Showing papers by "Silvio E. Inzucchi published in 2010"

The 11-Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients with Type 2 Diabetes Inadequately Controlled By Metformin Monotherapy

Abstract: OBJECTIVE 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11βHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7–11%). RESEARCH DESIGN AND METHODS This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety. RESULTS After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (−0.6%), fasting plasma glucose (−24 mg/dl), and homeostasis model assessment–insulin resistance (HOMA-IR) (−24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups. CONCLUSIONS INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.

Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes A Position Statement of the American Diabetes Association, a Scientific Statement of the American Heart Association, and an Expert Consensus Document of the American College of Cardiology Foundation

Abstract: The burden of cardiovascular disease (CVD) among patients with diabetes is substantial. Individuals with diabetes are at 2- to 4-fold increased risk of cardiovascular events compared with age- and sex-matched individuals without diabetes. In diabetic patients over the age of 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke.1 A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation,2 increased platelet reactivity,3 and worsened endothelial dysfunction.4 The increased risk for cardiovascular events and mortality in patients with diabetes has led to considerable interest in identifying effective means for cardiovascular risk reduction. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with myocardial infarction (MI) or stroke (secondary prevention).5 The Food and Drug Administration has not approved aspirin for use in primary prevention, and its net benefit among patients with no previous cardiovascular events is more controversial, for both patients with and without a history of diabetes.5 The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults. They did not differentiate their recommendations based on the presence or absence of diabetes.6,7 In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended that aspirin therapy (75–162 mg/d) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).8 These recommendations were derived from several older …

Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes: A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation

Abstract: The burden of cardiovascular disease (CVD) among patients with diabetes is substantial. Individuals with diabetes are at two- to fourfold increased risk of cardiovascular events compared with age- and sex-matched individuals without diabetes. In diabetic patients over the age of 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke (1). A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation (2), increased platelet reactivity (3), and worsened endothelial dysfunction (4). The increased risk for cardiovascular events and mortality in patients with diabetes has led to considerable interest in identifying effective means for cardiovascular risk reduction. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with myocardial infarction (MI) or stroke (secondary prevention) (5). The Food and Drug Administration has not approved aspirin for use in primary prevention, and its net benefit among patients with no previous cardiovascular events is more controversial, for both patients with and without a history of diabetes (5). The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults. They did not differentiate their recommendations based on the presence or absence of diabetes (6,7). In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended that aspirin therapy (75–162 mg/day) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) (8). These recommendations were …

Scientific Principles and Clinical Implications of Perioperative Glucose Regulation and Control

Abstract: Development of hyperglycemia after major operations is very common and is modulated by many factors. These factors include perioperative metabolic state, intraoperative management of the patient, and neuroendocrine stress response to surgery. Acute insulin resistance also develops perioperatively and contributes significantly to hyperglycemia. Hyperglycemia is associated with poor outcomes in critically ill and postsurgical patients. A majority of the investigations use the term "hyperglycemia" very loosely and use varying thresholds for initiating treatment. Initial studies demonstrated improved outcomes in critically ill, postsurgical patients who received intensive glycemic control (IGC) (target serum glucose <110 mg/dL). These results were quickly extrapolated to other clinical areas, and IGC was enthusiastically recommended in the perioperative period. However, there are few studies investigating the value of intraoperative glycemic control. Moreover, recent prospective trials have not been able to show the benefit of IGC; neither an appropriate therapeutic glycemic target nor the true efficacy of perioperative glycemic control has been fully determined. Practitioners should also appreciate technical nuances of various glucose measurement techniques. IGC increases the risk of hypoglycemia significantly, which is not inconsequential in critically ill patients. Until further specific data are accumulated, it is prudent to maintain glucose levels <180 mg/dL in the perioperative period, and glycemic control should always be accompanied by close glucose monitoring.

