Educational Objectives

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1 05 MAY 18 William J. Elliott, M.D., Ph.D. Cardiovascular Consequences of Diabetes Disclosure Statement The speaker s research and educational activities have been supported in the past by essentially every pharmaceutical company that makes, markets or distributes antihypertensive drugs in the USA. The information presented is therefore likely to be biased. Healthcare providers are therefore strongly cautioned NOT to use the information presented in their daily practices (see, for example, The People of the United States of America v Peter Gleason) until and unless the specific agent or therapy receives formal approval from the US FDA for exactly the indication under consideration by the healthcare provider. Affidavit of Originality The following material is based exclusively on the speaker s own opinion, knowledge and expertise. There is no organization, company, or entity that has exercised any control or influence over the content of this presentation, nor has any other person or organization had any part in drafting, scripting or designing its content. The information presented is based on the principles of Evidence- Based Medicine, and is intended to avoid promotion of any specific commercial interest, product, or company. Disclaimers The speaker has participated (with known experts in the field) in writing a Scientific Statement from the American Heart Association on the topic of Treatment of Hypertension in Patients with Coronary Heart Disease. This presentation does not reflect opinion, consensus, or recommendations from the American Heart Association. The speaker currently serves as the Chair of the Continuing Education Committee and on the Education Committee of the American Society of Hypertension, which has recently been involved in reconciling US hypertension guidelines. This process is embargoed, and will not be discussed. Educational Objectives At the end of this 50-minute presentation, the awake audience member should be able to: 1. Cite a summary odds ratio or hazard ratio, derived from epidemiological data, that reflects the relative risk of the following cardiovascular outcomes in diabetic persons, compared to those without diabetes mellitus, after adjusting for all other appropriate risk factors: a. Stroke. b. Myocardial infarction (or acute coronary syndrome) c. Heart failure. d. Cardiovascular death. e. First occurrence of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death (sometimes also including heart failure in the composite endpoint). 2. Review recent clinical trials involving different approaches to controlling plasma glucose in diabetic subjects, with regard to impact on the risk of.

2 a. Stroke. b. Myocardial infarction (or acute coronary syndrome). c. Heart failure. d. Cardiovascular death. e. First occurrence of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death (sometimes also including heart failure in the composite endpoint). 3. Explain the design and results of the STENO-2 randomized trial (performed in Denmark), and its implications for optimal management of Americans with diabetes mellitus. Evidence-Based Resources American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2018;41 (Suppl 1):S1-S159. Chen G, Levy D. Contributions of the Framingham Heart Study to the epidemiology of coronary heart disease. JAMA Cardiol. 2016;1: Qazi MU, Malik S. Diabetes and cardiovascular disease: Insights from the Framingham Heart Study. Global Heart. 2013;8:43-8. Fox CS, Coady S, Sorlie PD, et al. Trends in cardiovascular complications of diabetes. JAMA. 2004;292: Kannel WB, McGee DL. Diabetes and cardiovascular disease: The Framingham study. JAMA. 1979:241: Chen R, Ovgiagele B, Feng W. Diabetes and stroke: Epidemiology, pathophysiology, pharmaceuticals and outcomes. Am J Med Sci. 2016;351: Cummings DM, Kirian K, Howard G, et al. Consequences of comorbidity of elevated stress and/or depressive symptoms and incident cardiovascular outcomes in diabetes: Results from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Diabetes Care. 2016:39: Regensteiner GJ, Golden S, Huebschmann AG, et al. Sex differences in the cardiovascular consequences of diabetes mellitus: A scientific statement from The American Heart Association. Circulation. 2015;132: Seshasai SR, Kaptoge S, Thompason A, et al. Diabetes mellitus, fasting glucose, and risk of causespecific death. N Engl J Med. 2011;364: Yusuf S, Hawken S, Ounpuu S, et al., for the INTERHEART study investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study). Lancet. 2004;364: Rosengren A, Hawken S, Ounpuu S, et al,, for the INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11,119 cases and 13,648

3 controls from 52 countries (the INTERHEART study): Case-control study. Lancet. 2004;364: O Donnell, MJ, Chin SL, Rangarajan S, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): A case-control study. Lancet. 2016;388: Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Eur Heart J. 2013;34: c. Beckman JA, Paneni F, Cosentino F, Creager MA. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part II. Eur Heart J. 2013;34: d. Intensive blood-glucose control with sulphonoureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: Holman RR, Paul SK, Bethel MA, Matthews DR. Neil HA. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359: Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360: Hayward RA, Reaven PD, Emanuele NV, for the VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;372: Gerstein HC, Miller ME, Byington RP, et al., for the Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: ACCORD Study Group. Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care. 2016;39: Patel A, MacMahon S, Chalmers J, et al., for the ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: Zoungas S, Chalmers J, Neal B, et al., for the ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371: Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcome trials in type 2 diabetes: Where do we go from here? Reflections from a Diabetes Care editors expert forum. Diabetes Care. 2018;41:14-31.

