Cardiovascular Protection in People With Diabetes.

Abstract

Key Messages•Diabetes significantly accelerates the development and natural history of cardiovascular disease compared to individuals without diabetes.•Healthy behaviour interventions and pharmacological approaches aimed at cardiovascular disease risk reduction can significantly reduce morbidity and mortality, and are an important cornerstone of the management of diabetes.•Although young people with diabetes rarely have a high proximate (<10 year) risk for cardiovascular disease events, they have a relative proximate risk manyfold greater than individuals of similar age without diabetes.•Historically, pharmacological cardiovascular protection approaches have focused on low-density lipoprotein cholesterol and blood pressure reduction, and have demonstrated significant and clinically meaningful cardiovascular risk reduction. Recent data have indicated that certain antihyperglycemic agents are also cardioprotective.•The requirement for pharmacological cardiovascular protection therapies (statins, angiotensin-converting enzyme inhibitors or aldosterone receptor blockers, and anti-platelets) should consider both an individual's proximate and lifetime cardiovascular disease event risk.•There is emerging recognition that nonatherothrombotic cardiovascular disease complications, such as heart failure, are an important cause of morbidity and mortality in diabetes.Key Messages for People with Diabetes•Ask your doctor about the ABCDEs to reduce your risk of heart attack and stroke:◦A = A1C – Blood glucose control. The target is usually 7.0% or less.◦B = BP – Blood pressure control (less than 130/80 mmHg).◦C = Cholesterol – LDL-cholesterol less than 2.0 mmol/L. Your physician/nurse practitioner may advise you to start cholesterol-lowering medication.◦D = Drugs to protect your heart – These include blood pressure pills (ACE inhibitors or ARBs), cholesterol-lowering medication (“statins”), and, in people with existing cardiovascular disease, certain blood glucose lowering medications. These blood glucose-lowering medications can protect your heart even if your blood pressure and/or LDL-cholesterol are already at target.◦E = Exercise/Eating — Regular physical activity, which includes healthy eating, and achievement and maintenance of a healthy body weight.◦S = Stop smoking and manage stress. •Diabetes significantly accelerates the development and natural history of cardiovascular disease compared to individuals without diabetes.•Healthy behaviour interventions and pharmacological approaches aimed at cardiovascular disease risk reduction can significantly reduce morbidity and mortality, and are an important cornerstone of the management of diabetes.•Although young people with diabetes rarely have a high proximate (<10 year) risk for cardiovascular disease events, they have a relative proximate risk manyfold greater than individuals of similar age without diabetes.•Historically, pharmacological cardiovascular protection approaches have focused on low-density lipoprotein cholesterol and blood pressure reduction, and have demonstrated significant and clinically meaningful cardiovascular risk reduction. Recent data have indicated that certain antihyperglycemic agents are also cardioprotective.•The requirement for pharmacological cardiovascular protection therapies (statins, angiotensin-converting enzyme inhibitors or aldosterone receptor blockers, and anti-platelets) should consider both an individual's proximate and lifetime cardiovascular disease event risk.•There is emerging recognition that nonatherothrombotic cardiovascular disease complications, such as heart failure, are an important cause of morbidity and mortality in diabetes. •Ask your doctor about the ABCDEs to reduce your risk of heart attack and stroke:◦A = A1C – Blood glucose control. The target is usually 7.0% or less.◦B = BP – Blood pressure control (less than 130/80 mmHg).◦C = Cholesterol – LDL-cholesterol less than 2.0 mmol/L. Your physician/nurse practitioner may advise you to start cholesterol-lowering medication.◦D = Drugs to protect your heart – These include blood pressure pills (ACE inhibitors or ARBs), cholesterol-lowering medication (“statins”), and, in people with existing cardiovascular disease, certain blood glucose lowering medications. These blood glucose-lowering medications can protect your heart even if your blood pressure and/or LDL-cholesterol are already at target.◦E = Exercise/Eating — Regular physical activity, which includes healthy eating, and achievement and maintenance of a healthy body weight.◦S = Stop smoking and manage stress. Of the many complex complications of diabetes, adverse cardiovascular (CV) events have the greatest capacity to cause sudden or premature death and devastating disability. Myocardial infarction (MI), stroke and amputation are all manifestations of the aggressive atherosclerosis that can occur with diabetes. However, not every person with diabetes is at equal risk for CV atherosclerotic events and not everyone will benefit equally from healthy behaviour and pharmacological interventions intended to reduce cardiovascular disease (CVD) event risk. Over the last 2 decades, strong evidence has continued to accumulate that the CV risks of diabetes can be reduced significantly through comprehensive and treatment target-driven risk factor modification (1Haffner S.M. Lehto S. Ronnemaa T. et al.Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.N Engl J Med. 1998; 339: 229-234Crossref PubMed Scopus (5915) Google Scholar, 2Stevens R.J. Kothari V. Adler A.I. et al.The UKPDS risk engine: A model for the risk of coronary heart disease in type II diabetes (UKPDS 56).Clin Sci. 2001; 101: 671-679Crossref PubMed Scopus (1013) Google Scholar, 3Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3820) Google Scholar, 4Gaede P. Lund-Andersen H. Parving H.H. et al.Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2787) Google Scholar, 5Bittner V. Bertolet M. Barraza Felix R. et al.Comprehensive cardiovascular risk factor control improves survival: The BARI 2D trial.J Am Coll Cardiol. 2015; 66: 765-773Crossref PubMed Scopus (97) Google Scholar). There is also growing appreciation that, in addition to atherothrombotic consequences, other CV disorders, such as heart failure, are an important cause of morbidity and mortality in diabetes. People with diabetes are clearly at increased risk of premature morbidity and mortality related to CVD (6Booth G.L. Kapral M.K. Fung K. et al.Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: A population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar). Diabetes confers a CVD event risk that is equivalent to aging approximately 15 years, with a transition from intermediate to high risk in men at age 47.9 years, and in women at 54.3 years (6Booth G.L. Kapral M.K. Fung K. et al.Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: A population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar). The term “vascular age” refers to models of CVD event risk that predict an individual's CVD event risk and compare the event risk to age-adjusted CVD event risk. Vascular age is a primary determinant in both proximate (<10 years) and lifetime risk of adverse CVD events. In people with diabetes with low-to-normal levels of blood pressure (BP), low-density lipoprotein cholesterol (LDL-C) and blood glucose (BG), chronological age and vascular age are usually in close continuity. However, in the presence of elevated levels of those same variables, together with smoking and physical inactivity, vascular age accelerates far more rapidly than chronological age. As a powerful catalyst of vascular inflammation, diabetes is the disease state that accelerates vascular age at the greatest rate. Thus, the use of pharmacotherapy for CVD risk factor reduction in younger persons with diabetes who are not at a high proximate risk but, as a consequence of their diabetes, have a steep CVD event risk trajectory, can be justified by the potentially substantial long-term benefits of earlier and lifelong therapy (3Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3820) Google Scholar, 4Gaede P. Lund-Andersen H. Parving H.H. et al.Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2787) Google Scholar, 5Bittner V. Bertolet M. Barraza Felix R. et al.Comprehensive cardiovascular risk factor control improves survival: The BARI 2D trial.J Am Coll Cardiol. 2015; 66: 765-773Crossref PubMed Scopus (97) Google Scholar, 7Stock S. Drabik A. Buscher G. et al.German diabetes management programs improve quality of care and curb costs.Health Aff (Millwood). 2010; 29: 2197-2205Crossref PubMed Scopus (100) Google Scholar, 8Bergner D.W. Goldberger J.J. Diabetes mellitus and sudden cardiac death: What are the data?.Cardiol J. 2010; 17: 117-129PubMed Google Scholar). Traditional CVD event risk models predict an individual's proximate CVD event risk based on risk factors, such as diabetes, hypertension, serum lipids and smoking. These models discriminate poorly between higher- and lower-risk populations, particularly for younger individuals (9Guzder R.N. Gatling W. Mullee M.A. et al.Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed type 2 diabetes: Results from a United Kingdom study.Diabet Med. 2005; 22: 554-562Crossref PubMed Scopus (139) Google Scholar, 10Lloyd-Jones D.M. Leip E.P. Larson M.G. et al.Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.Circulation. 2006; 113: 791-798Crossref PubMed Scopus (930) Google Scholar, 11Stone J.A. Framing cardiovascular disease event risk prediction.Can J Cardiol. 2011; 27: 171-173Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 12Fox C.S. Pencina M.J. Wilson P.W.F. et al.Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham Heart study.Diabetes Care. 2008; 31: 1582-1584Crossref PubMed Scopus (162) Google Scholar). In addition, no current CVD event risk model can reliably exclude people with diabetes who are unlikely to benefit from long-term CV protection strategies given the well-documented lifetime risk of CVD events. As a result, far in advance of the appearance of CV symptomatology, most people with diabetes are very likely to benefit from CVD risk factor reduction and the adoption of healthy behaviours (3Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3820) Google Scholar, 4Gaede P. Lund-Andersen H. Parving H.H. et al.Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2787) Google Scholar, 5Bittner V. Bertolet M. Barraza Felix R. et al.Comprehensive cardiovascular risk factor control improves survival: The BARI 2D trial.J Am Coll Cardiol. 2015; 66: 765-773Crossref PubMed Scopus (97) Google Scholar, 7Stock S. Drabik A. Buscher G. et al.German diabetes management programs improve quality of care and curb costs.Health Aff (Millwood). 2010; 29: 2197-2205Crossref PubMed Scopus (100) Google Scholar, 8Bergner D.W. Goldberger J.J. Diabetes mellitus and sudden cardiac death: What are the data?.Cardiol J. 2010; 17: 117-129PubMed Google Scholar). The phrase “vascular protection” was originally coined in recognition of the apparent ability of some pharmacologic interventions to evoke greater reductions in the incidence of CVD events than would have been predicted based on their separate direct effects on the risk factors for atherosclerosis (13Dagenais G.R. Pogue J. Fox K. et al.Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: A combined analysis of three trials.Lancet. 2006; 368: 581-588Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar). This putative protective effect has been attributed to the enhancement of vascular endothelial functions that inhibit thrombosis, suppress macrophage and monocyte adherence to the endothelium, and minimize oxidative stress at the level of the endothelium (14Zachary I. Mathur A. Yla-Herttuala S. et al.Vascular protection: A novel nonangiogenic cardiovascular role for vascular endothelial growth factor.Arterioscler Thromb Vasc Biol. 2000; 20: 1512-1520Crossref PubMed Scopus (136) Google Scholar). Over time, the protective effect from adverse CVD events has also been extended to comprehensive healthy behaviour interventions and simultaneous multifactorial atherosclerosis risk factor reductions, such that the whole in CV protection is indeed greater than the sum of the parts (3Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3820) Google Scholar, 4Gaede P. Lund-Andersen H. Parving H.H. et al.Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2787) Google Scholar, 5Bittner V. Bertolet M. Barraza Felix R. et al.Comprehensive cardiovascular risk factor control improves survival: The BARI 2D trial.J Am Coll Cardiol. 2015; 66: 765-773Crossref PubMed Scopus (97) Google Scholar). The mechanistic explanation for why multifaceted CV protection interventions are multiplicative, rather than simply additive, is almost certainly related to, but not necessarily limited to, their favourable modulation of the pro-inflammatory, pro-thrombotic and pro-proliferative atherosclerotic vascular environment in diabetes. In the STENO-2 Trial, a very small number of participants with type 2 diabetes (n=160) were randomized to usual care or a program of comprehensive healthy behaviour interventions (smoking cessation, weight management, physical activity) and the treatment target-driven pharmacological therapy of BP and serum lipids (3Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3820) Google Scholar, 4Gaede P. Lund-Andersen H. Parving H.H. et al.Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2787) Google Scholar). Despite the very small number of participants, there was a 53% relative risk reduction in major adverse cardiac events (MACE) and a 20% absolute risk reduction after 13 years of follow up. The number needed to treat (NNT) for mortality reduction was a mere 5 persons. More recently, data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study have demonstrated that, following cardiac revascularization, participants who had their CVD risk factors controlled benefited from significantly improved CVD morbidity and mortality over 5 years of follow up (5Bittner V. Bertolet M. Barraza Felix R. et al.Comprehensive cardiovascular risk factor control improves survival: The BARI 2D trial.J Am Coll Cardiol. 2015; 66: 765-773Crossref PubMed Scopus (97) Google Scholar). Similarly, in a population-based observational study of 867 newly diagnosed individuals with diabetes, the relative risk of MACE was increased over 4-fold during 5 years of follow up for those persons who adopted no healthy behaviour changes vs. those who adopted either 3 or 4 healthy behaviours (15Long G.H. Cooper A.J.M. Wareham N.J. et al.Healthy behavior change and cardiovascularoutcomes innewly diagnosed type 2 diabetic patients: A cohort analysis of the addition-cambridge study.Diabetes Care. 2014; 37: 1712-1720Crossref PubMed Scopus (34) Google Scholar). Although the number of participants in these trials is relatively small compared to those in randomized trials of pharmacological agents, the data suggest that efficacious CV protection can be achieved through a combination of healthy behaviours and pharmacologic treatment of CVD risk factors