Stuart Kupfer

Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes

BACKGROUND To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. METHODS We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. CONCLUSIONS Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes: The PERISCOPE Randomized Controlled Trial

CONTEXT No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. OBJECTIVE To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. INTERVENTIONS A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. MAIN OUTCOME MEASURE Change in percent atheroma volume (PAV) from baseline to study completion. RESULTS Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. CONCLUSION In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00225277.

Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?

Context Experts debate the consequences of excessive lowering of diastolic pressure in patients with hypertension and coronary artery disease. Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease. The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infarction, with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg, that is, the lower the diastolic pressure, the higher the risk. Cautions The study examined associations between blood pressure and outcomes; it could not prove that the antihypertensive therapy that lowered diastolic pressure too much caused the adverse outcomes. The Editors For 2 decades, the hypertension literature has been haunted by the phenomenon of a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure (J-curve). Indeed, several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications (1-13). After doing a review and meta-analysis of pertinent studies, Farnett and colleagues (14) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure, there was a consistent J-shaped relationship for cardiac events and diastolic pressure. These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease. These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) (15), which stated that the relationship between pressure and risk was strong, continuous, independent, predictive and etiologically significant. Within the past decade, the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients (16-30). Not surprisingly, arguments regarding whether a J-curve could be clinically significant have become somewhat contentious. That is, some rely on evidence that on-treatment diastolic pressure below 70 mm Hg does not increase risk for cardiovascular disease and thus deny an impairment of vital organ perfusion within the usual values achievable by antihypertensive treatment. Others, however, consider the J-curve a more real possibility, particularly for the heart. In contrast to other organs, the heart is perfused mostly during diastole and thus could be more vulnerable to diastolic pressure reduction. If a J-curve did exist, it should be most evident in patients with limited coronary perfusion, in other words, in those with manifest coronary artery disease (CAD). Optimal blood pressure in patients with hypertension and CAD remains controversial because few randomized clinical trials have been done in this population (31, 32). The International Verapamil-Trandolapril Study (INVEST) (33), a randomized trial, evaluated more than 22000 patients with CAD and hypertension. This patient profile, together with unprecedented levels of blood pressure control, provided a unique opportunity to critically investigate the hypothesis that the risk for CAD would increase with an excessive decrease in diastolic pressure. Methods Study Design and Intervention The INVEST design, methods, and principal results have been previously published (33). The trial used an open design with blinded end point assessment. In brief, clinically stable patients with CAD and hypertension were randomly assigned to a verapamil sustained-releasebased or atenolol-based strategy. Patients with previous myocardial infarction (MI) within 3 months of enrollment or class IV or V congestive heart failure were excluded. Blood pressure goals were based on JNC VI (systolic pressure <140 mm Hg and diastolic pressure <90 mm Hg or systolic pressure <130 mm Hg and diastolic pressure <85 mm Hg in patients with diabetes or renal impairment) (15). The addition of trandolapril or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment. Documented CAD was defined as any of the following: remote (3 months before enrollment) confirmed MI, coronary angiography showing more than 50% narrowing of at least 1 major coronary artery, diagnosis of classic angina pectoris, or concordant abnormalities on 2 different signals (electrocardiography, echocardiography, or radionuclide scans) from stress test findings concordant for ischemia (for example, ST-segment depression or perfusion defects on radionuclide scanning or wall-motion abnormalities on echocardiography or radionuclide scanning). Patient Monitoring and Follow-up Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled. Patients were assessed for response to treatment, symptoms, treatment adherence, and adverse effects at each visit and at the end of the study as detailed elsewhere (33). Patient follow-up was complete when we received a final assessment form through the online data system or a death report. The Internet-based electronic data collection method used in INVEST did not accept the entry until all required fields were complete. Blood pressure was measured by using a standard mercury sphygmomanometer with an appropriately sized cuff applied to the upper nondominant arm at heart level. By auscultation at the brachial artery, systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound. Blood pressure was measured twice, at least 2 minutes apart, and the measurements were averaged. Study Outcomes The primary outcome was the first occurrence of all-cause death, nonfatal MI, or nonfatal stroke by intention-to-treat analysis. The MI and stroke definitions are detailed elsewhere (34). These 3 components individually were the main secondary outcomes. For this analysis, additional outcomes included fatal and nonfatal MI, fatal and nonfatal stroke, and average on-treatment blood pressure before outcome or censoring. Ascertainment and blinded adjudication of outcomes were described previously (32). Follow-up data were available for 22008 (97.5%) patients. Statistical Analysis The main conclusions of INVEST were that the 2 treatment strategies were equivalent with respect to the primary outcome, main secondary outcomes, and on-treatment systolic and diastolic pressures. Thus, data for all enrolled patients were combined and included in these analyses following the intention-to-treat principle. A P value of 0.05 or less was considered statistically significant. Patients without a primary outcome event were censored at their latest follow-up visit. Average follow-up systolic and diastolic pressures were calculated for each patient by using all post-baseline results, up to the date of primary outcome or censoring. The baseline value was substituted for patients with no post-baseline data (n= 1154). In this exploratory analysis, the proportions of patients were pooled by 10mm Hg strata of average follow-up systolic pressure, and the distribution of primary outcome event rate was evaluated to determine whether the relationship was linear. A similar presentation was prepared for diastolic pressure. Because the frequency distributions seemed consistent with a quadratic curve, a quadratic Cox proportional hazards model was formed for the time to primary outcome for each blood pressure variable, with factors for blood pressure and blood pressure squared. Similarly, the relationship between each 10mm Hg stratum of average systolic pressure and diastolic pressure and all-cause death, fatal and nonfatal MI, and fatal and nonfatal stroke was evaluated. For the time to primary outcome, a second model was fitted, adjusting for the following baseline covariates: age (10-year increments), sex, race and ethnicity (white, Asian, black, Hispanic, multiracial, or other), previous MI, heart failure (classes I to III), body mass index in increments of 5 kg/m2, U.S. residency, renal impairment, peripheral vascular disease, left ventricular hypertrophy, smoking history, coronary revascularization, dyslipidemia, stroke or transient ischemic attack, angina pectoris, arrhythmia, diabetes, cancer, aspirin use, and average systolic pressure or diastolic pressure and systolic pressure squared or diastolic pressure squared. To identify clinically relevant interactions between the J-shaped curve and baseline diastolic pressure, demographic characteristics, and comorbid conditions for the primary outcome, a 2-step procedure was used. First, baseline covariates were tested individually by adding the variable and 2 interaction terms (variablediastolic pressure and variable[diastolic pressure squared]) to the Cox proportional hazards model. Variables included were age older than 70 years, sex, previous MI, heart failure (classes I to III), previous stroke or transient ischemic attack, diabetes, cancer, renal impairment, hypercholesterolemia, peripheral vascular disease, smoking history, U.S. residency, body mass index greater than 29 kg/m2 (mean baseline body mass index), and diastolic pressure greater than 86 mm Hg (mean baseline diastolic pressure). The change in log likelihood was used to assess the significance of simultaneously adding the 2 interaction terms. The second step in identifying clinically relevant interactions between the J-shaped curve and baseline covariates was to plot the hazard ratios for the primary outcome versus diastolic pressure in the pr

Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke: Results From PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04)

Background and Purpose— Diabetes is an important risk factor for stroke. We conducted analyses in patients who had entered the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) with a history of stroke or without stroke. Methods— The prospective, double-blind PROactive (mean duration, 34.5 months) randomized 5238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone (titrated to 45 mg) or placebo, in addition to current diabetes and cardiovascular medications. Cardiovascular end-point events were independently adjudicated. This analysis evaluated the risk of stroke and other cardiovascular outcomes in patients with (n=984) and without (n=4254) prior stroke. Results— In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0.78, event rate=20.2% pioglitazone vs 25.3% placebo; 95% CI=0.60–1.02; P=0.0670) and for the main secondary end point of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.78, event rate=15.6% pioglitazone vs 19.7% placebo; 95% CI=0.58–1.06; P=0.1095). Pioglitazone reduced fatal or nonfatal stroke (HR=0.53, event rate=5.6% pioglitazone vs 10.2% placebo; 95% CI=0.34–0.85; P=0.0085) and cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.72, event rate=13.0% pioglitazone vs 17.7% placebo; 95% CI=0.52–1.00; P=0.0467). Higher event rates were observed in patients with prior stroke compared with those without prior stroke. In patients without prior stroke, no treatment effect was observed for a first stroke. Conclusions— In a subgroup analysis from PROactive, pioglitazone reduced the risk of recurrent stroke significantly in high-risk patients with type 2 diabetes.

Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: A multicentre, randomised, double-blind trial

BACKGROUND The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial. METHODS Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708. FINDINGS 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. INTERPRETATION In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes. FUNDING Takeda Development Center Americas.

