Strategies for Optimizing Glycemic Control and Cardiovascular Prognosis in Patients With Type 2 Diabetes Mellitus
2011; Elsevier BV; Volume: 86; Issue: 2 Linguagem: Inglês
10.4065/mcp.2010.0434
ISSN1942-5546
AutoresJames H. O’Keefe, Mohammad Abuannadi, Carl J. Lavie, David S.H. Bell,
Tópico(s)Diet and metabolism studies
ResumoType 2 diabetes mellitus (DM) is a major cardiovascular (CV) risk factor and, as such, is considered a coronary artery disease risk equivalent. Although glycemic control is associated with decreased CV events epidemiologically, many prospective clinical trials have failed to conclusively demonstrate that aggressive glycemic control improves the CV prognosis of patients with type 2 DM, especially those with long-standing DM. Many therapies for type 2 DM with widely divergent mechanisms of action are available. Some of these drugs, in addition to their glucose-lowering actions, have properties that may reduce or increase CV events. Agents that lower both insulin resistance and postprandial hyperglycemia while at the same time avoiding hypoglycemia may be beneficial for CV health. This article reviews the evidence regarding the use of these agents and appropriate glycemic control targets for improving the adverse CV prognosis associated with type 2 DM. We conducted a systematic review of English articles using MEDLINE and the Cochrane Controlled Trials Register (1970-2010) using the following search terms: cardiovascular disease, randomized trials, hypoglycemia, and insulin resistance. Type 2 diabetes mellitus (DM) is a major cardiovascular (CV) risk factor and, as such, is considered a coronary artery disease risk equivalent. Although glycemic control is associated with decreased CV events epidemiologically, many prospective clinical trials have failed to conclusively demonstrate that aggressive glycemic control improves the CV prognosis of patients with type 2 DM, especially those with long-standing DM. Many therapies for type 2 DM with widely divergent mechanisms of action are available. Some of these drugs, in addition to their glucose-lowering actions, have properties that may reduce or increase CV events. Agents that lower both insulin resistance and postprandial hyperglycemia while at the same time avoiding hypoglycemia may be beneficial for CV health. This article reviews the evidence regarding the use of these agents and appropriate glycemic control targets for improving the adverse CV prognosis associated with type 2 DM. We conducted a systematic review of English articles using MEDLINE and the Cochrane Controlled Trials Register (1970-2010) using the following search terms: cardiovascular disease, randomized trials, hypoglycemia, and insulin resistance. The importance of abnormally elevated blood glucose as a cardiovascular (CV) risk factor is well established epidemiologically.1O'Keefe JH Abuannadi M Lavie CJ Role of oral agents in improving cardiovascular prognosis in diabetes mellitus [letter reply].Mayo Clin Proc. 2010; 85: 99-101Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 2Stratton IM Adler AI Neil HA et al.Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Scopus (6919) Google Scholar, 3Khaw KT Wareham N Bingham S Luben R Welch A Day N Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk.Ann Intern Med. 2004; 141: 413-420Crossref PubMed Scopus (845) Google Scholar, 4Elley CR Kenealy T Robinson E Drury PL Glycated haemoglobin and cardiovascular outcomes in people with type 2 diabetes: a large prospective cohort study.Diabet Med. 2008; 25: 1295-1301PubMed Google Scholar Glycated hemoglobin (HbA1c), a marker of long-term glycemic control, is directly associated with CV risk2Stratton IM Adler AI Neil HA et al.Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Scopus (6919) Google Scholar and all-cause mortality (Figure 1).3Khaw KT Wareham N Bingham S Luben R Welch A Day N Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk.Ann Intern Med. 2004; 141: 413-420Crossref PubMed Scopus (845) Google Scholar The UKPDS (United Kingdom Prospective Diabetes Study), a study of recent-onset diabetes, showed a 14% reduction in the risk of myocardial infarction (MI) for each 1% decrease in the mean level of HbA1c.2Stratton IM Adler AI Neil HA et al.Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Scopus (6919) Google Scholar Similarly, in a study of 48,444 patients with type 2 diabetes mellitus (DM) and without known CV disease, each 1% increase in the level of HbA1c during a period of 2.4 years was associated with an 8% increase in MI and a 9% increase in stroke.4Elley CR Kenealy T Robinson E Drury PL Glycated haemoglobin and cardiovascular outcomes in people with type 2 diabetes: a large prospective cohort study.Diabet Med. 2008; 25: 1295-1301PubMed Google Scholar The UKPDS randomized 3867 patients newly diagnosed as having DM to either intensive therapy (with either a sulfonylurea or insulin) or conventional therapy (predominantly diet alone).5UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354(9178):602].Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar The median achieved HbA1c value during the study was 7.0% for the intensive therapy group compared with 7.9% for the conventional group.6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar The intensive therapy group had a 25% lower risk of developing microvascular complications, which was primarily driven by a lower frequency of retinal photo-coagulation. A trend toward reduction of MI was noted in the intensive therapy group during 10 years of follow-up; however, it was not statistically significant.5UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354(9178):602].Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar In contrast, in another arm of the UKPDS trial in which obese patients with type 2 DM were randomized to either metformin or conventional therapy (primarily diet), a lower all-cause mortality was found with metformin therapy.7UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7473) Google Scholar A median HbA1c value of 7.4% was achieved in the group assigned to metformin vs an HbA1c value of 8.0% in the conventional therapy group.7UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7473) Google Scholar Compared with conventional therapy, metformin lowered diabetes-related death and all-cause mortality during a 10-year period in these patients with newly diagnosed type 2 DM.7UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7473) Google Scholar Although metformin was less effective at lowering HbA1c values than intensive therapy regimens with a sulfonylurea or insulin, it was associated with a lower risk of death and stroke (although not MI) and, importantly, a much lower risk of hypoglycemia (Figure 2).7UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7473) Google Scholar Yet, the UKPDS patients who received metformin as an add-on to maximum-dose sulfonylurea had an increased mortality rate, a controversial finding because this subgroup of patients was small.7UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7473) Google Scholar In the epidemiological 10-year UKPDS follow-up study, patients were monitored on an annual basis after the end of the intervention portion of the trial. Despite similar HbA1c levels in the 2 groups for the remainder of the follow-up study, the original intensive therapy group (insulin/sulfonylurea) had a 15% lower risk of an MI(P=.01), as well as a 13% decrease in all-cause mortality (P=.007), compared with the original conventional therapy group.8Holman 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: 1577-1589Crossref PubMed Scopus (5242) Google Scholar Again, despite similar HbA1c levels during the poststudy follow-up, MI decreased by 33% (P=.005) and all-cause mortality by 27% (P=.002) in the metformin group when compared with those originally receiving conventional therapy.8Holman 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: 1577-1589Crossref PubMed Scopus (5242) Google Scholar Similarly, the DCCT (the Diabetes Control and Complications Trial)/EDIC (Epidemiology of Diabetes Interventions and Complications) trial, which examined intensive vs conventional control using insulin therapy for patients with type 1 DM, showed evidence for a "metabolic memory." The intensively treated patients who had a lower HbA1c level during the 6.5-year study had significantly fewer events than the conventionally treated group during the 10-year posttrial period, despite similar HbA1c levels in the 2 groups during the decade after the trial ended.9Albers JW Herman WH Pop-Busui R et al.Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study.Diabetes Care. 2010; 33: 1090-1096Crossref PubMed Scopus (276) Google Scholar In contrast to UKPDS, 3 recent large randomized trials have shown no reduction in CV events with aggressive vs more conservative glucose control in patients with type 2 DM, possibly because of a longer mean duration of type 2 DM and a shorter duration of follow-up than in the UKPDS trial.6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar, 10Duckworth 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 (3866) Google Scholar, 11Patel A MacMahon S Chalmers J et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar Indeed, after 3.5 years, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial showed significantly higher all-cause mortality in type 2 DM patients randomized to intensive glycemic control as compared with conventional control; as a result, the glycemic control portion of ACCORD was stopped prematurely.6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar Yet, on detailed scrutiny of the data, higher HbA1c values predicted increased risk of death in the intensive arm of the ACCORD trial, in which most of the deaths occurred in the subgroup of patients whose HbA1c values remained high despite attempted intensive glycemic control.12Riddle MC Ambrosius WT Brillon DJ et al.Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial.Diabetes Care. 2010; 33: 983-990Crossref PubMed Scopus (353) Google Scholar Moreover, in the subgroup of patients without documented CV disease at baseline, a subanalysis suggested that intensive glycemic control was associated with a reduced risk of CV death and nonfatal CV events.6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar The Veterans Affairs Diabetes Trial (VADT), which compared intensive and standard treatment strategies in patients with type 2 DM, did not show a statistically significant difference in the incidence of major CV events after a median follow-up of 5.6 years.10Duckworth 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 (3866) Google Scholar In this study, the intensive control group achieved an HbA1c of 6.9% compared with 8.4% in the standard control group.10Duckworth 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 (3866) Google Scholar Not surprisingly, 8.5% of the patients in the intensive therapy group were reported to have had at least 1 episode of hypoglycemia vs 3.1% in the standard therapy group.10Duckworth 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 (3866) Google Scholar In a substudy of VADT, patients without significant coronary atherosclerosis (as documented by a coronary artery calcium score of <100) experienced a decrease in CV events with intensive vs conservative therapy.13Piarulli F Sartore G Ceriello A et al.Relationship between glyco-oxidation, antioxidant status and microalbuminuria in type 2 diabetic patients.Diabetologia. 2009; 52: 1419-1425Crossref PubMed Scopus (46) Google Scholar Although certainly not definitive, these findings from VADT and ACCORD suggest that intensive glucose control may reduce CV events in patients with a shorter duration of DM and in those who do not have significant preexisting CAD.7UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7473) Google Scholar, 14Reaven PD Moritz TE Schwenke DC et al.Intensive glucose-lowering therapy reduces cardiovascular disease events in Veterans Affairs Diabetes Trial participants with lower calcified coronary atherosclerosis.Diabetes. 2009; 58: 2642-2648Crossref PubMed Scopus (147) Google Scholar After a median follow-up of 5 years, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial showed no difference between intensive control and standard control groups in macrovascular outcomes.13Piarulli F Sartore G Ceriello A et al.Relationship between glyco-oxidation, antioxidant status and microalbuminuria in type 2 diabetic patients.Diabetologia. 2009; 52: 1419-1425Crossref PubMed Scopus (46) Google Scholar, 14Reaven PD Moritz TE Schwenke DC et al.Intensive glucose-lowering therapy reduces cardiovascular disease events in Veterans Affairs Diabetes Trial participants with lower calcified coronary atherosclerosis.Diabetes. 2009; 58: 2642-2648Crossref PubMed Scopus (147) Google Scholar, 15Gerstein HC Mann JF Yi Q et al.Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.JAMA. 2001; 286: 421-426Crossref PubMed Scopus (2052) Google Scholar Mean HbA1c values achieved in the ADVANCE study were 6.5% in the intensive control group and 7.3% in the standard control group.11Patel A MacMahon S Chalmers J et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar Similar to ACCORD and VADT, the rate of combined primary end point (composite of microvascular and macrovascular events) was significantly lower with intensive vs conservative glucose control among patients who did not have established CV disease at baseline. Compared with the UKPDS, the ACCORD, ADVANCE, and VADT trials were of shorter duration, and the patients were older, had a longer duration of type 2 DM (8-10 years), and had more established CV disease at baseline. The benefits of early and intensive glycemic control may accrue only after several years, which may be why trials of longer duration, such as UKPDS, EDIC,12Riddle MC Ambrosius WT Brillon DJ et al.Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial.Diabetes Care. 2010; 33: 983-990Crossref PubMed Scopus (353) Google Scholar and STENO-2,16Gaede 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: 383-393Crossref PubMed Scopus (3813) Google Scholar show stronger benefits with aggressive management of hyperglycemia than do trials of shorter duration. Likely because of a lesser availability of therapies for type 2 DM at that time, the HbA1c levels achieved in the intensive treatment arm at the end of the UKPDS were higher than those achieved in the intensive therapy arms of the other 3 trials.5UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354(9178):602].Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar, 10Duckworth 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 (3866) Google Scholar, 11Patel A MacMahon S Chalmers J et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar A recent meta-analysis by Mannucci et al17Mannucci E Monami M Lamanna C Gori F Marchionni N Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials.Nutr Metab Cardiovasc Dis. 2009; 19: 604-612Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar examined the effects of intensive glycemic control on CV outcomes in pooled data from UKPDS, ACCORD, ADVANCE, and VADT, in addition to the PROACTIVE (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study. This meta-analysis showed that an overall decrease in HbA1c values of 0.9% resulted in modest reduction in the risk of CV events and MI in the intensive therapy groups (for CV events: odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83-0.95; for MI: OR, 0.86; 95% CI, 0.78-0.93) but no significant reductions in all-cause or CV mortality or stroke. In a similar meta-analysis, Ray et al18Ray KK Seshasai SR Wijesuriya S et al.Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1765-1772Abstract Full Text Full Text PDF PubMed Scopus (1136) Google Scholar showed a 17% reduction in nonfatal MI in the intensive vs conservative control groups that was not accompanied by a significant difference in mortality. A recent retrospective cohort study from the UK General Practice Research Database examined survival in 47,970 patients with type 2 DM who were advanced from oral monotherapy to combination oral therapy with a sulfonylurea and metformin or to an insulin-based regimen. This study showed that an HbA1c value of 7.5% was associated with the lowest mortality.19Currie CJ Peters JR Tynan A et al.Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (706) Google Scholar The cumulative data from these studies suggest that the potential for benefit or harm from intensive therapy may be determined by the presence or absence of significant atherosclerosis at the time of therapy initiation5UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354(9178):602].Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar, 10Duckworth 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 (3866) Google Scholar, 11Patel A MacMahon S Chalmers J et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar and that a less aggressive approach, with an HbA1c target of 7.0% to 7.5%, appears to be the preferred strategy for patients with limited life expectancy and/or those with established CV disease or long-standing type 2 DM (who generally also have significant coronary atherosclerosis). In contrast, patients who are younger with a shorter duration of type 2 DM and no established CV disease may be better candidates for more intensive glycemic control. Hypoglycemia is a common problem in patients with type 2 DM who need to be treated with insulin or sulfonylureas, and hypoglycemia occurred more frequently in the intensive therapy arms of the ACCORD, ADVANCE, VADT, and UKPDS trials.5UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354(9178):602].Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 6Gerstein HC Miller ME Byington RP et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6455) Google Scholar, 10Duckworth 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 (3866) Google Scholar, 11Patel A MacMahon S Chalmers J et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5944) Google Scholar Hypoglycemia, especially when severe, is a powerful stimulant of the sympathetic nervous system, which in turn may trigger adverse CV events, such as cardiac arrhythmias, sudden cardiac arrest, and acute MI.20Curtis BM O'Keefe Jr, JH Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.Mayo Clin Proc. 2002; 77: 45-54Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 21DeRosa MA Cryer PE Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation.Am J Physiol Endocrinol Metab. 