4 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373: Wanner C, Inzucchi SE, Lachin JM. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375: Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375: Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375: Neal B, Perkovic V, Kmahaffey KW, et al, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377: Marso SP, McGuire DK, Zinman B, et al., for the DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377: Holman R, Bethel MA, Mentz RJ, et al., for the EXSCEL Study Group Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377: Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348: Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Session Description This 50-minute session will briefly summarize the world s epidemiological literature comparing the incidence of various cardiovascular endpoints in individuals with and without diabetes mellitus at baseline. Since it was originally thought that the primary mediator of increased cardiovascular risk among diabetics was simply their dysglycemia, several clinical trials were organized to test the hypothesis that more intensive glucose lowering would lead to a reduced risk of cardiovascular events; sadly, the results of these studies were inhomogeneous. In the last several years, long-term results of several of these studies have been published, which adds only a little clarity to the proposition that tight control of plasma glucose is beneficial. The most recent studies that found a cardiovascular benefit of more intensive glucose lowering are: EMPA-REG, LEADER, and SUSTAIN-6. At the risk of being disingenuous, because several of these included in their factorial design, an arm comparing blood pressure targets in the same patients (in whom glycemic control was separately randomized), it is possible to compare the effects of glycemic and blood pressure control, the latter of which appears to be more beneficial (as long as it is sustained). As a result, nearly all authorities now recommend a multi-pronged approach to reducing cardiovascular risk in people with diabetes. The best evidence for the efficacy of such an approach comes from the STENO-2 trial, done in Denmark, which showed not only improved cardiovascular outcomes in its original 7.8-year follow-up, but also reduced all-cause mortality when median follow-up was extended to 13.3 years.

5 Multiple-Choice CME Questions 1. A 65-year old man visits his primary care medical home because screening at a healthfair included an A1c of 6.5%, and he was told he had type 2 diabetes mellitus. He asks, Based on data from men in the original Framingham Heart Study, this new diagnosis puts me at greatest risk for which of the following, after statistical adjustment for all other risk factors (e.g., age, systolic blood pressure, smoking, left ventricular hypertrophy on the electrocardiogram)? The most appropriate response is which of the following? a. Acute myocardial infarction. b. Acute ischemic stroke. c. Cardiovascular death. d. Congestive heart failure. e. Intermittent claudication. 2. In the INTERHEART study, involving 15,152 people with incident myocardial infarction in 262 participating centers in 52 countries, compared to 14,820 age-, gender-, and geographicallymatched controls without heart disease, which of the following had the highest odds ratio for acute myocardial infarction, after statistical adjustment for all other risk factors? a. Current smoking b. Diabetes mellitus. b. Dyslipidemia. c. Hypertension. d. Psychosocial factors. 3. Which of the following classes of hypoglycemic agents is associated with a significantly lower risk of cardiovascular events in placebo-controlled, long-term, outcome-based clinical trials? a. Biguanides (e.g., metformin). b. DiPeptidyl Peptidase-4 (DPP-4) Inhibitors (e.g., sitagliptin). c. Sodium-GLucose Transporter-2 (SGLT-2) inhibitors (e.g., empagliflozin). d. Sulfonylureas (e.g., glyburide). e. Thiazoladinediones (e.g., rosiglitazone). 4. In the STENO-2 clinical trial involving 160 Danish subjects with type 2 diabetes, which of the following was increased (albeit not significantly) in those subjects randomized to the intensive, compared to standard therapy regimen after a mean follow-up of 7.8 years? a. Diabetic autonomic neuropathy. b. Diabetic eye disease (blindness or progressive retinopathy). c. Major adverse cardiovascular events (the primary endpoint). c. Major hypoglycemic events. d. Renal endpoints (proteinuria > 300 mg/d, or dialysis). Abstract Diabetes mellitus has long been recognized as a strong risk factor for major adverse cardiovascular (CV) events, but the proportion by which it increases these risks depends on many factors, including the population studied, the definition of diabetes mellitus, the type of cardiovascular event, and concomitant treatment (if any) for other risk factors (e.g., hypertension, dyslipidemia, etc.). In 1961,

