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Background: In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain. Methods: Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ 2 statistic for trend. Results: During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5–0.86]; P =0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63–1.06]; P =0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P =0.011; HR, 0.85 for 4 mg, P =0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P P =0.0009), MACE or any death (HR, 0.67 for 6 mg, P =0.0021; HR, 0.81 for 4 mg, P =0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P =0.0072; HR, 0.97 for 4 mg, P =0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P =0.0002; HR, 0.81 for 4 mg, P =0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018). Conclusions: The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03496298.

BACKGROUND: The goal of this work was to investigate trends (2001–2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. METHODS: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. RESULTS: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4–86.8) and 41.0 (95% CI, 39.5–42.6); coronary artery disease, 205.1 (95% CI, 186.8–227.5) and 80.2 (95% CI, 78.2–82.3); cerebrovascular disease, 83.9 (95% CI, 73.6–98.5) and 46.2 (95% CI, 44.9–47.6); and HF, 98.3 (95% CI, 89.4–112.0) and 75.9 (95% CI, 74.4–77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35–1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. CONCLUSIONS: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. Methods: Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor–by–treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term. Results: The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58–0.94] and 0.70 [0.37–1.30], respectively), expanded MACEs (0.77 [0.62–0.96] and 0.87 [0.51–1.48]), renal composite (0.70 [0.59–0.83] and 0.52 [0.33–0.83]), and MACEs or death (0.74 [0.59–0.93] and 0.65 [0.36–1.19]) did not differ by baseline SGLT2 inhibitor use ( P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P ≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use. Conclusions: The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03496298.

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Background: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed. Methods: First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies. Results: Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor–like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70–0.88; P =1.46×10 −5 ) and TNFSF12 (OR=0.86; 95% CI, 0.81–0.91; P =7.69×10 −7 ) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31–1.78; P =3.32×10 −8 ) and intracerebral (OR=1.34; 95% CI, 1.14–1.58; P =4.05×10 −4 ) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47–0.81; P =5.20×10 −4 ). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5. Conclusions: Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.

Introduction: In the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial, weekly subcutaneous dulaglutide 1.5 mg, a glucagon-like peptide-1 receptor agonist, compared with matched placebo reduced MACE (cardiovascular [CV] death, non-fatal myocardial infarction or non-fatal stroke) (594 versus 663 events) in 9901 participants with type 2 diabetes at moderate CV risk [mean (SD) age 66.2 (6.5) years, 46.3% women, 31% with chronic CV disease and the others with CV risk factors] and followed for a median of 5.4 years. These findings, based on a time to first event analysis, do not reflect total CV event or mortality burden. Objective: To better reflect the burden of disease, the following outcomes were assessed: 1) total number of MACE or fatal events and 2) total number of CV (MACE, unstable angina, heart failure or revascularization) or fatal events in the REWIND participants. Methods: Incidence was estimated per 1000 person-years (py), and hazard ratios (HR) were calculated using conditional time gap and proportional means models. Results: A total of 1972 MACE outcomes or deaths and of 3673 CV outcomes or deaths occurred in the 9901 participants. Of the1128 all-cause deaths, 465 were non-CV. The incidence of total MACE or deaths was 35.8 in the dulaglutide group versus 40.3/1000 py in the placebo group [absolute reduction=4.5/1000 py; conditional time gap HR, 0.90 (95%CI, 0.82-0.98), P =0.020, and proportional means HR, 0.89 (95% CI, 0.80-0.98), P =0.022]. The incidence of total CV or fatal events on dulaglutide was 67.1 and 74.7/1000 py on placebo [absolute reduction=7.6/1000 py; conditional time gap HR, 0.93 (95% CI, 0.87-0.99), P =0.023, and proportional means HR, 0.90 (95% CI 0.82-0.99), P =0.028]. Similar effect sizes were noted for the first occurrence of MACE or deaths such that the absolute risk reduction was 4.1/ 1000 py. Conclusions: These findings suggest that weekly subcutaneous dulaglutide was associated with reduced total MACE, CV or fatal event burden in people with type 2 diabetes and moderate CV risk. This analysis illustrates the clinical relevance of assessing total events in addition to first events in clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique Identifier NCT01394952)

