H ypoglycemia is a well-recognized side effect of glucoselowering therapies in patients with diabetes mellitus. The incidence of mild self-reported hypoglycemic episodes in patients with type 1 diabetes mellitus is approximately 30 episodes per patient per year, whereas the incidence of severe hypoglycemic episodes (ie, those that require third-party assistance) may be as high as 3.2 episodes per patient per year. 1-3 Hypoglycemic episodes occur much less frequently in patients with type 2 diabetes mellitus, in whom the incidence of mild and severe hypoglycemic episodes is 2 to 10 per patient per year and 0.1 to 0.7 per patient per year, respectively. 2 When patients are alerted to the occurrence of a hypoglycemic episode by symptoms such as tremor, diaphoresis, tachycardia, malaise, hunger, and anxiety, they can abort these episodes by consuming carbohydrates. However, if hypoglycemic episodes occur rapidly or are unrecognized and untreated, the resulting neuroglycopenia may cause confusion, seizures, accidents, angina, and, rarely, death or permanent cognitive impairment. 3,4 Patients who experience frequent episodes of hypoglycemia are especially at risk of having unrecognized hypoglycemic episodes (and their sequelae), because their counterregulatory response to hypoglycemia becomes blunted. Indeed, the rare occurrence of sudden death during sleep in young patients with type 1 diabetes mellitus (the so-called dead-in-bed syndrome) has been attributed to hypoglycemia, although this cause is seldom proven. [5][6][7] It is well known that hypoglycemic episodes are associated with a surge of sympathetic activity and a release of catecholamines. 8 -10 These observations have supported the suggestion that the tachycardia and the rise in blood pressure observed during a hypoglycemic episode might destabilize an atherosclerotic plaque. 11 These hemodynamic changes, the increased myocardial work, and hypoglycemia-induced increases in platelet aggregation, platelet activity, 12-14 and hematocrit 15,16 may precipitate cardiac and cerebral ischemic events in patients at high risk of cardiovascular disease. 17 Support for this possibility comes from a number of small studies and case reports. For example, continuous glucose and ECG monitoring in 19 patients with coronary artery disease and type 2 diabetes mellitus 18 revealed a higher frequency of ischemic ECG changes when glucose levels fell below 3.9 mmol/L (70 mg/dL). A similar study in 24 patients with type 1 diabetes mellitus 19 revealed a nocturnal increase in the corrected QT interval and some minor rhythm disturbances when nocturnal glucose levels fell below 3.5 mmol/L (63 mg/dL) that were not observed when nocturnal glucose levels were Ͼ5 mmol/L (90 mg/dL). Experimentally induced hypoglycemia prolonged the corrected QT interval and reduced potassium levels in healthy adults 10 and in people with type 1 and type 2 diabetes mellitus. 20,21 Finally, case reports have shown a relationship between ischemic cerebral changes and concurrent severe hypoglycemia in patie...

OBJECTIVEEpidemiologic studies linking insulin glargine and glucose-lowering therapies to cancers and n-3 fatty acids to cancer prevention have not been confirmed. We aimed to assess the effect of insulin glargine and n-3 fatty acids on incident cancers within the context of the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial. RESEARCH DESIGN AND METHODSThe ORIGIN trial is an international, long-term, randomized two-by-two factorial study comparing insulin glargine with standard care and n-3 fatty acids with placebo (double blind) in people with dysglycemia at high risk for cardiovascular events. The primary outcome measure (cancer substudy) was the occurrence of any new or recurrent adjudicated cancer. Cancer mortality and cancer subtypes were also analyzed. RESULTSAmong 12,537 people (mean age 63.5 years, SD 7.8; 4,388 females), 953 developed a cancer event during the median follow-up of 6.2 years. In the glargine and standard care groups, the incidence of cancers was 1.32 and 1.32 per 100 person-years, respectively (P = 0.97), and in the n-3 fatty acid and placebo groups, it was 1.28 and 1.36 per 100 person-years, respectively (P = 0.39). No difference in the effect of either intervention was noted within predefined subgroups (P for all interactions ‡0.17). Cancer-related mortality and cancer-specific outcomes also did not differ between groups. Postrandomization HbA 1c levels, glucose-lowering therapies (including metformin), and BMI did not affect cancer outcomes. CONCLUSIONSInsulin glargine and n-3 fatty acids have a neutral association with overall and cancer-specific outcomes, including cancer-specific mortality. Exposure to glucoselowering therapies, including metformin, and HbA 1c level during the study did not alter cancer risk.Both type 2 diabetes mellitus (hereafter referred to as diabetes) and cancer are common diseases that are rising in incidence and prevalence throughout the world. Moreover, epidemiologic data suggest that diabetes is associated with an increased risk of several different cancers (1). Reasons for this association may include metabolic features typical of diabetes such as hyperglycemia, insulin resistance, and/or

The clinical response to short-term IIT is variable, consistent with the heterogeneity of T2DM. However, preserved late-phase insulin secretion may identify those patients who can benefit from this intervention with improved beta-cell function.