose lowering from a more fundamental effect on diabetes development. At this time, FPG and A1C levels were assessed, and a final OGTT was performed on participants with no diabetes.

33. DREAM: 2 x 2 factorial design The 2 x 2 factorial design compared daily doses of: Rosiglitazone 8 mg plus ramipril 15 mg Rosiglitazone 8 mg plus placebo Ramipril 15 mg plus placebo Placebo plus placebo Rosiglitazone was initiated at 4 mg/day and uptitrated. Ramipril was initiated at 5 mg/day and uptitrated. The 2 x 2 factorial design compared daily doses of: Rosiglitazone 8 mg plus ramipril 15 mg Rosiglitazone 8 mg plus placebo Ramipril 15 mg plus placebo Placebo plus placebo Rosiglitazone was initiated at 4 mg/day and uptitrated. Ramipril was initiated at 5 mg/day and uptitrated.

34. DREAM: Inclusion criteria Age =30 years IFG and/or IGT Fasting plasma glucose 100�125 mg/dL 2-hour 75 g OGTT 140�199 mg/dL Individuals with prediabetes (IFG and/or IGT) at least 30 years of age were included in this study. IFG: Fasting plasma glucose was 100 to 125 mg/dL. IGT: Plasma glucose level after a 2-hour 75 mg OGTT was <200 mg/dL.Individuals with prediabetes (IFG and/or IGT) at least 30 years of age were included in this study. IFG: Fasting plasma glucose was 100 to 125 mg/dL. IGT: Plasma glucose level after a 2-hour 75 mg OGTT was <200 mg/dL.

35. DREAM: Key exclusion criteria ACEI/TZD use or contraindication LVEF <40% or other CVD with ACEI indication Diabetes Renal disease, including renal artery stenosis Diseases/medications that affect glucose tolerance Use of steroids/niacin Pregnancy Individuals were excluded from this study if they had known CV disease, including LVEF <40%, CHF, previous MI or stroke, revascularization, or uncontrolled hypertension. Criteria for study exclusion also included: Intolerance of ACE inhibitors or TZDs Prior history of diabetes or use of oral antiglycemic medications Renal or hepatic diseaseIndividuals were excluded from this study if they had known CV disease, including LVEF <40%, CHF, previous MI or stroke, revascularization, or uncontrolled hypertension. Criteria for study exclusion also included: Intolerance of ACE inhibitors or TZDs Prior history of diabetes or use of oral antiglycemic medications Renal or hepatic disease

36. DREAM: Baseline characteristics The study included both sexes (58.5% women) and the mean age was 54.7 years. Participants were typically overweight or obese (mean BMI = 30.5 kg/m2) and had hypertension (43.5%) and hyperlipidemia (35.5%).The study included both sexes (58.5% women) and the mean age was 54.7 years. Participants were typically overweight or obese (mean BMI = 30.5 kg/m2) and had hypertension (43.5%) and hyperlipidemia (35.5%).

37. DREAM: Baseline glucose status Isolated IGT 1835 (35%) Isolated IFG* 739 (14%) IGT and IFG* 2692 (51%) FPG (mean) 104 2-hr plasma glucose (mean) 157 Approximately half of the participants had both IGT and IFG, whereas 35% and 14% had isolated IGT and IFG, respectively. This study population does not reflect the prevalence of isolated IFG in the general population since the inclusion criteria were expanded in 2003 to include individuals with isolated IFG. The average FPG and 2-hour plasma glucose after OGTT were 104 mg/dL and 157 mg/dL, respectively.Approximately half of the participants had both IGT and IFG, whereas 35% and 14% had isolated IGT and IFG, respectively. This study population does not reflect the prevalence of isolated IFG in the general population since the inclusion criteria were expanded in 2003 to include individuals with isolated IFG. The average FPG and 2-hour plasma glucose after OGTT were 104 mg/dL and 157 mg/dL, respectively.

38. DREAM: Beyond diabetes prevention IFG and IGT are strong risk factors for CV disease Does treatment with rosiglitazone and/or ramipril improve IFG, IGT, and glucose control? Positive result for either or both drugs will: Affirm that links between RAAS, glucose homeostasis, andCV disease are clinically important Highlight relevance of elevated glucose levels as modifiablerisk factors for CV disease Since CV and renal events will be followed, the study implications are expected to extend beyond the effect of ACE inhibitors and TZDs on diabetes prevention. CV event reduction with a TZD will highlight elevated plasma glucose as a modifiable CV risk factor. Additive benefits with both drugs would suggest a clinically relevant link between RAAS, glucose homeostasis, and CV disease. Thus, the DREAM trial will determine whether TZDs and/or ACE inhibitors can repair an abnormal glucometabolic state. Since CV and renal events will be followed, the study implications are expected to extend beyond the effect of ACE inhibitors and TZDs on diabetes prevention. CV event reduction with a TZD will highlight elevated plasma glucose as a modifiable CV risk factor. Additive benefits with both drugs would suggest a clinically relevant link between RAAS, glucose homeostasis, and CV disease. Thus, the DREAM trial will determine whether TZDs and/or ACE inhibitors can repair an abnormal glucometabolic state.