6 the Framingham Heart Study was the first to use the term, risk factor to connect age, cigarette smoking, weight, blood pressure and serum cholesterol with adverse heart-related outcomes. Interestingly, 18 more years were required in Framingham to tease out glucose intolerance as a significant contributor to cardiovascular events. In Kannel and McGee s classic 1979 JAMA paper, after statistical adjustment for baseline differences in age, systolic blood pressure, cigarettes/day, serum cholesterol, and the presence of left ventricular hypertrophy on the electrocardiogram, diabetes increased the risk of cardiovascular events in each gender as follows: CV Event Heart Failure Claudication Stroke Coronary Disease CV Death Men Women The task of generating these relative risk estimates required 20 years of observation of the original cohort of 5209 individuals, development of statistical techniques for time-dependent, multivariate analysis, and used classic (my students would say, outdated, or Fajan s ) criteria for the diagnosis of diabetes mellitus. Despite these challenges, these estimates are not far from those derived from many other sources (e.g., meta-analyses of large, prospective studies or outcome-based clinical trials). The most recent of these was a compilation of 123,205 deaths in 97 prospective studies, which showed the hazard ratio for diabetics (vs. non-diabetics) for all-cause death was 1.80 (95% confidence interval, 95% CI: ), for vascular death was 2.32 (95% CI: ), for cancer death was 1.25 (95% CI: ), and for other death was 1.73 (95% CI: ). The most recent attempt to study the relative impact of cardiovascular risk factors in a global population comes from the INTERHEART family of studies, which compiled data from 262 participating centers in 52 countries, comparing 15,152 people with incident myocardial infarction and 14,820 age-, gender-, and geographically-matched controls without heart disease. Significantly associated with MI were: dyslipidemia, with an odds ratio (OR) of 3.25, and population-attributable risk (PAR) of 49%; smoking, OR 2.87, PAR 36%; psychosocial factors, OR = 2.67, PAR 33%; obesity, OR = 1.12, PAR 20%; hypertension, OR = 1.91, PAR 18%; diabetes, OR = 2.37, PAR 10%; daily fruits/vegetables, OR = 0.70, PAR 14%; regular physical activity, OR = 0.86, PAR 12%; and.regular alcohol intake, OR = 0.91, PAR 7%. More recently, 26,919 acute stroke survivors and 13,472 controls from 32 countries were compared in the INTERSTROKE study. Significantly associated with acute stroke were hypertension, OR = 2.98, PAR 48%; regular physical activity, OR = 0.70, PAR 36%; dyslipidemia, OR = 1.84, 27% PAR; healthy diet, OR = 0.60, 23% PAR; waisthip ratio, OR = 1.44, 19% PAR; psychosocial factors, OR = 2.20, 17% PAR; smoking, OR = 1.67, 12% PAR; cardiac conditions, OR = 3.17, 9% PAR; alcohol consumption OR = 2.09, 6% PAR; and diabetes mellitus, OR 1.16, 4% PAR. Since diabetes mellitus contributes greatly to the risk of cardiovascular events, as demonstrated in both epidemiological studies and vital statistics data, efforts to control diabetes were evaluated in several clinical trials to assess their effects on cardiovascular and other complications. Some of the larger, longer, and more noteworthy trials were: the United Kingdom Prospective Diabetes Study (UKPDS), Avoiding Cardiovascular Complications of Diabetes (ACCORD), Action in Diabetes and Vascular disease: Preterax and Diamicron -MR Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT). Interestingly, three of these trials also incorporated a simultaneous blood pressure-lowering arm, which allows a comparison of the cardiovascular benefits of glycemic and blood pressure control in type 2 diabetics. Although the details of the studies merit attention in an attempt to explain their disparate results, they can be summarized reasonably succinctly, as follows. The first trial (UKPDS) showed, over the 9 years of planned follow-up, a significant reduction in all diabetes-related endpoints (the primary endpoint) with more intensive glycemic control