Diabetes mellitus increases the incidence of recurrent heart failure through a variety of potential mechanisms, including ischemic myocardial damage, hyperglycemia, and the effects of the glucose-linked metabolic abnormalities on the myocardium.1 To date, randomized controlled trials of more versus less glucose lowering with a menu of drugs, including insulin, have reported a neutral effect on incident heart failure. Nevertheless, epidemiological studies and the sodium-retaining properties of insulin have fueled concerns about a possible link.2 The ORIGIN trial (Outcome Reduction With Initial Glargine Intervention) allocated 12 537 people (mean age, 64 years; 35% women) with diabetes mellitus (88%), impaired glucose tolerance, or impaired fasting glucose to either basal insulin-mediated normoglycemia or therapy without insulin and reported a neutral effect on cardiovascular events during a median follow-up of 6.2 years. People with New York Heart Association class 3 or 4 heart failure were excluded. Heart failure requiring hospitalization was a prespecified component of the primary outcome and was defined as evidence of overnight hospitalization or attendance in an acute care setting for at least 2 of the following: signs or symptoms of heart failure; radiological evidence of congestive heart failure; treated with intravenous diuretics, or a first or increased dose of an oral diuretic, intravenous or oral vasodilator, or intravenous or oral inotrope.3 Both first and recurrent episodes were prospectively collected and …

Patients with a recent coronary event are at high risk of further cardiovascular events, including hospitalization for heart failure (HFH).1,2 Knowledge of the pathophysiological changes preceding HFH provides insight into the temporal course of the progression of HF and may help identify those at imminent risk of this event. B-type natriuretic peptide (BNP) and NT-proBNP (N-terminal prohormone BNP) change rapidly in relation to changes in filling pressures and wall stress, making them useful for monitoring clinical status and response to treatment and clinical status in HF.3 Because there are limited data on temporal changes in natriuretic peptides (NPs) preceding HFH, we examined concentrations of NPs preceding HFH in patients with a recent coronary event and type 2 diabetes mellitus enrolled in the ELIXA trial [Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide); NCT01147250]. The design and primary findings of ELIXA have been published.4 A total of 6068 patients with type 2 diabetes mellitus and an acute coronary syndrome (index event) occurring within 180 days of randomization were enrolled. The trial was designed to assess the efficacy and safety of lixisenatide, a glucagon-like peptide-1 receptor agonist, with respect to cardiovascular morbidity and mortality.5 Sampling of BNP and NT-proBNP occurred at baseline and at weeks 24, 76, and 108 after randomization, yielding 19 585 samples. Samples were collected and analyzed at a core laboratory (Covance Central Laboratory Services, Meyrin, Switzerland). ELIXA was approved by appropriate institutional or central review boards. All participants provided …

Background—Serum biomarkers may identify people at risk for cardiovascular (CV) outcomes. Biobanked serum samples from 8494 participants with dysglycemia in the completed Outcome Reduction With Initial Glargine Intervention trial were assayed for 284 biomarkers to identify those that could identify people at risk for a CV outcome or death when added to clinical measurements.Methods and Results—A multiplex analysis measured a panel of cardiometabolic biomarkers in 1 mL of stored frozen serum from every participant who provided biobanked blood. After eliminating undetectable or unanalyzable biomarkers, 8401 participants who each had a set of 237 biomarkers were analyzed. Forward-selection Cox regression models were used to identify biomarkers that were each independent determinants of 3 different incident outcomes: (1) the composite of myocardial infarction, stroke, or CV death; (2) these plus heart failure hospitalization or revascularization; and (3) all-cause death. When added to clinical variables, 10 biomarkers were independent determinants of the 1405 CV composite outcomes observed during follow-up; 9 biomarkers (including 8 of these 10) were independent determinants of the 2435 expanded composite outcomes; and 15 (including the 10 CV composite biomarkers) were independent determinants of the 1340 deaths. Adjusted C statistics increased from 0.64 for the clinical variables to 0.71 and 0.68 for the 2 CV composite outcomes, respectively, with the greatest increase to 0.75 for death (PConclusions—A systematic hypothesis-free approach identified combinations of up to 15 cardiometabolic biomarkers as independent determinants of CV outcomes or death in people with dysglycemia.Clinical Trial Registration—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00069784.

