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Controversies in the cardiovascular management oftype 2 diabetes Lionel H Opie,1 Derek M Yellon,2 Bernard J Gersh3 1Hatter Cardiovascular Research low-density lipoprotein cholesterol (LDL-C) from Institute, Department of In patients with type 2 diabetes mellitus, intense control about 3.1 mmo/l (118 mg/dl) to 1.94 mmol/l Medicine, Faculty of Health of blood pressure, lipids and glucose, aiming at (72 mg/dl), and decreased major cardiovascular Sciences, University of Cape theoretically ideal values, is bought at a cost. Intense events, including stroke reduction, by 48%. In the Town, Observatory, Cape Town,South Africa blood pressure control has renal complications. Intense diabetic subgroup of a subsequent large meta- 2The Hatter Cardiovascular lipid control, thus far, has worked for reduction of analysis, decreasing LDL-C by 1 mmol/l (about Institute, University College low-density lipoprotein-cholesterol, paradoxically at the 40 mg/dl) reduced the calculated major vascular London Hospital and Medical cost of a small increase in new diabetes. Intense control events by 21% irrespective of the starting value.3 School, London, UK3Mayo Clinic College of of glycaemia generally requires insulin added to oral Overall, these observations suggest, but do not Medicine, Division of agents, which is consistently accompanied by weight prove, that the higher the statin dose and the lower Cardiovascular Diseases, Mayo gain, while increased hypoglycaemia has a long-term risk the LDL-C value, the better the outcome. There Clinic, Rochester, Minnesota, of cerebral damage. Intense glycaemic control has not still is need for a prospective study in patients with consistently reduced mortality, whereas a strategy DM2 at relatively low cardiovascular risk to Correspondence to based on tight control of lipids and blood pressure with confirm the benefit of further decreasing LDL-C.4 Professor Derek M Yellon, The modestly tight glucose control has succeeded. Looking Hatter Cardiovascular Institute, to the future, incretin mimetics may come to the fore as New side effects, including diabetes, evoked by University College London prime agents because they can reduce weight and Hospital and Medical School, 67Chenies Mews, London WC1E glycaemia with little significant hypoglycaemia, thereby Besides the well-known statin-related side effects 6HX, UK; [email protected] making tight glucose control easier to achieve.
such as myalgia and altered liver function, tworecently identified problems are increased cataract Accepted 11 October 2010 formation and acute renal failure.5 According toa newly proposed algorithm, using data obtainedon over 2 million patients soon after the onset of statin treatment, three of these side effects In regard to risk factors for the development of (moderate to severe myalgia, liver dysfunction and cardiovascular disease in patients with type 2 cataracts) could be predicted with reasonable diabetes (DM2), the fundamental message was accuracy.5 The number needed to harm for acute delivered by the large and ongoing United Kingdom renal failure were 434 over 5 years to cause one Prospective Diabetes Study (UKPDS). The major additional case. For myopathy the number needed factor was the ratio of total cholesterol to high- to harm was 259, for liver dysfunction it was 136 density lipoprotein cholesterol (HDL-C), which and for cataract only 33. The rather rare renal side accounted for 45% of the risk.1 Next came the effects, thus far not well recognised, include acute significance of systolic blood pressure (SBP), renal failure besides increased proteinuria, and accounting for 33% of the risk while last was the could not be predicted. Simvastatin was by far the glycosylated haemoglobin (HbA1c) at 22%. We will most frequently prescribed drug followed by ator- review controversies, starting with those that are vastatin. The unexpected advent of new diabetes as more modest in relation to lipid control and BP a side effect still makes statin treatment desirable management, followed by major controversies in for all with DM2, while watching for an increasing relation to glycaemic control. An intuitively logical HbA1c level.4 6 However, in view of the persisting hypothesis would be that the more normal each of residual cardiovascular risk despite statin treat- these three factors is, the better the clinical ment, would additional co-therapy with fibrates outcome (figure 1). Yet some recent studies have give added benefit? cast doubt on the simplicity of the direct straightline type of relationship and rather argue for Fibrates give modest benefits beyond statins a trough or U-shaped curve with a dip which could High blood triglyceride levels are an independent be the optimal range.
