Is it to lower blood sugar? It is just plain “common sense,” right? The pervading logic of Type 2 diabetes treatment is that since it is an issue of high blood sugar, then the lower the blood sugar, the better is the patient. But is that all? Is there a higher purpose as to why the blood sugar should be controlled?
To know the answer to this issue, let us look at several studies involving thousands of diabetics that compared two treatments. Aggressive versus standard. The intensive treatment group was given a higher dose of medicines to achieve lower glycosylated hemoglobin (HbA1c) values, which is a measure of diabetes control the previous 3 months.
ACCORD STUDY
The Action to Control Cardiovascular Risk in Diabetes Study Group was published in 2008. ACCORD is a well-designed study involving 10,251 diabetic patients. The patients were randomized to eliminate bias, and one group had intensive control of their blood sugar and glycosylated hemoglobin or HbA1c for monitoring. The medications used were metformin, glimepiride, glyburide, gliclazide, rosiglitazone or pioglitazone, acarbose, and exenatide, repaglinide, or nateglinide, and insulin. All the groups were equally compared.
The study had to be halted after 3.5 years because of the increase in cardiovascular mortality in the group that is being treated more aggressively. The study concluded:
As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes
I don’t think the ACCORD study is a bust. I believe it is successful because it brings out scientific truth. By now, you can see that lowering blood sugar is not the primary goal of diabetes treatment, but the reduction in cardiovascular morbidity and mortality is the most important goal.
The ACCORD was followed by other studies with the same objective. To assess and compare the cardiovascular outcome in diabetes patients who received aggressive treatment to lower their blood sugar and standard regimen.
The authors of the VADT study compared the results of their research with the ACCORD and ADVANCE studies and wrote:
Our study, along with the ADVANCE and ACCORD studies, examined different populations with different approaches and came to similar conclusions. Intensive glucose control did not reduce cardiovascular events in patients with previously diagnosed type 2 diabetes.
The Intensive glucose control and macrovascular outcomes in type 2 diabetes is a meta-analysis. It combined the results of the ACCORD, ADVANCE, VADT, and the UKPDS study. A meta-analysis is a better study because it has a bigger sample size that may correct for any biases or errors in one research. A total of 27,049 participants and 2,370 vascular events were obtained. The result has confirmed the results of the previous studies in that the more intensive group had higher all-cause mortality, higher cardiovascular mortality, and higher non-cardiovascular mortality.
While the studies presented, do not support the initial thesis showed that the lower the blood sugar, the better for the diabetics. These studies have value because it changes our expectations with regards to diabetes treatment. It is not all about the blood sugar. Still, a reduction in the final outcomes which are the number of macrovascular events like myocardial infarction, stroke, deaths from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene are the ones that matter the most.
How can Aggressive Diabetes treatment lead to Cardiovascular Disease?
Skeletal muscle tissue is the biggest organ that can absorb blood glucose. In a state of insulin resistance, the usual amount of insulin secreted by the pancreas is not enough; that is why the pancreas secretes more insulin that leads to hyperinsulinemia.
Medications like the sulfonylureas (glyburide, glimepiride, gliclazide, and others) stimulate the cells of the pancreas to secrete more insulin. Sulfonylureas lower blood glucose but make Type 2 diabetes worse by contributing to the already existing hyperinsulinemia. Prescription insulin also raises insulin levels.
Hyperinsulinemia makes the cardiovascular disease worse by:
- Sodium and water retention contributes to hypertension
- High insulin constricts the blood vessels adding to hypertension
- Promoting growth and proliferation of the cells around the blood vessels making the lumen smaller and increased vascular resistance and work of the heart.
- Promotes the build-up of the atherosclerotic plaque
- Increasing triglyceride and VLDL synthesis that thickens the atherosclerotic plaque
- Increasing cholesterol deposits in the arteries.
- Promoting clot formation.
- Decrease heart function (cardiomyopathy) and diastolic dysfunction
- The increase in body weight/mass secondary to insulin increases the work of the inefficient heart.
- Increasing the work and oxygen demand of the heart, coupled with a decrease in the blood supply from diseased coronaries, increase the risk for a heart attack.
Take-Home Message
Diabetes management is not all about blood sugar control, but it should also address insulin resistance and hyperinsulinemia, which are the main drivers of Type 2 or Adult-onset diabetes.
The goal of diabetes management is to decrease the risk of cardiovascular disease.
Do not stop taking your diabetes medications, especially the sulfonylureas and insulin, without talking to your doctor first. Stopping them can lead to very high blood sugar, which is dangerous and life-threatening. Ask your doctor about other alternatives for diabetes medications.
Related Readings:
- What is Insulin Resistance?
- Hyperinsulinemia
- What is the Goal of Diabetes Treatment?
- I’m Only Pre-Diabetic, So I’m Still OK, Right?
- Prescriptions that Promote and Pharmaceuticals that Prevent Ischemic Preconditioning – Taking Sulfonylureas increases cardiac mortality
- Nitric Oxide in Medicine
- Reactive Oxygen Species
- How Diabetes Destroys the Body
References:
- Gerstein et al., Effects of Intensive Glucose Lowering in Type 2 Diabetes, The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358:2545-2559
DOI: 10.1056/NEJMoa0802743 - Burchfiel et al., Hyperinsulinemia, and cardiovascular disease in elderly men: the Honolulu Heart Program. Arterioscler Thromb Vasc Biol. 1998 Mar;18(3):450-7.
- Duckworth et al., Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med 2009; 360:129-139 DOI: 10.1056/NEJMoa0808431
- Lakka H, Lakka TA, Tuomilehto J, Sivenius J, Salonen JT. Hyperinsulinemia and the Risk of Cardiovascular Death and Acute Coronary and Cerebrovascular Events in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Arch Intern Med. 2000;160(8):1160–1168. doi:10.1001/archinte.160.8.1160
- The ADVANCE Collaborative Group., Intensive Blood Glucose Control, and Vascular Outcomes in Patients with Type 2 Diabetes., N Engl J Med 2008; 358:2560-2572
DOI: 10.1056/NEJMoa0802987 - Turnbull, F.M., Abraira, C., Anderson, R.J. et al. Diabetologia (2009) 52: 2288. https://doi.org/10.1007/s00125-009-1470-0. Intensive glucose control and macrovascular outcomes in type 2 diabetes.
- Image Credits:
Diabetes Symptoms by Häggström, Mikael (2014). “Medical gallery of Mikael Häggström 2014“. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.
Youtube Sources:
MedPage Today., ADA: ACCORD Diabetes Trial a Complete Bust
Medvidblog., Understanding the ACCORD, ADVANCE, and VA Trials
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