39. DREAM: Substudies STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone) (N = 1427) Carotid atherosclerosis progression The Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR) substudy (N = 1427) will assess effects of treatment on carotid atherosclerosis as measured by B-mode ultrasound. The EpiDREAM epidemiologic study will assess novel determinants (dietary, lifestyle-related, demographic, clinical, etc) of diabetes, IFG, IGT, and other metabolic and clinical outcomes.The Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR) substudy (N = 1427) will assess effects of treatment on carotid atherosclerosis as measured by B-mode ultrasound. The EpiDREAM epidemiologic study will assess novel determinants (dietary, lifestyle-related, demographic, clinical, etc) of diabetes, IFG, IGT, and other metabolic and clinical outcomes.

40. ADOPT: Study objective What is the long-term efficacy of monotherapy with rosiglitazone vs metformin or glyburide on glucose control in patients with type 2 diabetes (diagnosed=3 years)? A Diabetes Outcome Progression Trial (ADOPT) will directly compare the impact of metformin, glyburide, and rosiglitazone, three mechanistically distinct oral antidiabetic agents, on metabolic and clinical outcomes in patients with recently diagnosed type 2 diabetes (within 3 years). Although metformin and sulfonylureas (eg, glyburide) improve glycemic control in the short term, they do not prevent progressive beta-cell failure or deterioration in glycemia over the long-term. A Diabetes Outcome Progression Trial (ADOPT) will directly compare the impact of metformin, glyburide, and rosiglitazone, three mechanistically distinct oral antidiabetic agents, on metabolic and clinical outcomes in patients with recently diagnosed type 2 diabetes (within 3 years). Although metformin and sulfonylureas (eg, glyburide) improve glycemic control in the short term, they do not prevent progressive beta-cell failure or deterioration in glycemia over the long-term.

41. ADOPT: Study design ADOPT is a blinded, randomized, controlled, international investigation designed to test the hypothesis that improving glycemic control in drug-na�ve patients with newly-diagnosed type 2 diabetes may alter disease progression. Patients (N ~3600) diagnosed with diabetes (<3 years) who were previously managed with diet and exercise only are randomized to rosiglitazone =8 mg, metformin =2 g, or glyburide =15 mg, each titrated to the maximum effective daily dose to achieve fasting plasma glucose <140 mg/dL. The primary outcome is time to monotherapy failure, when fasting plasma glucose exceeds 180 mg/dL despite maximal treatment after =6 weeks of treatment. Secondary outcomes will assess effects of treatment on glycemic control, beta-cell function, insulin sensitivity, CV risk markers, and renal function. ADOPT is a blinded, randomized, controlled, international investigation designed to test the hypothesis that improving glycemic control in drug-na�ve patients with newly-diagnosed type 2 diabetes may alter disease progression. Patients (N ~3600) diagnosed with diabetes (<3 years) who were previously managed with diet and exercise only are randomized to rosiglitazone =8 mg, metformin =2 g, or glyburide =15 mg, each titrated to the maximum effective daily dose to achieve fasting plasma glucose <140 mg/dL. The primary outcome is time to monotherapy failure, when fasting plasma glucose exceeds 180 mg/dL despite maximal treatment after =6 weeks of treatment. Secondary outcomes will assess effects of treatment on glycemic control, beta-cell function, insulin sensitivity, CV risk markers, and renal function.

42. CHICAGO: Study objective How effective is pioglitazone in controlling the progression of atherosclerosis in patients with type 2 diabetes, as measured by carotid artery thickness? CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) trial will compare the effects of pioglitazone vs the sulfonylurea glimepiride in subjects withtype 2 diabetes on progression of atherosclerosis, based on ultrasound assessment of carotid IMT. The results of this study will indicate the effectiveness of pioglitazone in controlling atherosclerosis progression in patients with type 2 diabetes. Results are anticipated in 2006. CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) trial will compare the effects of pioglitazone vs the sulfonylurea glimepiride in subjects withtype 2 diabetes on progression of atherosclerosis, based on ultrasound assessment of carotid IMT. The results of this study will indicate the effectiveness of pioglitazone in controlling atherosclerosis progression in patients with type 2 diabetes. Results are anticipated in 2006.

43. CHICAGO: Study design The CHICAGO trial is a double-blind, randomized, active control, parallel efficacy study being conducted in ~462 patients with type 2 diabetes who are asymptomatic for CAD. Subjects were randomized to treatment with pioglitazone or glimepiride for 18 months. The primary outcome of the study is the effect of pioglitazone on absolute changes in carotid IMT. Secondary endpoints include coronary artery calcium as measured by electron-beam computed tomography as well as visceral and subcutaneous fat distribution, markers of lipoprotein metabolism and inflammation, and coagulation factors. An important aspect of this study is that glimepiride will be used as an active comparator. Therefore, any effect of pioglitazone on carotid IMT will be independent of changes in glycemia. The CHICAGO trial is a double-blind, randomized, active control, parallel efficacy study being conducted in ~462 patients with type 2 diabetes who are asymptomatic for CAD. Subjects were randomized to treatment with pioglitazone or glimepiride for 18 months. The primary outcome of the study is the effect of pioglitazone on absolute changes in carotid IMT. Secondary endpoints include coronary artery calcium as measured by electron-beam computed tomography as well as visceral and subcutaneous fat distribution, markers of lipoprotein metabolism and inflammation, and coagulation factors. An important aspect of this study is that glimepiride will be used as an active comparator. Therefore, any effect of pioglitazone on carotid IMT will be independent of changes in glycemia.