Identifying Dysglycemic States in Older Adults: Implications of the Emerging Use of Hemoglobin A1c

Abstract: Context: Hemoglobin A1c (A1c) was recently added to the diagnostic criteria for diabetes and prediabetes. Objective: Our objective was to examine performance of A1c in comparison with fasting plasma glucose (FPG) in diagnosing dysglycemia in older adults. Design and Setting: We conducted a cross-sectional analysis of data from the Health, Aging, and Body Composition study at yr 4 (2000–2001) when FPG and standardized A1c measurements were available. Participants: Of 3075 persons (aged 70–79 yr, 48% men, 42% Black) at study entry, 1865 participants without known diabetes who had appropriate measures were included. Main outcome measures: Sensitivity and specificity of A1c-based diagnoses were compared with those based on FPG and the proportion of participants identified with dysglycemia by each measure. Results: Of all participants, 2.7 and 3.1% had undiagnosed diabetes by FPG ≥126 mg/dl and A1c ≥6.5%, respectively. Among the remaining participants, 21.1% had prediabetes by impaired fasting glucose (≥100 mg...

Initial Combination Therapy with Alogliptin and Pioglitazone in Drug-Naïve Patients With Type 2 Diabetes

Abstract: Objective— To assess efficacy and tolerability of alogliptin plus pioglitazone for initial combination therapy in drug-naive type 2 diabetes patients. Research design and methods— This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: alogliptin 25 mg qd monotherapy, pioglitazone 30 mg qd monotherapy, or alogliptin (A12.5 or A25 mg qd) plus pioglitazone (P30 mg qd) combination therapy. Primary efficacy was HbA1c change from baseline with the high-dose combination (A25+P30) versus each monotherapy. Results— Combination therapy with A25+P30 resulted in greater reductions in HbA1c (−1.7±0.1% from an 8.8% mean baseline) versus A25 (−1.0±0.1%, P <0.001) or P30 (−1.2±0.1%, P <0.001) and in FPG (−2.8±0.2 mmol/L) versus A25 (−1.4±0.2 mmol/L, P <0.001) or P30 (−2.1±0.2 mmol/L, P =0.006). The A25+P30 safety profile was consistent with those of its component monotherapies. Conclusions— Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes.

Discontinuation of Antihyperglycemic Therapy and Clinical Outcomes After Acute Myocardial Infarction in Older Patients With Diabetes

Abstract: Background— Patients with diabetes are frequently admitted for acute myocardial infarction (AMI) on antihyperglycemic agents but may be discharged without glucose-lowering therapy. We examined the frequency of this practice and evaluated the associated outcomes of readmission and mortality. Methods and Results— We conducted a retrospective study of 24 953 Medicare beneficiaries with diabetes discharged after hospitalization for AMI. We examined the frequency of discontinuation of antihyperglycemic agents on discharge among those patients admitted on a diabetic regimen. The independent association between discharge on versus off antihyperglycemic therapy 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 for AMI, heart failure, and all causes. There were 8751 patients admitted on a...

Management of Diabetes and Hyperglycemia in the Hospital Setting

Abstract: Diabetes mellitus and hyperglycemia are frequently encountered in hospitalized patients and present complex management problems. This issue will continue to stress the health-care system in the United States as an increase in the overall diabetes prevalence is anticipated over the coming decades.1 Since diabetic patients are hospitalized more often than their non-diabetic peers, hyperglycemia in the hospital will become an increasingly common scenario. Hospitalizations can relate directly to uncontrolled diabetes, such as diabetic ketoacidosis (DKA), hyperosmotic hyperglycemic syndrome (HHS), or severe hypoglycemia; or to the complications of diabetes including cardiac disease, stroke, foot infections, amputations, and kidney disease; or to the variety of general medical conditions to which the diabetic patient is predisposed (community acquired pneumonia, influenza, etc.). National hospital discharge data from 2004 estimate that 609,000 admissions to the hospital involved a primary diagnosis of diabetes, while 5.2 million admissions carried a non-diabetic principal diagnostic code (i.e., diabetes as a “secondary diagnosis”).2 Trends toward monitoring patients more closely in an outpatient setting, with adherence to new practice guidelines concerning glucose management, may potentially decrease hospitalization rates related to metabolic control.