Effects of the Angiotensin Receptor Blocker Azilsartan Medoxomil Versus Olmesartan and Valsartan on Ambulatory and Clinic Blood Pressure in Patients With Stages 1 and 2 Hypertension

Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (−14.3 mm Hg) more than 320 mg of valsartan (−10.0 mm Hg; P<0.001) and 40 mg of olmesartan (−11.7 mm Hg; P=0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: −1.4 mm Hg [95% CI: −3.3 to 0.5]). For clinic systolic BP, both doses of azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.

Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all‐cause mortality, cause‐specific mortality, relevant non‐fatal morbidity (e.g. all‐cause and cause‐specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient‐reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA‐ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12–13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the groups recommendations for achieving common views on heart failure endpoints in clinical trials.

The Comparative Effects of Azilsartan Medoxomil and Olmesartan on Ambulatory and Clinic Blood Pressure

The current study assesses the antihypertensive efficacy and safety of the investigational angiotensin receptor blocker (ARB), azilsartan medoxomil (AZL‐M), compared with placebo and the ARB olmesartan medoxomil (OLM‐M). This randomized, double‐blind, placebo‐controlled, multicenter study assessed change from baseline in mean 24‐hour ambulatory systolic blood pressure (SBP) following 6 weeks of treatment. Patients with primary hypertension (n=1275) and baseline 24‐hour mean ambulatory systolic pressure ≥130 mm Hg and ≤170 mm Hg were studied; 142 received placebo and the remainder received 20 mg, 40 mg, or 80 mg AZL‐M or 40 mg OLM‐M. Mean age of participants was 58±11 years, baseline mean 24‐hour SBP was 146 mm Hg. Dose‐dependent reductions in 24‐hour mean SBP at study end occurred in all AZL‐M groups. Reduction in 24‐hour mean SBP was greater with AZL‐M 80 mg than OLM‐M 40 mg by 2.1 mm Hg (95% confidence interval, −4.0 to −0.1; P=.038), while AZL‐M 40 mg was noninferior to OLM‐M 40 mg. The side effect profiles of both ARBs were similar to placebo. AZL‐M is well tolerated and more efficacious at its maximal dose than the highest dose of OLM‐M. J Clin Hypertens (Greenwich). 2011;13:81–88.

Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes : Results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10)

BACKGROUND Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes. METHODS PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months. RESULTS At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points (P < .05) and a trend to benefit in the sixth (P = .052), with hazard ratios of 0.79 to 0.83. CONCLUSIONS In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.

Lowering the triglyceride/high-density lipoprotein cholesterol ratio is associated with the beneficial impact of pioglitazone on progression of coronary atherosclerosis in diabetic patients: insights from the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study.

OBJECTIVES The purpose of this study was to determine the factors associated with the favorable effect of pioglitazone on atheroma progression. BACKGROUND Diabetes mellitus is associated with accelerated coronary atheroma progression. Pioglitazone slowed progression compared with glimepiride in this population. METHODS In all, 360 diabetic patients with coronary artery disease were treated with pioglitazone or glimepiride for 18 months in the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study. Coronary atheroma progression was evaluated by serial intravascular ultrasound. The relationship between changes in biochemical parameters, percent atheroma volume, and total atheroma volume was investigated. RESULTS Pioglitazone-treated patients demonstrated greater increases in high-density lipoprotein cholesterol (HDL-C) and reductions in glycated hemoglobin, triglycerides, and C-reactive protein. Significant correlations were observed between changes in percent atheroma volume and triglycerides (r = 0.15, p = 0.04), triglyceride/HDL-C ratio (r = 0.16, p = 0.03), and glycated hemoglobin (r = 0.16, p = 0.03) with pioglitazone, and changes in low-density lipoprotein cholesterol (r = -0.15, p = 0.05), apolipoprotein B (r = -0.16, p = 0.04), and apolipoprotein A-I (r = -0.20, p = 0.01) with glimepiride. Substantial atheroma regression, compared to progression, was associated with greater relative increases in HDL-C (14.2% vs. 7.8%, p = 0.04), relative decreases in triglycerides (-13.3% vs. -1.9%, p = 0.045), triglyceride/HDL-C ratio (-22.5 vs. -9.9%, p = 0.05), and decrease in glycated hemoglobin (-0.6% vs. -0.3%, p = 0.01). Multivariable analysis revealed that pioglitazone-induced effects on triglyceride/HDL-C were associated with changes in percent atheroma volume (p = 0.03) and total atheroma volume (p = 0.02). CONCLUSIONS Favorable effects of pioglitazone on the triglyceride/HDL-C ratio correlated with delayed atheroma progression in diabetic patients. This finding highlights the potential importance of targeting atherogenic dyslipidemia in diabetic patients with coronary artery disease.