risk factor for coronary heart disease, albeit not forstroke.7 Fenofibrate, the peroxisome proliferator- LIPID CONTROL: EXTENDING BEYOND STATINS? activated receptor (PPAR) a agonist, when added Present evidence supports the use of statin treat- to pre-existing statin treatment in DM2 decreased ment in all patients with DM2. The crucial study the triglyceride values and slowed retinopathy was the Collaborative Atorvastatin Diabetes Study progression.8 In the larger FIELD study over 5 years (CARDS) study, in which the entry criteria were on 9795 people with DM2, fenofibrate similarly DM2 and at least one other cardiovascular risk reduced triglyceride levels.9 Coronary revascularisa- factor such as hypertension, smoking or diabetic tion rates fell by 21% (p¼0.003) with less albu- complications (retinopathy or maculopathy, micro- minuria progression and less severe retinopathy. The or macroalbuminuria).2 Atorvastatin reduced the costs were pulmonary embolism, and a consistent Heart 2011;97:6e14. doi:10.1136/hrt.2010.214031

Lipids: SummaryAt present, intense LDL-C lowering by a statin remains thecornerstone of lipid-lowering treatment despite newly reportedside effects. To reduce triglyceride levels and/or to delay reti-nopathy, the best evidence is for fenofibrate added to statins.
BLOOD PRESSURE CONTROL: HOW LOW TO GO?The controversy: What is the ideal systolic BP in DM2?In an observational cohort study from the UKPDS series,suggesting an optimal SBP of about 110e120 mm Hg, as the SBPfell from >160 mm Hg to <120 mm Hg, there were lineardecreases in MI, stroke and microvascular disease.17 The conclu-sion was that for each 10 mm Hg reduction in blood pressurethere was a 12% decrease in mortality. The lower, the better itseemed (figure 1). However, subsequent trial data did not supportthese predictions.18e20 There are plausible reasons for the devia- Population studies yield a near-straight line relationship tion from the straight line shown in figure 1. In the UKPDS between any diabetic end point and, on the left, the mean systolic blood observational study (see left panel in Table 1 of reference17) the pressure (SBP) and, on the right, the glycated haemoglobin (HbA1c) participants were younger with a lower body mass index, and the level. However, these observational data appear not to be based on diabetes was newly diagnosed versus 10 years in ACCORD.
prospective trial information, with which they conflict. Figures modifiedwith permission from the These factors could differentiate the two studies. and account for British Medical Journal, on the left for systolic blood pressure (Adler AI, et al. BMJ 2003;321:412) and on the right for the straight-line relationship in figure 1. From the ACCORD the HbA1c level (Stratton IM, et al. BMJ 2000;321:405).
study,19 the main conclusion to draw must be that a SBP target <120 mm Hg in patients with DM2 is not justified by theevidence. For ADVANCE, the initial mean BP was 145/81mm and puzzling reversible increase in plasma creatinine of Hg, which decreased by 5.6/2.2 mm Hg to a mean of 139/ 10e12 mmol/l.9 Overall, fibrates may be indicated with statins if 79mm Hg,18 almost exactly where ACCORD started from (139/ the lipid profile in DM2 demonstrates an increased triglyceride 76 mm Hg). That difference may explain why renal outcomes level, with the aim of delaying retinopathy. The largest database were improved as the BP fell in ADVANCE and the BP fall was is for fenofibrate. However, the benefits of exercise and weight well tolerated.21 loss on both triglyceride levels and cardiovascular events shouldnot be forgotten.
Practical policy for BP controlInitial data came from UKPDS 38, wherein a mean BP of Bezafibrate, a combined PPARa and PPARg agonist 154/97 mm Hg to 144/82 mm Hg over a mean of 8.4 years This combination of PPARa and PPARg agonist effects is reduced all diabetes-related end points by 24%.22 More current attractive because the added g agonism activates glucose studies argue for a SBP <140 mm Hg in DM2, within the band metabolism to reduce plasma glucose concentrations, while the component increases HDL-C.10 In non-diabetic patients with e140 mm Hg,20 as also found in ADVANCE.18 ACCORD does not support <120 mm Hg.19 In hypertensive patients with coronary artery disease (CAD) bezafibrate reduced new DM2 by diabetes and CAD, INVEST does not support <130 mm Hg.20 30% over 6.2 years.10 However, these data antedated the wide- Thus the major studies do not support the linear relation spread use of statins and ACE inhibitors and need to be between BP and any diabetic end point as suggested by the confirmed in the current era.
