Management of Type 2 Diabetes in Patients with Cardiac Risk Factors

“Effects of Intensive Glucose Lowering in Type 2 Diabetes” – The Action to Control Cardiovascular Risk in Diabetes Study Group, The New England Journal of Medicine, June 12, 2008

Introduction

Type 2 Diabetes is a disease well known to cause major secondary complications such as renal failure, blindness, amputations and cardiac disease. Control of diabetes is measured by control of blood sugar levels, and treatments, whether they include oral drugs or injected insulin, are aimed at maintaining blood sugar levels within a normal range of < 125 mg/dL. Improved blood glucose control correlates with fewer complications from diabetes. However, as discussed in previous inpatient studies (NICE-SUGAR), there are complications associated with over-controlling blood sugar levels, such as episodes of hypoglycemia, and the overall mortality was higher when blood sugars were strictly controlled in the Intensive Care Unit (ICU). However, before the ACCORD trial, there were conflicting data regarding the best targets to control type 2 diabetes as an outpatient.

Glycosylated hemoglobin, or hemoglobin A1c (HgbA1c), is a useful surrogate to measure the average blood sugar concentration over the previous 2-3 months. It has become the standard of measurement for diabetes control. However, the exact HgbA1c value to target was previously unknown. An average blood glucose of 125 mg/dL correlates with an HgbA1c of ~ 6%, but as expected with diabetic patients, these averages inherently include abnormal high and consequently abnormal low blood sugar episodes. In order to determine the best target for HgbA1c, the ACCORD trial tested whether patients receiving either an intensive blood sugar management regimen with a goal of 6.0% for all patients or a standard liberal schedule where sugars were maintained between 7.0 – 7.9% differ in terms of non-fatal myocardial infarctions, non-fatal strokes, deaths from cardiovascular causes and all-cause mortality. The study population was old and sick (40-79 years of age with cardiovascular disease or 55-79 years of age with precursor cardiovascular disease or multiple risk factors).

Results

The average HgbA1c of the patients in the study at the start was 8.1%. Patients in the intensive and liberal groups achieved and maintained HgbA1c’s of 6.4% and 7.5%, respectfully, after one year of the study. The trial was terminated 18 months prior to schedule due to increased all-cause mortality in the intensive therapy arm. This was a secondary outcome. There was an emerging decreased incidence of the composite primary outcome (non-fatal myocardial infarction, non-fatal stroke and death from cardiovascular causes) in the intensive therapy arm after three years, but this finding was not statistically significant. There was a significant decrease in non-fatal myocardial infarction but increase in death from cardiovascular causes in the intensive therapy arm.

Why We Do What We Do

Treatment of type 2 diabetes is essential to prevent or delay the numerous complications it is associated with. Cardiovascular causes are leading causes of morbidity and mortality in this population, but cannot be the only determinant for therapy. This study served to examine the risks and benefits of intensive glucose management with respect to cardiovascular disease in generally older and sicker patients. The results showed that intensive glucose management may have a benefit in long term cardiovascular outcomes, especially myocardial infarction, but was associated with increased all-cause and cardiovascular mortality in the first few years following initiation of intensive therapy.

The treatment goals for older patients with multiple risk factors are therefore more liberal in practice today, such as a HgbA1c of 7.5%. How this level is achieved, in terms of which drugs, insulin regimens or diet and exercise routines are used, is dependent on the physician and the patient, but treating to this goal avoids the immediate complications of low blood sugars and excessive pharmacotherapy. However, the additional results from this study also indicate that intensive therapy if tolerated over a longer term will start to show benefits in non-fatal cardiovascular outcomes. Therefore, a physician may choose to adjust targets along the course of a patient’s treatment once a tolerable regimen has been established. In studies of inpatient management of hyperglycemia, younger, healthier patients tolerated intensive therapy better and actually showed improved outcomes when compared with liberal approaches. Similarly, younger, healthier patients with type 2 diabetes may avoid the early complications and experience benefits from intensive glucose management. However, further study is necessary to confirm this.

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC,
Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S,
Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT.
Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun
12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6. PubMed PMID:
18539917.

Statins: Game Changers in CVD

In a recent post we had discussed the use of aspirin in the setting of an acute MI. Our second look at landmark trials examining the treatment of coronary vascular disease (CVD) focuses on primary prevention of CVD. Elevated cholesterol levels have long been implicated in the progression of CVD, and numerous medications have been developed to reduce plasma cholesterol levels as a means to reduce the incidence of myocardial infarctions and other cardiovascular events. In fact, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) revealed that the CVD risk reduction was proportional to the reduction in LDL cholesterol. Through the 1980s, fibrates and bile acid resins (cholestyramine) were in use, and studies from multiple institutions had demonstrated their ability to moderately reduce cholesterol levels. Used alone, neither cholestyramine nor the fibrates could achieve greater than a 10-15% reduction in LDL. The most promising development was the approval of HMG-CoA reductase inhibitors, otherwise known as statins. Several smaller studies suggested an improvement in plasma cholesterol levels and cardiovascular outcomes with statin therapy. The Scandinavian Simvastatin Survival Study (4S) assessed the effect of simvastatin on total mortality and cardiovascular outcomes and confidently addressed the question.

Between 1988 and 1994, 4444 patients between the ages of 35 and 70 were randomly assigned to receive various doses of simvastatin or placebo. Dosing was titrated to a specific serum cholesterol value; patients who were above this value received up to 40mg per day, and those below this value were titrated down. The study group was followed for an average of 5.4 years. The primary endpoint for 4S was total mortality – an important distinction since a few research trials with fibrates, including one from the WHO, had shown an increase in non-cardiovascular deaths. Randomization was successful in evenly dividing patients already on multiple medications for hypertension, angina and diabetes. A similar study conducted at the same time in Scotland, the WOSCOP study, was looking at the effect of pravastatin on primary prevention. While 4S was not as straightforward as WOSCOPS, it was far more generalizable in a number of ways. For one, it included women. Other aspects of the study that stand out are the broader age range, existing CVD or diabetes and a percentage of smokers closer to that of the US.

The data from 4S were impressive. Patients on simvastatin on average saw a 35% decrease in LDL cholesterol. More importantly, this decrease correlated with a relative risk of death of 0.70 when compared to placebo (182 vs 256 deaths). This reduction in deaths was attributable to a 42% decrease in cardiovascular mortality. Likewise, simvastatin also lead to a pronounced decrease in non-fatal cardiovascular events (RR 0.66). Adverse effects were few – 1 episode of rhabdomyolysis in the simvastatin group. Complaints of myalgias and elevations in LFTs were similar between placebo and simvastatin.

Prior to this study, the benefits of lipid-lowering therapy lacked a consensus. The 4S trial conclusively determined that statin therapy was a safe and more effective treatment choice in lowering serum LDL cholesterol than other lipid-lowering agents. Moreover, it provided the largest reduction in cardiovascular mortalities, and the benefit was witnessed in all age groups. Today many newer variations of statins exist but simvastatin continues to be the first line therapy for many of our patients.

 

The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994. 344:1383-1389.