to achieve the targets recommended by evidence-informed clinical practice guidelines (16Tobe S.W. Stone J.A. Walker K.M. et al.Canadian Cardiovascular Harmonized National Guidelines Endeavour (C-CHANGE): 2014 update.CMAJ. 2014; 186: 1299-1305Crossref PubMed Scopus (18) Google Scholar). Therefore, all people with diabetes should receive a comprehensive, multifactorial strategy to reduce CVD event risk. In 1 prospective cohort study of 867 people with newly diagnosed diabetes aged 40 to 69 years, CVD risk was inversely associated with the number of healthy behaviour changes adopted in the year after the diagnosis of diabetes (15Long G.H. Cooper A.J.M. Wareham N.J. et al.Healthy behavior change and cardiovascularoutcomes innewly diagnosed type 2 diabetic patients: A cohort analysis of the addition-cambridge study.Diabetes Care. 2014; 37: 1712-1720Crossref PubMed Scopus (34) Google Scholar). The CV protection benefits of each of the healthy behaviour interventions discussed below can be attributed to their significant anti-inflammatory, antithrombotic and anti-proliferative effects (17de Meirelles L.R. Matsuura C. Resende Ade C. et al.Chronic exercise leads to antiaggregant, antioxidant and anti-inflammatory effects in heart failure patients.Eur J Prev Cardiol. 2014; 21: 1225-1232Crossref PubMed Scopus (37) Google Scholar). In individuals with diabetes, smoking is an independent risk factor for all-cause mortality. It increases the risk of MI 1.4-fold, stroke by 30% (18Folsom A.R. Szklo M. Stevens J. et al.A prospective study of coronary heart disease in relation to fasting insulin, glucose, and diabetes. The Atherosclerosis Risk in Communities (ARIC) study.Diabetes Care. 1997; 20: 935-942Crossref PubMed Scopus (260) Google Scholar), and progression to end stage renal disease (ESRD) (19Yacoub R. Habib H. Lahdo A. et al.Association between smoking and chronic kidney disease: A case control study.BMC Public Health. 2010; 10: 731Crossref PubMed Scopus (56) Google Scholar); and is associated with poorer glycemic control. Quitting smoking has been shown to reduce CV risk in people with diabetes (20Chaturvedi N. Stevens L. Fuller J.H. Which features of smoking determine mortality risk in former cigarette smokers with diabetes? The World Health Organization Multinational Study Group.Diabetes Care. 1997; 20: 1266-1272Crossref PubMed Scopus (71) Google Scholar). In several randomized trials, exercise has been shown to improve CV risk factors (dyslipidemia, BP and body composition) in people with type 2 diabetes (21Chudyk A. Petrella R.J. Effects of exercise on cardiovascular risk factors in type 2 diabetes: A meta-analysis.Diabetes Care. 2011; 34: 1228-1237Crossref PubMed Scopus (216) Google Scholar). However, no clinical trials have demonstrated a reduction in major CV endpoints or mortality. The Look AHEAD (Action for Health in Diabetes) trial was the largest randomized trial to date evaluating the efficacy of a physical activity and dietary control intervention (targeting a ≥7% weight loss), in older adults with type 2 diabetes (22Wing R.R. Bolin P. et al.Look AHEAD Research GroupCardiovascular effects of intensive lifestyle intervention in type 2 diabetes.N Engl J Med. 2013; 369: 145-154Crossref PubMed Scopus (1858) Google Scholar). In this study, at least 175 min/week of unsupervised exercise was targeted as part of the Intense Lifestyle Intervention (ILI), while the control group (Diabetes Support and Education-DSE group) received usual care. After a median follow up of 9.6 years, the composite primary outcome (death from CV causes, nonfatal MI, nonfatal stroke and hospitalization for angina) occurred in a similar number of participants in the intervention and control groups (22Wing R.R. Bolin P. et al.Look AHEAD Research GroupCardiovascular effects of intensive lifestyle intervention in type 2 diabetes.N Engl J Med. 2013; 369: 145-154Crossref PubMed Scopus (1858) Google Scholar). Possible reasons for this finding include the lower-than-expected rates of CV events in both groups, improved overall CV risk factor treatment with antihypertensive agents and statins, enrollment of a relatively healthy population and gradual weight loss in the control group (difference in weight loss between the 2 groups was 2.5% at the end of the study). Importantly, and perhaps one explanation for why there was no significant effect on CVD outcomes, after the first year of the trial, the intervention group and the control group were virtually performing the same amounts of exercise and physical activity (see Physical Activity and Diabetes chapter, p. S54). Several prospective cohort studies have shown that physical activity is associated with improvement in CV outcomes and a reduction in CV and overall mortality in people with type 2 diabetes or impaired glucose tolerance and CVD. In the Nurses' Health Study, among women who reported having type 2 diabetes, the women who spent at least 4 hours per week performing moderate (including walking) or vigorous exercise had a 40% lower risk of developing CVD (including