UKPDS observational study in figure 1. There were few patientsin ACCORD with previous stroke, so our recommendations of Increasing HDL-C, niacin and thiazolidinediones HDL-C is often low in DM2 and its normal vasoprotective e140 mm Hg cannot be applied directly to this group. Furthermore, much depends on clinical judgement effects are impaired.11 Nicotinic acid (niacin) would logically be applied to the individual patient. For example, in selected the preferred treatment but is poorly tolerated. The recently patients, the BP aim could even be 125 mm Hg if it were easy introduced long-acting formulation (Niaspan) elevates HDL-C to achieve without multiple drugs. In summary, in BP control in DM2 and increases the endothelial-protective effects.11 there is conflict between the idealised observational data that Thiazolidinediones, also called the ‘glitazones', are drugs that predict a straight-line relationship between decreases in BP and activate the PPARg transcriptional system thereby promoting the CV disease (figure 1),17 and the practical reality of controlled metabolism of glucose, while having indirect PPARa stimulating therapeutic trials.
properties thereby reducing both glycaemia and triglycerides,while increasing HDL-C.12 Rosiglitazone and pioglitazone bothincreased total LDL-C but to a greater extent with rosiglitazone, GLYCAEMIC CONTROL: GLUCOTOXICITY VERSUS LIPOTOXICITY which increased LDL-C particle concentration, whereas pioglita- Optimal glycaemic control is correctly stressed by major zone reduced it.13 Pioglitazone increased total HDL-C particle diabetes societies, while often emphasising HbA1c levels of concentration and size, whereas rosiglitazone decreased them; <7.0% or, sometimes, <6.5%. Supporting this view is the nonetheless both increased HDL-C cholesterol. Experimentally, apparent straight-line relationship between HbA1c and any pioglitazone reduced infarct size.14 Overall, these observations diabetic end point in DM2 (figure 1) and the concept of an might help to explain why rosiglitazone but not pioglitazone optimal HbA1c of about 3.9e5.59% as found in 260 361 people monotherapy has been associated with increased myocardial with no known diabetes.23 Logically, reversal of the abnormali- infarction (MI) in some but not all studies.15 16 (See later for ties of glucose metabolism found in DM2 should be the key to thiazolidinediones and heart failure (HF).) improving prognosis. However, an equally fundamental problem Heart 2011;97:6e14. doi:10.1136/hrt.2010.214031

might lie in the increased circulating levels of potentially toxicfree fatty acids (FFAs), released from abdominal fat to promoteinsulin resistance.24 The result is decreased uptake of glucose bybody tissues including muscle and liver, which explains thehyperglycaemia of DM2.
The glucoseefatty acid cycle and fatty acid toxicityIn a classic article in 1963, Randle et al described the glucoseefatty acid cycle, whereby an alternating interaction betweenglucose and FFA metabolism could explain metabolic abnor-malities in obesity and diabetes.25 In hearts perfused with FFAsand glucose, glucose oxidation is inhibited,26 because glycolysisis blocked, while increased levels of glucose and insulin inhibitthe release of FFAs from adipose cells.25 These mechanismsexplain why glucose is the dominant fuel of the heart in thepostprandial phase and FFA uptake dominates in fasting as theblood glucose falls Experimentally, glucose and/or insulin werecardioprotective27 and, conversely, high levels of FFAs harmfulto the heart.28 Adipose tissue mediates cytokine damage. Proposed role of free fatty acid (FFA) in promoting cytokine-induced organ damage. For Experimentally, high circulating FFA levels oppose the vaso- data, see Shoelson SE, et al. J Clin Invest 2006;116:1793. Copyright LH dilatory and protective role of the anti-atherogenic endothelial nitric oxide (NO) molecule.29 Marked FFA elevation causesmitochondrial uncoupling and oxygen wasting, and cytokine- reactive oxygen species33 (figure 3). However, these experiments induced organ damage.30 31 (figure 2) However, in DM2 there has typically use external glucose values of 10e33 mmol/l only been limited proof of FFA toxicity with increased muscle glucose,34e41 all well above the limits of acceptable care in DM2.