7 (compared to usual care, by 12%, P < 0.03); the effect of intensive BP control on this endpoint was even more impressive (reduction of 24%, P < 0.005). Ten years after the trial stopped, there was a significant 9% persistent benefit for the primary endpoint for individuals initially randomized to glucose-lowering therapy. However, the 7% benefit on this endpoint for individuals initially randomized to more intensive BP control was not significant, presumably because, after the trial stopped, the BPs were indistinguishable between the randomized groups. The ACCORD-Glucose trial was terminated after only 3.5 of its planned 5 years, because of an unanticipated significant 22% increase in all-cause mortality in the 5128 diabetic subjects treated to an A1c of < 6.0%, compared to the 5123 treated to an A1c target of < %; this was attributed to an increased risk of sudden cardiac death and hypoglycemia in the intensively-treated group. The ACCORD-BP trial may have been underpowered (based on SPRINT), but it observed a nonsignificant (P = 0.20), 12% reduction in cardiovascular events in the 2362 diabetics randomized to systolic BP < 120 mm Hg over 4.7 years, compared to the 2371 diabetics randomized to systolic BP < 140 mm Hg. About 4 years after ACCORD was stopped, the only outcome that remained significantly elevated in those randomized to an A1c of < 6.0%, compared to those with a target A1c of % was cardiovascular death (which was originally 49% higher when ACCORD-Glucose was stopped, and was attenuated to only 20% higher when the follow-up period was included). About 4 years after ACCORD-BP was stopped, those initially treated to systolic BP < 120 mm Hg had a 9%, nonsignificant (P = 0.19) reduction in the primary endpoint, and the systolic BP difference between groups shrank from 14.5 to 4.2 mm Hg. Less confusing was the glucose-lowering arm of the ADVANCE trial, which showed a small but significant (P = 0.01) 10% reduction in its primary composite endpoint (attributed mostly to prevention of microvascular endpoints) over 5 years of follow-up among 5571 diabetics given a sustained-release preparation of glyclazide, compared to 5569 diabetics given usual care (which excluded glyclazide). The BP-lowering arm of the ADVANCE trial also showed a small but significant (P = 0.04) 9% reduction in the shared primary composite endpoint (also seen with cardiovascular and all-cause mortality) in the 5569 diabetics given the combination of low-dose perindopril + indapamide over 4.3 years of follow-up, compared to the 5571 diabetics given placebo. About 6 years after ADVANCE was stopped, significant differences were still evident in both allcause (9%, P = 0.03) and cardiovascular mortality (12%, P = 0.04) favoring those who received the two BP-lowering drugs (compared to placebo), but no significant differences in any endpoint were seen across the two groups in the glucose-lowering arm. Lastly, the Department of Veterans Affairs Diabetes Trial showed a nonsignificant (P = 0.14) 12% benefit on a complex composite primary endpoint among 892 poorly-controlled diabetic US veterans treated with an intensive glucose-lowering regimen (achieved A1c = 6.9%) over 5.6 years, compared to 899 who received standard treatment (and achieved an A1c of 8.4%). All other cardiovascular risk factors were treated similarly in the VADT. After a further ~5 years of followup, however, the primary endpoint was significantly (P = 0.04) reduced by 17% in the intensivelytreated group; no significant differences were seen in all-cause (+5%, P = 0.54) or cardiovascular mortality (-12%, P = 0.42). Proper interpretation of these results is controversial and contentious. Some believe that the major conclusion of ACCORD-Glucose is that too low a target A1c is likely harmful, but individualized glucose control has beneficial effects on cardiovascular events in the long-term (ADVANCE, ADVANCE-ON, VADT-EXTENSION). Most believe that the less intensive BP target (< 180/105 mm Hg) in the BP-lowering arm of UKPDS is no longer relevant, and that lowering of BP has beneficial cardiovascular effects in diabetics that persists only as long as BP is controlled (ADVANCE, ADVANCE-ON, ACCORD-BP, ACCORDION).

