Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: insights from the National Heart Care Project.

OBJECTIVE Thiazolidinediones (TZDs) and metformin are insulin-sensitizing antihyperglycemic agents with reported benefits on atherosclerosis. Despite extensive use in patients with diabetes and cardiovascular disease, there is a paucity of outcomes data with metformin and none yet with TZDs. We sought to determine the impact of these insulin sensitizers on outcomes in diabetic patients after hospitalization with acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study of 24,953 Medicare beneficiaries with diabetes discharged after hospitalization with AMI between April 1998 and March 1999 or July 2000 and June 2001. The independent association between discharge prescription for metformin, TZD, or both agents and outcomes at 1 year was assessed in multivariable Cox proportional hazards models, adjusting for patient, physician, and hospital variables. The primary outcome was time to death within 1 year of discharge; secondary outcomes were time to first rehospitalization within 1 year of discharge for AMI, heart failure, and all causes. RESULTS There were 8,872 patients discharged on an antihyperglycemic agent, of which 819 were prescribed a TZD, 1,273 metformin, and 139 both drugs. After multivariable analysis, compared with patients prescribed an antihyperglycemic regimen that included no insulin sensitizer, mortality rates were not significantly different in patients treated with either metformin (hazard ratio [HR] 0.92 [95% CI 0.81-1.06]) or a TZD (0.92 [0.80-1.05]) but were lower in those prescribed both drugs (0.52 [0.34-0.82]). The results were similar among patients with heart failure. The prescription of a TZD was associated with a borderline higher risk of all-cause readmission (1.09[1.00-1.20]), predominately due to a higher risk for heart failure readmission (1.17 [1.05-1.30]). CONCLUSIONS Individually, prescription of insulin-sensitizing drugs is not associated with a significantly different risk of death in older diabetic patients within 1 year following AMI compared with other antihyperglycemic agents. Combined, however, metformin and TZDs may exert benefit. TZD prescription is associated with a higher risk of readmission for heart failure after myocardial infarction.

[1]  H. Krumholz,et al.  Thiazolidinediones, Metformin, and Outcomes in Older Patients With Diabetes and Heart Failure: An Observational Study , 2005, Circulation.

[2]  T. Elasy,et al.  Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: a consensus statement from the American Heart Association and American Diabetes Association Response to Nesto , 2004 .

[3]  John Dormandy,et al.  The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. , 2004, Diabetes care.

[4]  B. Davis,et al.  Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. , 2004, The American journal of cardiology.

[5]  P. Teirstein,et al.  1025-41 Insulin sensitizers are associated with improved outcomes in diabetic patients undergoing brachytherapy , 2004 .

[6]  B. Horne,et al.  810-5 Use of either metformin or thiazolidinedione is associated with improved survival among patients with type 2 diabetes from a registry of 16,203 diabetic patients , 2004 .

[7]  O. Raitakari,et al.  Diabetic background retinopathy is associated with impaired coronary vasoreactivity in people with Type 1 diabetes , 2004, Diabetologia.

[8]  R. Ratner,et al.  The roles of insulin resistance, hyperinsulinemia, and thiazolidinediones in cardiovascular disease. , 2003, The American journal of medicine.

[9]  R. T. Hurst,et al.  Increased Incidence of Coronary Atherosclerosis in Type 2 Diabetes Mellitus: Mechanisms and Management , 2003, Annals of Internal Medicine.

[10]  V. Fonseca Management of diabetes mellitus and insulin resistance in patients with cardiovascular disease. , 2003, The American journal of cardiology.

[11]  K. Tanabe,et al.  Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. , 2003, American heart journal.

[12]  G. Reaven,et al.  Insulin resistance/compensatory hyperinsulinemia, essential hypertension, and cardiovascular disease. , 2003, The Journal of clinical endocrinology and metabolism.

[13]  A. Aljada,et al.  The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis-related complications in type 2 diabetes. , 2003, The Journal of clinical endocrinology and metabolism.

[14]  B. Hoogwerf,et al.  Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure. , 2003, Journal of the American College of Cardiology.

[15]  S. Mudaliar,et al.  Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy. , 2003, Diabetes.

[16]  Erik Jørgensen,et al.  Low restenosis rate of the NIR coronary stent: results of the Danish multicenter stent study (DANSTENT)--a randomized trial comparing a first-generation stent with a second-generation stent. , 2003, American heart journal.

[17]  S. Kihara,et al.  Association of Hypoadiponectinemia With Coronary Artery Disease in Men , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[18]  S. Inzucchi,et al.  Metformin: new understandings, new uses. , 2003, Drugs.

[19]  S. Haffner,et al.  Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus , 2002, Circulation.

[20]  S. Mudaliar,et al.  Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. , 2002, Diabetes care.

[21]  Ingi Lee Effects on Lipid Metabolism of Metformin and Troglitazone in Patients with Type 2 Diabetes Mellitus , 2002 .

[22]  H. Koshiyama,et al.  Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. , 2001, The Journal of clinical endocrinology and metabolism.

[23]  H. Foyt,et al.  The Effect of a Thiazolidinedione Drug, Troglitazone, on Glycemia in Patients with Type 2 Diabetes Mellitus Poorly Controlled with Sulfonylurea and Metformin: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial , 2001, Annals of Internal Medicine.

[24]  H. Krumholz,et al.  Aspirin and angiotensin-converting enzyme inhibitors among elderly survivors of hospitalization for an acute myocardial infarction. , 2001, Archives of internal medicine.

[25]  M. Pendergrass,et al.  Nonhypoglycemic Effects of Thiazolidinediones , 2001, Annals of Internal Medicine.

[26]  D. Einhorn,et al.  Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. , 2000, Clinical therapeutics.

[27]  T. Akasaka,et al.  Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study. , 2000, Journal of the American College of Cardiology.

[28]  J. Rosenstock,et al.  Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. , 2000, JAMA.

[29]  H. Krumholz,et al.  Beta-blocker therapy for secondary prevention of myocardial infarction in elderly diabetic patients. Results from the National Cooperative Cardiovascular Project. , 1999, Journal of the American College of Cardiology.

[30]  B. Sobel,et al.  A Review of Metabolic and Cardiovascular Effects of Oral Antidiabetic Agents: Beyond Glucose-Level Lowering , 1999, Journal of cardiovascular risk.

[31]  M. Rewers,et al.  Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. , 1999, Diabetes care.

[32]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[33]  R. Holman,et al.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) , 1998, The Lancet.

[34]  Carlsen,et al.  Folate administration reduces circulating homocysteine levels in NIDDM patients on long‐term metformin treatment , 1998, Journal of internal medicine.

[35]  S. Tanaka,et al.  Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. , 1998, The Journal of clinical endocrinology and metabolism.

[36]  G. Shulman,et al.  Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. , 1998, The New England journal of medicine.

[37]  K. Kenward The scope of the data available in the AMA's Physician Masterfile. , 1996, American journal of public health.

[38]  E. Fisher,et al.  Studying Outcomes and Hospital Utilization in the Elderly: The Advantages of a Merged Data Base for Medicare and Veterans Affairs Hospitals , 1992, Medical care.