lipid in biopsies from the vastus lateralis muscle.32 Logically, FFAcontrol should be a prime aim in DM2. The limitation is that measuring circulating FFA levels remains a specialised procedure, Taegtmeyer's group has emphasised the logical concept of hence not a feasible target in controlling DM2.
combined glucotoxicity and lipotoxicity,33 34 whereby modestglycaemia and modest lipaemia adversely combine to increase pancreatic damage (figure 4). The glycaemia may, through an There is no doubt that experimentally high external glucose unknown mechanism, downregulate PPARa activity, thereby concentrations potentially promote tissue damage by stimu- decreasing fatty acid oxidation and promoting the accumulation lating the various glycolytic-dependent pathological paths, acti- within the heart of damaging fatty acid derivatives such as vated by blocked glycolysis, that lead to increased formation of ceramide.33 Conversely increased circulating FFAs inhibit glucose Proposed role of inhibition of glycolysis in glucolipotoxicity.
Concurrent metabolism of elevatedblood levels of free fatty acids (FFAs) indiabetes mellitus type 2 inhibits cardiacglycolysis chiefly at the level ofpyruvate dehydrogenase (PDH),resulting in the accumulation ofglycolytic intermediates.25 The concepthere proposed is that further metabolicchanges induced by these accumulatedproducts of inhibited glycolysis increasethe formation of reactive oxygenspecies (ROS) at multiple levels,including feedback inhibition ofglycolysis at the level of glyceraldehydephosphate dehydrogenase (GAPDH),thereby promoting a vicious circle.
AGEs, advanced glycation end products.
Modified with permission fromBrownlee M. Nature 2001;414:813.
Heart 2011;97:6e14. doi:10.1136/hrt.2010.214031

hypoglycaemic death was actually lower in the arm receivingintense treatment than in the standard treatment arm. Thusthere could have been another ill-defined mechanism of death. Forexample, a post hoc and non-prespecified analysis of ACCORDhypothesises that there were systemic factors associated withpersisting HbA1C values $7, such as serious associated medical orsocial or cognitive problems beyond DM2.51 This elegant conceptneeds further testing by prospective studies.
Benefit versus harm of tight controlThere is no crucial clinical evidence that tight control of presetaims, such as HbA1c of 7.0% or even lower, gives a clear-cutbenefit to those with established DM2. Thus the predictedstraight-line relation between the HbA1C and all diabeticoutcomes, shown in figure 1, is not supported by several major Proposed mechanism whereby modest glucolipotoxicity can studies.52 Tight control might be more beneficial in the very promote pancreatic damage and increase the severity of diabetes early management of recently diagnosed DM2 as suggested by mellitus type 2 (DM2). FFAs, free fatty acids. Copyright LH Opie, 2010.
UKPDS 3353 but requires prospective randomised testing, as isnow planned. Tight control in four major trials, ACCORD,49 oxidation at the level of entry of pyruvate into the Krebs cycle UKPDS 33,53 VADT54 and ADVANCE,55 found large increases in thus leading to accumulation of glycolytic intermediates that in the relative risks of severe hypoglycaemic episodes and weight turn promote the formation of advanced glycation end products gain. All-cause and cardiovascular mortality only improved in and reactive oxygen species (figure 3). In clinical practice, studies one of the four studies; there were no changes in stroke, in patients with DM2 show that agents such as incretins and amputation or other peripheral vascular events, and none in pioglitazone control both glycaemia and FFA levels with neuropathy, progress to macular oedema, visual deterioration or decreased oxidative stress42 and improved muscle fat metabo- blindness; and only a borderline benefit for renal mortality or lism,32 thereby extending the control DM2 beyond blood FFA renal replacement as found in the other studies.52 However, non- and glucose levels.