Hypoglycemia is a well-recognized side effect of glucose-lowering 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,–,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,–, …

Background— Patients with diabetes mellitus (DM) are at high risk of developing congestive heart failure (CHF). However, the relationships between glucose levels and CHF in people with or without a history of DM have not been well characterized. Methods and Results— We evaluated the associations between fasting plasma glucose and risk of hospitalization for CHF during follow-up in patients at high cardiovascular risk and without CHF enrolled in a large-scale clinical trials program. Baseline fasting plasma glucose levels were assessed in 31 546 high-risk subjects with ≥1 coronary, peripheral, or cerebrovascular disease or DM with end-organ damage who are participating in 2 ongoing parallel trials evaluating the effects of telmisartan, ramipril, or their combination (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; n=25 620) and the effects of telmisartan against placebo in angiotensin-converting enzyme–intolerant patients (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease [TRANSCEND]; n=5926). Interim analyses blinded for randomized treatment were performed to compare baseline fasting plasma glucose with the adjusted CHF event rate at a mean follow-up of 886 days. Multivariable Cox regression models were performed, and associations were reported as hazard ratios and 95% confidence intervals. Among all subjects (mean age, 67 years; 69% men), of whom 11 708 (37%) had known DM and 1006 (3.2%) had newly diagnosed DM at baseline, 668 patients were hospitalized for CHF during follow-up. After adjustment for age and sex, a 1-mmol/L-higher fasting plasma glucose was associated with a 1.10-fold-increased risk of CHF hospitalization (95% confidence interval, 1.08 to 1.12; P P Conclusions— Fasting plasma glucose is an independent predictor of hospitalization for CHF in high-risk subjects. These data provide theoretical support for potential direct beneficial effects of glucose lowering in reducing the risk of CHF and suggests the need for specific studies targeted at this issue.

Background— Diabetes is a risk factor for heart failure, and both conditions are increasing. Identifying treatments that prevent both conditions will be clinically important. We previously reported that candesartan (an angiotensin receptor blocker) reduces cardiovascular mortality and heart failure hospitalizations in heart failure patients (CHARM: C andesartan in H eart Failure— A ssessment of R eduction in M ortality and Morbidity Program). Methods and Results— We assessed the impact of candesartan versus placebo on the development of diabetes, a predefined secondary outcome in a randomized, controlled, double-blind study involving 5436 of the 7601 patients with heart failure, irrespective of ejection fraction, who did not have a diagnosis of diabetes at entry into the trial. Patients received candesartan (target of 32 mg once daily) or matching placebo for 2 to 4 years. One hundred sixty-three (6.0%) individuals in the candesartan group developed diabetes, as compared with 202 (7.4%) in the placebo group (hazard ratio [HR], 0.78 with a 95% confidence interval [CI] of 0.64 to 0.96; P =0.020). The composite end point of death or diabetes occurred in 692 (25.2%) and 779 (28.6%), respectively, in the candesartan and placebo groups (HR, 0.86; 95% CI, 0.78 to 0.95; P =0.004). The results were not statistically heterogeneous in the various subgroups examined, although the apparent magnitude of benefit appeared to be smaller among those treated concomitantly with angiotensin-converting enzyme inhibitors at trial entry (HR, 0.88; 95% CI, 0.65 to 1.20) compared with those not receiving these drugs (HR, 0.71; 95% CI, 0.53 to 0.93; P for heterogeneity, 0.28). Conclusions— The angiotensin receptor blocker candesartan appears to prevent diabetes in heart failure patients, suggesting that the renin-angiotensin axis is implicated in glucose regulation.

