Donald A. Smith

Review: Omega-3 polyunsaturated fatty acid supplements do not reduce major cardiovascular events in adults

Source Citation Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review an...

Estrogen plus progestin reduced the incidence of diabetes in postmenopausal women with coronary heart disease.

P a r t i c i p a n t s 2763 postmenopausal women < 80 years of age (mean age 67 y, 89% white) who had objectively documented CHD. Exclusion criteria included CHD event ≤ 6 months or sex hormone use ≤ 3 months before entry, serum triglyceride levels ≥ 3.39 mmol/L, fasting glucose levels ≥ 16.5 mmol/L, and uncontrolled hypertension. 2029 women (mean age 67 y, 91% white) without diabetes were followed for incident diabetes with a follow-up of 98%. I n t e r v e n t i o n Women were allocated to HRT consisting of conjugated estrogen, 0.625 mg plus medroxyprogesterone acetate 2.5 mg once daily (n = 1380, including 999 without diabetes), or placebo (n = 1383, including 1030 without diabetes).

Incretin-based drugs were not linked to HF hospitalization compared with other oral antidiabetic drug combinations

Question In patients with {type 2}* diabetes, are incretin-based drugs associated with increased risk for heart failure (HF) compared with combinations of other oral antidiabetic drugs? Methods Design Nested casecontrol study, using administrative databases in Canada, a general practitioner database linked to hospital data in the UK, and insurance claims data in the USA. ClinicalTrials.gov NCT02456428. Setting Canada (Alberta, Manitoba, Ontario, and Saskatchewan), the UK, and the USA. Patients 1840467 patients 18 years of age who had a first-ever prescription for a noninsulin antidiabetic drug at any time were included in the base cohort. Exclusion criteria included previous insulin use. From the base cohort, 1499650 patients were prescribed a new antidiabetic drug after incretin drugs (e.g., dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 analogues) became available and were included in the study cohort (new drug prescription date = baseline), with stratification for previous HF at baseline. Prescriptions could be for new diabetes or for a new drug class in patients already using antidiabetic drugs. 29741 study cohort patients were hospitalized with HF during the study and classified as cases (admission date = case index date): 6536 had previous HF at baseline (mean age 74 y, 59% men, mean treated diabetes duration 1.8 y), and 23205 had no previous HF (mean age 69 y, 57% men, mean treated diabetes duration 0.7 y). Using risk-set sampling, each case was matched with 20 controls (n =100480 with previous HF and n =435777 with no previous HF) who were at risk for HF hospitalization at the case index date. Matching was based on age, sex, duration of treated diabetes, baseline date, and duration of follow-up. Risk factors Current use (prescription ongoing or ending 30 d before the case index date) of incretin-based drugs, {alone or with other antidiabetic drugs and used as first-, second-, or third-line treatment}*. Because incretins are intended to be second- or third-line drugs, the primary analysis used a reference group of patients using combinations of other oral antidiabetic drugs. Outcome HF hospitalization. Main results The main results are in the Table. Conclusion In patients with type 2 diabetes, incretin-based drugs were not linked to increased risk for heart failure hospitalization compared with combinations of other oral antidiabetic drugs. Incretin-based drugs vs 2 other oral antidiabetic drugs and risk for heart failure hospitalization in type 2 diabetes Population Incretin-based drug exposure Adjusted hazard ratio (95% CI) Previous heart failure All incretin-based drugs 0.86 (0.62 to 1.19) DPP-4 inhibitors 0.87 (0.63 to 1.21) GLP-1 analogues 0.75 (0.22 to 2.51) No previous heart failure All incretin-based drugs 0.82 (0.67 to 1.00) DPP-4 inhibitors 0.84 (0.69 to 1.02) GLP-1 analogues 0.95 (0.83 to 1.10) DPP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; CI defined in Glossary. Adjusted for comorbid conditions, alcohol-related disorders, diabetes-related microvascular complications, number of hospitalizations, number of unique nondiabetic drugs in the past year, number of antidiabetic drugs used before baseline, and use of selected drugs 1 y before baseline. Data from the UK database were also adjusted for body mass index, glycated hemoglobin level, and smoking status. Hazard ratios <1 indicate no increased risk for HF hospitalization associated with incretin-based drugs vs 2 other oral antidiabetic drugs. Commentary The increased risk for morbidity and mortality associated with congestive HF (CHF) in patients with diabetes may be underappreciated. CHF is a major cause of premature death in patients with diabetes. Although it is often caused by coronary heart disease or hypertension, CHF may also be independent of these 2 diagnoses and referred to as diabetic cardiomyopathy. In a study of Medicare claims, older patients with diabetes and incident CHF had higher mortality rates than those without CHF (33 vs 3.7/100 patient-years) (1). In addition, each 1% increase in hemoglobin A1c level has been associated with an 8% relative increase in incident CHF (2). Although glucose control has been shown to decrease incident myocardial infarction, it has not been shown to decrease CHF hospitalization or mortality (3). A recent meta-analysis of 14 trials assessing different glucose-lowering drugs or other strategies suggested that greater treatment-related weight gain was associated with greater risks for incident CHF (4). The conceptually complex, nested casecontrol study of incretin-based drugs by Filion and colleagues might reassure us that these drugs do not increase CHF risk. However, although a large 3-year trial found no increased risk for HF hospitalization with sitagliptin vs placebo (5), randomized trials found that saxagliptin increased HF hospitalizations, leading to a recent US Food and Drug Administration warning about both saxagliptin and alogliptin (6). This illustrates why individual placebo-controlled trials of diabetes drugs and CV outcomes are needed for adequate safety assessment. Clinicians should continue to focus on controlling lipids and hypertension to prevent coronary events that often precede CHF. In choosing methods to improve glucose control, one must take care not to use agents that promote CHF.

A lifestyle intervention did not reduce cardiovascular outcomes in overweight or obese patients with type 2 diabetes

Source Citation Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145-54. 23796131.

Adding niacin to simvastatin did not improve clinical outcomes in patients with CV disease and dyslipidemia

Source Citation AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-67. 22085343

Review: Hyperglycemia after myocardial infarction increases the risk for death in patients with and without diabetes mellitus

Source Citation Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview...

Review: Microalbuminuria predicts overall mortality and cardiovascular mortality and morbidity in non-insulin-dependent diabetes mellitus

Source Citation Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997 Jul 14;1413-8.

Nondiabetic men with high blood glucose levels were at increased risk for death

Source Citation Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. Diabetes Care. 1998 Mar;21:360-7.

Increased serum triglyceride concentrations and abdominal adiposity were associated with increased mortality in women

Source Citation Bengtsson C, Bjorkelund C, Lapidus L, Lissner L. Associations of serum lipid concentrations and obesity with mortality in women: 20 year follow up of participants in prospective pop...

Vasectomy was associated with lower mortality

Source Citation Giovannucci E, Tosteson TD, Speizer FE, Vessey MP, Colditz GA. A long-term study of mortality in men who have undergone vasectomy. N Engl J Med. 1992 May 21;326:1392-8.