fatal MI was less and the risk of MI fell by 15%.56 By contrast,metformin clearly improved clinical outcome without severe HYPOGLYCAEMIC REACTIONS DURING TIGHT GLUCOSE hypoglycaemia and weight gain.52 57 At present, we have found no convincing evidence in clinical Adverse side effects of antidiabetic drugs practice that allows extrapolation directly from modest The perils of hypoglycaemia and weight gain are self-evident. In increases in the blood HbA1c or glucose values to metabolic general, the possible long-term cerebral complications of hypo- harm for patients with DM2. Rather, a very large real-life glycaemia43 have not been carefully studied. The overall observational general practice study suggests a range of optimal improved control of DM2 may promote longevity,44 45 but at HbA1c values somewhere between 7.5% and 8.9% for non- the possible price of the greater potential threat of serious insulin treatments and a tighter band for insulin-based treat- cognitive loss since function of the brain is a glucose-requiring ments between 7.5% and 8%.58 Overall, HbA1c 7.5% was the organ.46 Thus the brain may be vulnerable to repetitive hypo- value that optimally reduced mortality (figure 5). Furthermore glycaemic attacks. In elderly patients with DM2, multiple a similar U-shaped pattern was found in a study on patients episodes of hypoglycaemia had a graded risk for dementia after with DM2 and HF in a USA teaching hospital (figure 6).
27 years of follow-up, the HR for three episodes versus none Overall, the aim should be to select treatment combinations being 1.94 (CI 1.42 to 2.64).43 It would be contradictory and that reduce MI, hypoglycaemia and glycaemia and weight gain.
catastrophic if achieving an HbA1c of <7.0% came at the cost of On available evidence, we would commend the multifactorial impaired brain function.
approach (next section).
There are striking differences in the incidences of serious hypoglycaemia, generally linked to insulin use, in major trials.
MULTIFACTORIAL APPROACH The ADVANCE study achieved a low HbA1c of 6.5% with the The STENO-2 study use of cardioprotective gliclazide,47 with added insulin in about This trial showed the benefits of multifactorial intervention.42 half.18 The fall of HbA1c during intensified treatment was slow, After a mean of 7.8 years of intensive treatment, the SBP fell taking several months, suggesting careful and unhurried clinical from 147 mm Hg to 130 mm Hg. LDL-C and triglyceride values observation, which may explain why hypoglycaemia was dropped to within the goals in most patients. Fasting lipid goals uncommon. The controlled randomised trial, UKPDS 34, found were: cholesterol level <4.5 mmol/l (175 mg/dl) and triglyceride that metformin, giving a mean HbA1c of 7.4%, substantially level <1.7 mmol/l (150 mg/dl). Nonetheless, there were signifi- reduced mortality and caused less weight gain and less hypo- cant reductions in both microvascular and macrovascular glycaemia than sulphonylurea treatment or insulin.48 By complications, including nephropathy (p¼0.003), retinopathy contrast, in ACCORD the rate of fall of HbA1c was much more (p¼0.02) and autonomic neuropathy (p¼0.002), with an abso- rapid and the incidence of hypoglycaemia much higher.49 lute 20% reduction in cardiovascular disease and a relativereduction of 53% (HR¼0.47, CI 0.24 to 0.73; p¼0.008). With the Implications of hypoglycaemic reactions during tight control multifactorial approach in STENO-2, unexpected benefits In a retrospective analysis of the ACCORD study,50 the associa- became apparent at the end of a further prolonged follow-up tion between severe hypoglycaemia and mortality was examined.
However, the unexpected finding was that, taking all those with Strikingly, attempts at glycaemic control were unable to reach at least one episode of hypoglycaemia in ACCORD, the risk of the aim of <6.5% HbA1c, achieved in only 15% of patients Heart 2011;97:6e14. doi:10.1136/hrt.2010.214031

Relative mortality and glycated haemoglobin (HbA1c) levels intype 2 diabetes in a large UnitedKingdom general practice observationalstudy.58 Note the narrow protectiveband of HbA1c values with use of oralantiglycaemic agents (left) and insulin(right). On the left are the results withoral agents, suggesting a relatively flatplateau of optimal HbA1c levelsbetween approximately 7.3 and 8.2%.