Diabetes mellitus is a common chronic disease that is characterized and defined by an elevated glucose level and that has grown in prevalence by 75% in the United States during a 20-year period ending in 2010.1 The exact reason for this rising prevalence is not known with certainty; however, a large body of evidence implicates changes in weight, caloric consumption, reduced physical activity, and migration to urban versus rural dwellings. Regardless of the reasons for this growth, epidemiological studies and analyses of administrative databases have repeatedly shown that people with diabetes mellitus are 2 to 3 times more likely to experience fatal and nonfatal cardiovascular outcomes than people without diabetes mellitus.2 This high risk was the basis for the intentional inclusion of ambulatory adults with diabetes mellitus in a large number of recent cardiovascular outcomes trials that either recruited large subpopulations or people with diabetes mellitus or were wholly restricted to people with diabetes mellitus. These trials showed that therapies that were shown to be cardioprotective in people without diabetes mellitus will also reduce cardiovascular outcomes in ambulatory people with diabetes mellitus. These include blood pressure lowering,3 low-density lipoprotein lowering with statins,4 angiotensin-converting enzyme inhibitors5 or angiotensin receptor blockers,6 and bypass surgery.7 During the same period, other therapies were shown to have a neutral effect on cardiovascular outcomes in people with diabetes mellitus, including vitamin E,8 omega 3 fatty acids,9 and basal insulin.10 Article see p 785 Implementation of the results of these trials may account for the decline in absolute risk of cardiovascular outcomes and death in people with diabetes mellitus over time.11,12 However, both the inability of these trials to reduce this risk to levels seen in people without diabetes mellitus6 and the inability …

Diabetes is a metabolic disorder that is diagnosed when the fasting and/or postload glucose level rises above well-established thresholds. These thresholds were chosen because they identified people at particularly high risk for retinopathy based on epidemiological data. These data also have shown that people with diabetes and poorly controlled glucose levels have higher risks of retinopathy than people with diabetes and well-controlled glucose levels.1,2 Moreover, recent studies have shown that the relationship between chronically elevated glucose levels (as measured by A1c) and retinal disease is not confined to people with diabetes and is apparent (although less marked) in people with high glucose levels that are below the diabetes cutoffs such as those with impaired glucose tolerance and/or impaired fasting glucose.3–5 Thus, there is a progressive relationship between glycemia and retinopathy that extends below glucose thresholds for diabetes. Article p 812 Clearly, diabetes also is a risk factor for many other serious chronic diseases, including cardiovascular disease.6 Indeed, a recent meta-analysis of large prospective studies comprising 450 000 people showed that men and women with diabetes are 2 and 3 times more likely, respectively, to die of coronary heart disease than men and women without diabetes.7 Other studies have shown that the degree of glucose elevation measured by A1c, fasting glucose, or postload glucose is progressively related to the incidence of cardiovascular outcomes in people with established diabetes and in people without diabetes after adjustment for age and varying numbers of other risk factors.8–15 Moreover, several studies that recruited people from both ambulatory and hospitalized settings suggest that there may be a stronger relationship between glycemia and incident cardiovascular outcomes in people without diabetes than in people with diabetes.8,9,15–17 Such a discrepancy may occur because in people with established diabetes, markers of …

Dr Chaudhuri and colleagues propose that insulin therapy in the form of glucose-insulin-potassium (GIK) infusion may have lowered mortality in hyperglycemic patients with acute myocardial infarction in the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation–Estudios Clinicos Latino America (CREATE-ECLA) and Organization for the Assessment of Strategies for Ischemic Syndromes-6 (OASIS-6) trials. Their hypothesis is based on our Table 6,1 which shows that among patients with postadmission hyperglycemia (glucose ≥140 mg/dL), the unadjusted …