coronary heart disease [CHD] and stroke) than those who did not. In another study of 2,896 adults with diabetes, those who walked for at least 2 hours per week had lower CV mortality rates compared to inactive individuals (hazard ratio [HR] 0.66, 95% CI 0.45–0.96) (23Gregg E.W. Gerzoff R.B. Caspersen C.J. et al.Relationship of walking to mortality among US adults with diabetes.Arch Intern Med. 2003; 163: 1440-1447Crossref PubMed Scopus (286) Google Scholar). Rates were even lower for those who walked 3 to 4 hours per week (HR 0.47, 95% CI 0.24–0.91). The CVD event risk reduction benefits of a Mediterranean style diet are well documented (see Nutrition Therapy chapter, p. S64) and may be related to anti-inflammatory and antioxidative effects. The PREDIMED (Prevencion con Dieta Mediterranea trial) randomized nearly 7,500 participants at high CV risk to a Mediterranean diet supplemented with extra-virgin olive oil or mixed nuts, or to a control diet. About 50% of participants had type 2 diabetes. The trial was stopped early after a 30% reduction in the primary composite outcome of CV death, MI or stroke was observed with the Mediterranean diet. People with existing diabetes (n=3,614) had results similar to the main trial population. No randomized prospective trials, including the Look AHEAD trial discussed above, have shown a reduction in major CV endpoints or mortality with weight loss in people with diabetes and obesity (22Wing R.R. Bolin P. et al.Look AHEAD Research GroupCardiovascular effects of intensive lifestyle intervention in type 2 diabetes.N Engl J Med. 2013; 369: 145-154Crossref PubMed Scopus (1858) Google Scholar) (see Physical Activity and Diabetes chapter, p. S54). The Diabetes Control and Complications Trial (DCCT) in type 1 diabetes (24Nathan D.M. Genuth S. et al.Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22760) Google Scholar), the Kumamoto trial (25Ohkubo Y. Kishikawa H. 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UK Prospective Diabetes Study (UKPDS) Group.Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7481) Google Scholar) in type 2 diabetes demonstrated that improved glycemic control significantly reduced the risk of microvascular complications, but had no significant effect on CV outcomes. Subsequent observational data from long-term follow up after termination of randomization periods of both the DCCT and UKPDS cohorts showed a persistence of significant microvascular benefits and also demonstrated an emergence of beneficial effect on CV outcomes attributed to intensive glycemic control (28Holman R.R. Paul S.K. Bethel M.A. et al.10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589Crossref PubMed Scopus (5258) Google Scholar, 29Nathan D.M. Cleary P.A. 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Neal B. et al.Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.N Engl J Med. 2014; 371: 1392-1406Crossref PubMed Scopus (457) Google Scholar), and Veterans Affairs Diabetes Trial (VADT) (33Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3876) Google Scholar, 34Moritz T. Duckworth W. Abraira C. Veterans affairs diabetes trial–corrections.N Engl J Med. 2009; 361: 1024-1025Crossref PubMed Scopus (52) Google Scholar)—examined the effect of intensive glycemic control on middle-aged or older (mean age 60 to 68 years) participants with established type 2 diabetes for 8 to 11 years, with either CVD or multiple CVD risk factors. These studies compared intensive glycemic control with an A1C of 6.4% to 6.9% vs. 7.0% to 8.4% in the standard glycemic control cohort. No benefit on CV outcomes was seen in any of the 3 studies. The ACCORD trial was stopped early because of a 22% increase in all-cause mortality (HR 1.22, 95% CI 1.01-1.46) driven predominantly by CV mortality (30Gerstein H.C. Miller M.E. et al.Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6478) Google Scholar). The reasons for the increased mortality associated with intensive glycemic control are unclear (see Targets for Glycemic Control chapter, p. S42). A retrospective analyses of data from the ADVANCE trial suggests that visit-to-visit variability in A1C and fasting plasma glucose predicted future CV events, microvascular events and all-cause mortality independent of CVD risk factors (35Hirakawa Y. Arima H. Zoungas S. et al.Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: The ADVANCE trial.Diabetes Care. 2014; 37: 2359-2365Crossref PubMed Scopus (226) Google Scholar). Glycemic variability has been linked to mitochondrial superoxide overproduction, and oxidative stress is a key driver of atherosclerotic disease development and progression (36Monnier L. Mas E. Ginet C. et al.Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.JAMA. 2006; 295: 1681-1687Crossref PubMed Scopus (1856) Google Scholar, 37Brownlee M. Hirsch I.B. Glycemic variability: A hemoglobin A1c-independent risk factor for diabetic complications.JAMA. 2006; 295: 1707-1708Crossref PubMed Scopus (385) Google Scholar, 38Nishikawa T. Edelstein D. 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