On the right are the data forinsulin-based treatment, suggestinga smaller plateau of optimal benefit,round about 7.5e8% HbA1c. ‘Safe'zones are designated by the shadedareas. Figure modified with the permission ofThe Lancet from Currie et al. Lancet 2010;375:481e9.
receiving intensive treatment. The actual mean values for the Increased HF with thiazolidinediones HbA1c in the intensive group were 8.4% initially and 7.9% at the A series of meta-analyses 61e63 has confirmed a higher incidence end of the intervention study, reaching 7.7% at the end of of cardiac complications, such as congestive heart failure or MI.
follow-up. These values give no support for the concept that the In ADOPT rosiglitazone was associated with more cardiovas- ideal HbA1c of 6.5 or 7.0% had to be achieved to obtain major cular events, specifically HF, and bone fractures than glyburide.64 outcome benefit. Rather the benefit of triple therapy by Hence the boxed warning in the USA package insert which a reasonable degree of glycaemic control, with reasonably tight states that thiazolidinediones are not recommended in any SBP control to 130 mm Hg and tight lipid control was associated symptomatic HF.
with the long-term reduced mortality.
Comparing pioglitazone with rosiglitazone, the latter is associated with a 25% increase in the risk of HF and 14% DIABETES AND HEART FAILURE increased mortality according to an influential study emanating Heart failure is a common comorbidity in DM2. Mechanistically, from the American Federal Drug Agency.65 As this detailed study insulin resistance promotes progression of HF.59 In the large UK was of 227 571 Medicare patients aged $65 years, there seems to General Practice Research Database, standard anti-HF drugs be no compelling reason for the use of rosiglitazone by cardiol- reduced mortality. By contrast, metformin was the only anti- ogists taking care of elderly patients with DM2. Note that the glycaemic agent associated with decreased mortality (OR¼0.72; majority of patients were above 70 years old, while 90% had CI 0.59 to 0.90).60 The thiazolidinediones were seldom used in hypertension and 37% cardiovascular diseases before thiazolidi- general practice, and are the only class of antidiabetic agents nedione treatment. By contrast, another recent study found with adverse data for HF.
equal event rates with the two thiazolidinediones in 36 628people of mean age 54 years with full healthcare, of whom <4%had had previous cardiovascular events.66 Thus one feasibleproposal is that pioglitazone has the edge for safety data in anelderly population, whereas both drugs have equal effects whengiven to relatively healthy middle-aged populations. In middle-aged people with DM2 and a normal ejection fraction (60%),pioglitazone improved diastolic dysfunction while increasingwhole-body insulin sensitivity and myocardial glucose uptake.67 Paradoxical myocardial beneficial effects of rosiglitazonerelevant to HFEven when HF is precipitated by pioglitazone, mortality andmorbidity are not increased.68 The simplest explanation for thisapparent paradox may be that there is only fluid retention andnot congestive HF.69 There are two PPARg-independent cardiaceffects of pioglitazone. First, pioglitazone experimentally atten-uates angiotensin-induced cardiac fibrosis by inhibiting myocar-dial macrophage infiltration, thereby lessening cardiac fibrosis,which is one the causes of left ventricular (LV) dysfunction.70Second, pioglitazone may beneficially lessen the accumulation of Relation between initial HbA1c and 2-year mortality, studied harmful saturated FFAs in the myocardium.32 67 in 5815 patients with heart failure in an Veterans Affair USA academiccentre. Proportion of diabetic patients who had died by 2 years of Other antidiabetic drugs and HF follow-up in relation to initial HbA1c values. Calculated from data infigure1 of Aguilar D, Metformin, beneficial in the UK General Practice study55 and et al. J Am Coll Cardiol 2009;54:422e8; for limitations of study, see Weinrauch LA and Lewis EF. J Am Coll Cardiol experimentally,71 needs direct prospective comparative studies to prove its anti-HF benefits.
Heart 2011;97:6e14. doi:10.1136/hrt.2010.214031 Ranolazine, currently available in the USA and Europe, coronary artery bypass grafting (CABG) or percutaneous coro- improves the diabetic status of patients with acute coronary nary intervention (PCI) versus medical treatment with regard to syndrome.72 Experimentally, when combined with enalapril or death and MI.
metoprolol, it slows the progression of HF.73 By Na+/Ca+ We emphasise that randomisation occurred after angiography exchange inhibition, ranolazine improves diastolic function in and that these were stable patients with mild to moderate myocardium taken from failing human hearts.74 These effects of symptoms, or patients who were asymptomatic with positive ranolazine warrant prospective trials in patients with DM2 with stress tests, but nonetheless with an event rate as high as 20% at diastolic HF.