2004; 287: E2-E41Crossref Scopus (91) Google Scholar Prolongation of the QT interval, ventricular arrhythmias, and impaired autonomic function are also associated with hypoglycemic episodes.20Curtis BM O'Keefe Jr, JH Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.Mayo Clin Proc. 2002; 77: 45-54Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 21DeRosa MA Cryer PE Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation.Am J Physiol Endocrinol Metab. 2004; 287: E2-E41Crossref Scopus (91) Google Scholar, 22Marques JL George E Peacey SR et al.Altered ventricular repolarization during hypoglycaemia in patients with diabetes.Diabet Med. 1997; 14: 648-654Crossref PubMed Scopus (225) Google Scholar, 23Adler GK Bonyhay I Failing H Waring E Dotson S Freeman R Antecedent hypoglycemia impairs autonomic cardiovascular function: implications for rigorous glycemic control.Diabetes. 2009; 58: 360-366Crossref PubMed Scopus (167) Google Scholar Hypoglycemia is also proinflammatory and can increase the risk of plaque inflammation, rupture, and CV events.24Dotson S Freeman R Failing HJ Adler GK Hypoglycemia increases serum interleukin-6 levels in healthy men and women.Diabetes Care. 2008; 31: 1222-1223Crossref PubMed Scopus (61) Google Scholar, 25Packard RR Libby P Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction.Clin Chem. 2008; 54: 24-38Crossref PubMed Scopus (764) Google Scholar In their meta-analysis of glycemic control and CV events, Mannucci et al17Mannucci E Monami M Lamanna C Gori F Marchionni N Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials.Nutr Metab Cardiovasc Dis. 2009; 19: 604-612Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar suggested an association between CV death in the intensive therapy arms and severe hypoglycemia. Moreover, a recent case control study showedthat, when compared with a control group, patients with type 2 DM with a first MI were more likely to have had a major hypoglycemic episode within the previous year, especially within the 2-week period before the MI.26Miller DR, Fincke G, Lafrance JP, et al. Hypoglycaemia and risk of myocardial infarction in U.S. veterans with diabetes [abstract]. Presented at: European Association for the Study of Diabetes 45th Annual Meeting; Vienna, Austria; September 29, 2009-October 2, 2009.Google Scholar Although speculative, the CV toxicity caused by recurrent or severe hypoglycemia induced by an aggressive glycemic control strategy (particularly with insulin or sulfonylureas) may supersede the CV benefits of improved glycemic control. This may be particularly true for those who have a predisposition to adverse CV events, such as persons with significant atherosclerosis and/or structural heart disease, such as left ventricular (LV) hypertrophy or systolic and/or diastolic dysfunction. Thus, it is not surprising that patients with long-standing type 2 DM (with its associations with atherosclerosis and myocardial structural and functional abnormalities) and/or existing CV disease may be more susceptible to the cardiotoxicity induced by hypoglycemia. Another possible reason for the failure of glucose-lowering strategies to improve CV prognosis is the use of glucose-lowering therapies that are directed more to the lowering of fasting and preprandial glucose levels than to the lowering of postprandial glucose levels. Postprandial hyperglycemia has been shown to be associated with an increased risk of CV events in patients with and without type 2 DM.27Cavalot F Petrelli A Traversa M et al.Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study.J Clin Endocrinol Metab. 2006; 91: 813-819Crossref PubMed Scopus (471) Google Scholar, 28O'Keefe JH Gheewala NM O'Keefe JO Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health.J Am Coll Cardiol. 2008; 51: 249-255Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 29Bell DS O'Keefe JH Jellinger P Postprandial dysmetabolism: the missing link between diabetes and cardiovascular events?.Endocr Pract. 2008; 14: 112-124Crossref PubMed Scopus (64) Google Scholar, 30O'Keefe JH Bell DS Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor.Am J Cardiol. 2007; 100: 899-904Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar Postprandial glucose excursions, especially when accompanied by increased postprandial triglyceride levels, are pathophysiologically linked to increased oxidative stress, systemic inflammation, and endothelial dysfunction, all of which are related to increases in atherosclerosis and CV events.31Monnier 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 (1847) Google Scholar, 32Ceriello A Quagliaro L Piconi L et al
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