8 More recently, we have the results of several cardiovascular safety trials undertaken with newer hypoglycemic agents, in response to the FDA s requirement that their sponsors demonstrate that these new drugs do not significantly increase cardiovascular risk (so called non-inferiority trials). The first of these was the EMPA-REG OUTCOME trial, which has resulted (on 02 DEC 16) in an FDA-approved indication for empagliflozin (which was extended, on 05 JAN 17, to all combination products containing empagliflozin): to reduce the risk of cardiovascular death in adult type 2 diabetics with cardiovascular disease. This trial randomized 7020 diabetics with established cardiovascular disease from 590 sites in 42 countries to one of two doses of empagliflozin or placebo, in addition to whatever other therapies were thought by the treating physician to be appropriate. The primary outcome was nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death, comparing placebo with the pooled empagliflozin arms. After 3.1 years of median follow-up, there was a 14% lower risk of the primary endpoint (P < for non-inferiority, P = 0.04 for superiority) in the empagliflozin-treated group. In addition, they enjoyed a 32% numerically lower risk of death, and a 38% numerically lower risk of cardiovascular death (these were NOT evaluated statistically). The Primary Principal Investigator of this trial (Silvio Inzucchi) has said, This is the first time in my lifetime that a diabetes drug has shown improved outcomes in high-risk cardiovascular patients. A subsequent analysis of renal outcomes in EMPA REG showed a significantly reduced risk of nephropathy (by 41%), doubling of serum creatinine (by 44%), and renal replacement therapy (by 55%) in the group given empagliflozin. The second of these trials was LEADER, which compared liraglutide and placebo (when added to standard care ) in 9340 diabetics with high cardiovascular risk over 3.8 years. The liraglutide group enjoyed a significant (P = 0.01 for superiority), 13% benefit on the primary composite outcome (identical to EMPA REG), as well as a 22% reduction in cardiovascular death and 15% reduction in all-cause mortality. On 25 AUG 17, the FDA approved liraglutide for cardiovascular event prevention, based on LEADER. The third such trial was SUSTAIN-6, which compared, over 2 years, two doses of semaglutide or placebo (when added to standard care ) at 230 sites in 20 countries in 3297 diabetics, 83% of whom had either established cardiovascular disease or chronic kidney disease. The primary comparison was the time-to-event for cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction, using a non-inferiority margin of 1.80 for the upper bound of the 95% confidence interval of the hazard ratio. As with the two previous trials, the semaglutide group not only fulfilled criteria for noninferiority, but also achieved a significant (P = 0.02 for superiority) 26% reduction in the primary endpoint, compared to placebo. Unlike the two previous trials, there was no suggestion of benefit on either all-cause (+5%) or cardiovascular death (-2%), but many adverse secondary endpoints (nonfatal stroke, retinopathy, nephropathy) were numerically reduced. Once-weekly semaglutide was FDA-approved on December 5, 2017, but was not (yet?) approved to reduce CV endpoints. The fourth such set of trials was the CANVAS Program, which consisted of 2 trials. One compared placebo, 100 mg/d or 300 mg/d of canagliflozin; the other compared placebo with 100 mg/d of canagliflozin, which could be increased to 300 mg/d after 13 weeks. Enrollment criteria were identical for the 2 trials: type 2 diabetes and high cardiovascular risk; together they enrolled 10,142 participants (63.3 years of age, 36% women, 13.5 years of diabetes, 66% with preexisting cardiovascular disease). Over 3.6 years of median follow-up, there was a significantly lower risk of cardiovascular death, nonfatal MI or nonfatal stroke in the group given canagliflozin (hazard ratio: 0.86, 95% confidence limits: , P = 0.02 for superiority, P < for non-inferiority. Although not prespecified, there was a suggestion of benefit on progression of albuminuria and for the hard renal endpoint (sustained 40% reduction in glomerular filtration rate, end-stage renal disease or death). Adverse experiences were all as expected, except for a nearly double risk of

9 amputations (mostly at the level of toe or metatarsal) in the canagliflozin group. The FDA had already approved canagliflozin in 2013, but has not yet added cardiovascular protection to its label. Taken together, these data suggest that several modern hypoglycemic agents can, when used as part of standard care, not only NOT increase, but also significantly decrease cardiovascular risk. Because these trials were funded by companies (and their shareholders) that will likely profit financially from them, many skeptics desire clinical trial evidence that directly demonstrates cardiovascular outcome benefits of treatment in diabetics that must be independent of Big Pharma. Such data are available from the Steno Diabetes Center in Gentofte, Denmark (named after Nicholas Steno, , a Danish anatomist/scientist who late in life became a priest, bishop of Munich and later Titiopolis, and was beatified [third of four steps to sainthood] in 1988). In 1993, investigators at the Steno Diabetes Center randomized 160 of their diabetics to either conventional therapy (according to Danish national guidelines, which changed in a major way in 2000), or an intensive regimen that involved a team approach targeting hyperglycemia, hypertension, dyslipidemia, microalbuminuria, and platelet aggregation. The trial was stopped as planned at 7.8 years of followup, when significant differences in surrogate endpoints were seen in systolic blood pressure and total cholesterol levels, as well as dietary intake of carbohydrates and fat. The primary composite endpoint was the first occurrence of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, revascularization or amputation, which was seen in 35 of the 80 randomized to conventional therapy and 19 who received the intensive regimen, a significant difference (P = 0.02). Essentially all outcomes favored the more intensive regimen, as did the results of several sensitivity analyses. Danish diabetes guidelines were changed in 2004 to match the intensive regimen. Follow-up information nearly 6 years later showed a significant (P = 0.02) 46% reduction in all-cause mortality, and confirmed sustained benefits on each component of the primary endpoint, with little evidence for adverse effects. These are perhaps the most direct, and least confounded, data suggesting that concerted efforts to manage and appropriately control all aspects of diabetics medical care can result in a significantly reduced risk of major adverse cardiovascular events. [multiple choice CME questions: 1 e; 2 b; 3 c; 4 c]