4 years. In cost-conscious situations, cardiologists often firstemploy clinical assessment and a variety of stress tests, whichprovide a different entry point. A trial of a strategy of inter- DIABETIC CARDIOMYOPATHY vention versus medical treatment in patients enrolled at the The existence of this previously controversial entity, diabetic time of stress testing is currently in the design phase (Marron D, cardiomyopathy, has been put beyond reasonable doubt by Williams D and Hichman J; personal communication).
recent laboratory and clinical studies.69 75 76 Diabetic cardio-myopathy was originally described as a specific diabetes-relatedform of myocardial dysfunction often starting as diastolic Coronary revascularisation in patients at higher risk but with dysfunction.77 Excess storage of myocardial triglyceride (cardiac steatosis) in association with diastolic abnormalities precedes LV Outcomes with both PCI and CABG are substantially less useful systolic dysfunction.76 This is yet another complication of among diabetic than non-diabetic patients. The general princi- excess FFA supply in diabetes, so that the logical preventive ples of glycaemic control hold for management of diabetic treatment could include early use of incretins or pioglitazone.
patients undergoing PCI, for whom an added hazard is an Preclinical diabetic cardiomyopathy has now also been proposed increased risk of restenosis.88 Multiple randomised controlled as the combination of diabetes and echocardiographic diastolic trials have demonstrated no difference in death or MI between dysfunction in the absence of prior hypertension or ischaemic CABG and PCI with the exception of diabetics entered into the heart disease.78 On follow-up, previous diastolic dysfunction BARI-2D trial, in which mortality was lower in patients treated was associated with a lower event-free survival, 54% versus 87% with CABG than for those undergoing percutaneous trans- in controls (p¼0.001). Overall, diabetic cardiomyopathy still luminal coronary angioplasty.86 89 warrants further therapeutic study and clarification.
Our proposed explanation is that clinical judgement and doctor preference resulted in higher-risk patients being treatedsurgically. In the BARI-2D trial, those patients with more DM2 AND CORONARY HEART DISEASE complex anatomy were more likely to undergo CABG, which DM2 and coronary artery disease was associated with a reduction in non-fatal MI in comparison Here there is little controversy. The Euro Heart Survey found with medical treatment. Likewise in the SYNTAX trial of that of patients with acute CAD, 36% had abnormal oral glucose patients with three-vessel disease, including left main CAD, tolerance tests (OGTT) and 22% newly detected diabetes.79 there was a clear benefit from CABG with a lower mortality and In those with stable CAD, the percentages were 37% and a markedly lower rate of repeat revascularisation among patients 14%. These glucose abnormalities detected by the OGTT with the most extensive and complex anatomical coronary were more closely linked to CAD than were fasting plasma disease.90 Thus both these trials deliver a clear message: in glucose or HbA1c.80 The practical difficulties in carrying out patients requiring intervention, the clinically ‘sicker' patients routine OGTT then led to a gluco-metabolic index based on with 3 vessel disease and more complex anatomical disease as fasting plasma glucose, HDL-C and age to stratify the risks of often found in diabetic subjects, are best served with CABG. The further cardiovascular events in patients with CAD.81 The other lesson to be learnt is that many patients with stable overall message is that the diagnosis of CAD carries with it an disease and mild to moderate symptoms can be managed obligation to search for underlying DM2. Furthermore, there is medically. The trial that needs to be done, now in the planning no question that those with DM2 and CAD must have glucose- phase, is to compare revascularisation with medical treatment in lowering treatment.82 Do all those with DM2 and no symptoms patients with stable disease and mild symptoms but severe of CAD need screening by myocardial perfusion imaging? The ‘ischaemia' on stress testing.