Background— In patients with acute myocardial infarction (AMI), hyperglycemia predicts death, but the prognostic significance of hypoglycemia is controversial. Methods and Results— We evaluated the prognostic significance of hypoglycemia and hyperglycemia in 30 536 AMI patients in a post hoc analysis of 2 large trials of glucose-insulin-potassium therapy in AMI. Glucose levels on admission and at 6 and 24 hours after admission, as well as 30-day mortality, were documented. In separate multivariable Cox models for admission and postadmission glucose, we compared the prognostic value of hypoglycemia (≤70 mg/dL) and hyperglycemia (≥140 mg/dL) with normoglycemia (>70 and P P P =0.37), nor was postadmission hypoglycemia (adjusted hazard ratio 0.96, 95% confidence interval 0.72 to 1.26, P =0.75). Exploratory analyses that redefined hypoglycemia as glucose ≤60 mg/dL showed consistent results, as did analyses restricted to diabetic patients (18% of the study population). Postadmission hypoglycemia was more common in insulin (glucose-insulin-potassium)–treated patients (6.9%) than in untreated patients (3.4%) but did not predict mortality in either subgroup. Conclusions— Both admission and postadmission hyperglycemia predict 30-day death in AMI patients. In contrast, only hypoglycemia on admission predicted death, and this relationship dissipated after admission. These data suggest hypoglycemia may not be a direct mediator of adverse outcomes in AMI patients.

Introduction: According to clinical risk assessment guidelines, a history of diabetes mellitus (DM) portends poor outcomes following acute MI. Elevated in-hospital glucose levels also predict early mortality in acute MI patients, but the degree to which glucose levels and diabetic history independently predict post-MI mortality is unclear. Methods and Hypothesis: We analyzed data from the combined cohort of the CREATE-ECLA and OASIS-6 randomized trials that evaluated the impact of glucose-insulin-potassium (GIK) infusion versus no infusion on 30-day mortality in 22,943 patients hospitalized with acute ST-elevation MI. We calculated the average in-hospital glucose level for each patient (mean of the admission, 6-hour, and 24-hour glucose levels). Logistic regression was performed to determine whether average glucose level and history of DM remained significant mortality predictors after adjusting for age, sex, and GIK allocation. Results: Glucose data were recorded in 22,860 (99.6%) patients; 10,050 (44%) had an average in-hospital glucose level ≥ 8 mmol/L (144 mg/dL), of whom 65% did not have known prior DM. Among patients with glucose >8 mmol/L, 30-day mortality rates were similar in patients with and without known DM (Figure ). In-hospital glucose, but not history of DM, was a significant multivariable predictor of mortality (Table). Conclusions: By considering only history of DM and not in-hospital glucose levels, risk assessment guidelines for acute MI overlook a large proportion of patients at high risk for early death. Therefore, clinicians should emphasize elevated glucose levels in addition to history of DM as a risk marker in patients with acute MI.

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Background —Although unstable coronary artery disease is the most common reason for admission to a coronary care unit, the long-term prognosis of patients with this diagnosis is unknown. This is particularly true for patients with diabetes mellitus, who are known to have a high morbidity and mortality after an acute myocardial infarction. Methods and Results —Prospectively collected data from 6 different countries in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry were analyzed to determine the 2-year prognosis of diabetic and nondiabetic patients who were hospitalized with unstable angina or non–Q-wave myocardial infarction. Overall, 1718 of 8013 registry patients (21%) had diabetes. Diabetic patients had a higher rate of coronary bypass surgery than nondiabetic patients (23% versus 20%, P P Conclusions —Hospitalization for unstable angina or non–Q-wave myocardial infarction predicts a high 2-year morbidity and mortality; this is especially evident for patients with diabetes. Diabetic patients with no previous cardiovascular disease have the same long-term morbidity and mortality as nondiabetic patients with established cardiovascular disease after hospitalization for unstable coronary artery disease.