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Diabetes and Cardiovascular Risk
How Should Diabetes Be Treated to
Minimize the Risk of Cardiovascular Complications?
Saul M Genuth, MD
Professor of Medicine, Division of Molecular and Clinical Endocrinology, School of Medicine, Case Western Reserve University
Abstract
Recognizing the great need to finally resolve the issue of whether lowering blood pressure with intensive treatment will decrease cardiovascular
disease (CVD) events in type 2 diabetes, three randomized clinical trials were recently completed. ACCORD, VADT, and ADVANCE all found no
significant benefit on primary CVD outcomes and ACCORD reported a 20% increase in total and CVD mortality with intensive treatment. A post-trial
observational study by the UKPDS finally noted a decrease of 15% in myocardial infarction and 13% decrease in total mortality over a follow-up of
25 years from the diagnosis of diabetes. The BARI 2D trial found no significant overall advantage of insulin-sensitizing over insulin-providing drugs in
these outcomes, although insulin-sensitizing augmented the benefit of coronary bypass surgery over medical therapy. Lowering blood pressure,
low-density lipoprotein cholesterol, triglycerides, excessive body fat, and tobacco intake and raising high-density lipoprotein cholesterol may simply
overwhelm the small additional benefit gained from reducing glycemia. Metformin has the largest body of evidence supporting its use for decreasing
CVD events while reducing glycemia, but uncertainty still surrounds thiazolidinediones.
Keywords
Type 2 diabetes, cardiovascular disease, clinical trials, hypoglycemic drugs, metformin, thiazolidinediones, diabetes duration, meta-analyses
Disclosure: The author has no conflicts of interest to declare.
Received: August 12, 2009 Accepted: November 9, 2009
Correspondence: Saul M Genuth, MD, Case Western Reserve University, Division of Clinical and Molecular Endocrinology, 10900 Euclid Ave, Cleveland, OH 44106-4951.
E: smg15@cwru.edu
Cardiovascular disease (CVD) and diabetes, especially type 2, are closely events. To make it a clinical dictum that physicians should work with
intertwined and growing health threats in the US and many other patients to lower blood glucose in order to prevent CVD complications
regions of the world.
1,2
Fully one-third of coronary artery disease (CAD) requires a convincing demonstration that this benefit will in fact ensue. To
is attributed to or at least accompanied by diabetes, and in turn it is prove that one blood glucose therapy is superior to others in this respect
responsible for 60–80% of mortality in type 2 diabetes.
3,4
Death from CAD requires equally rigorous randomized clinical trial evidence. This article
is markedly increased by diabetes in both men
5
and women.
6
examines recent major clinical trial evidence bearing on these issues. Has
the evidence satisfactorily answered the critical questions? If not, what
The cause and effect relationship between CVD and type 2 diabetes therapeutic guidance has it provided physicians who care for the
remains uncertain, but there is enough reason to think of CVD as a 24,000,000 patients with diabetes in the US and the many millions more
complication of diabetes. There have therefore been major efforts to elsewhere in the world?
determine whether better glycemic control would reduce the incidence of
CVD. If this were unequivocally shown to be the case, it would add Trials Comparing Effects of Intensive
enormously to the necessity for intensive treatment of hyperglycemia in versus Standard Glycemic Control on
most patients. Moreover, because the pathogenesis of hyperglycemia is Cardiovascular Disease Events
complex and as new drugs with novel mechanisms of action that target The DCCT-EDIC Study
various pathways leading to hyperglycemia appear, how best to lower The incidence of CVD in both types of diabetes is similar,
12
thus this
blood glucose from the CVD standpoint has become an increasingly landmark study in type 1 diabetes, which clearly incriminates
prominent question. There is considerable evidence from epidemiological hyperglycemia as a likely causative contributor to CVD, may be
studies that hyperglycemia, expressed as fasting plasma glucose,
7
post- applicable to type 2 diabetes as well. The DCCT was a randomized
glucose challenge plasma glucose,
7,8
or glycated hemoglobin (HbA
1c
),
9–11
is clinical trial conducted in 1,441 volunteers with type 1 diabetes with no
a risk factor for CVD. Even the strongest of these studies can only prove or minimal evidence of microvascular complications and 5.5 years of
an association and then infer that hyperglycemia causes atherosclerosis, diabetes at baseline.
13
Patients were randomly assigned to either
myocardial infarction (MI), strokes, and peripheral vascular obstructive intensive glycemic treatment targeted at HbA
1c
<6.0% or to continuation
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