answer is ‘no', with the important caveat that this was a trial oflower-risk patients with specific inclusion and exclusion criteria.83 With so much changing, can we be dogmatic?This question applies to all of the controversies raised, perhaps Intervention in stable coronary artery disease especially to the tightness of glycaemic control. There are many Acute coronary syndrome and hyperglycaemia in acute MI have unresolved problems, all of which are currently in evolution: recently been reviewed,84 85 so that we are focusing on stable (a) the impact of primary and secondary prevention trials CAD. As is the case with views on non-diabetic subjects, the including very early glycaemic control; (b) the impact of ongoing management of patients with stable mild to moderate angina or trials of new surgical and percutaneous techniques; (c) the who are asymptomatic with positive stress tests remains selection of patients for coronary intervention; (d) new chal- a source of controversy and vigorous, often polarised, debate.
lenges introduced by the risks and benefits of such intervention The 5-year outcomes of the recent trial, Bypass Angioplasty in an increasingly older population with multiple comorbidities Revascularization Investigation in type 2 Diabetes (BARI-2D) and (e) the longer-term cardiovascular consequences and impact on 2368 patients with type 2 diabetes undergoing coronary of the diabetes pandemic.
angiography, support the conclusions of an earlier trial onpredominantly non-diabetic patients (33.5% diabetics).86 87These studies strongly suggest that in angiographically selected FUTURE CONTROVERSY: INCRETINS TO THE RESCUE? patients with chronic stable angina and preserved LV function Tight glycaemic control may bring in its wake complexity of there is no overall benefit from coronary revascularisation with treatment, hypoglycaemia, weight gain and increased costs, all Heart 2011;97:6e14. doi:10.1136/hrt.2010.214031 for benefits that may be certain. Is it now time for ‘an evidence- Acknowledgements The stimulus to this article was the 2010 meeting on based about-face' as argued in a provocative article from the Cardiology and Diabetes at the Limits in Cape Town, South Africa. However, theviews here expressed are those of the authors.
Mayo Clinic?52 We would agree. It is increasingly realised thathypoglycaemia is the major downside of tighter control that Competing interests None to declare.
offsets a relatively small cardiovascular mortality reduction.56 Provenance and peer review Not commissioned; externally peer reviewed.
Thus it would be logical to turn to agents such as the incretinswhich, in general, avoid hypoglycaemia and lead to loss rather than gain of weight and may directly protect the pancreas by Stevens RJ, Kothari V, Adler AI, et al. The UKPDS risk engine: a model for the risk of lessening apoptosis.91 Incretin mimetics, which are glucagon-like coronary heart disease in Type II diabetes (UKPDS 56). Clin Sci (Lond) peptide-1 receptor agonists, include exenatide and liraglutide, while incretin enhancers such as sitagliptin and vildagliptin are Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention ofcardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative inhibitors of the enzyme dipetidylpeptidase-4 that degrades Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled glucagon-like peptide-1. In obese patients with DM2, exenatide trial. Lancet 2004;364:685e96.
once weekly added to metformin over 26 weeks gave better Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-loweringtreatment: prospective meta-analysis of data from 90,056 participants in 14 control of glycaemia without any major hypoglycaemia and randomised trials of statins. Lancet 2005;366:1267e78.
with greater weight loss than with either sitagliptin or piogli- Hippisley-Cox J, Coupland C. Individualising the risks of statins in men and women tazone.92 The proportion of patients reaching a target HbA1c of in England and Wales: population-based cohort study. Heart 2010;96:939e47.
<7% from an initial mean of 8.5% was nearly 60%, significantly Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular eventsin men and women with elevated C-reactive protein. N Engl J Med more than with sitagliptin or pioglitazone.92 The downside was a greater incidence of nausea (24% with exenatide, 10% Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: with sitagliptin and only 5% with pioglitazone). Nonetheless, a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735e42.
Patel A, Barzi F, Jamrozik K, et al. Serum triglycerides as a risk factor for quality-of-life scores were equally high with exenatide and cardiovascular diseases in the Asia-Pacific region. Circulation 2004;110:2678e86.
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management of type 2 diabetes
Lionel H Opie, Derek M Yellon and Bernard J Gersh 2011 97: 6-14 originally published online November 23, 2010 Updated information and services can be found at: These include: This article cites 90 articles, 38 of which can be accessed free at: Article cited in: Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
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