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Why Focusing On Intensive Glucose Control With Drugs Alone Is Counterproductive

May 4, 2002

Current Drug Practices

At a recent diabetes conference, a speaker lamented that diabetes is an epidemic spiraling out of control, and therefore we need new and better drugs. Think for a moment at how illogical is this line of reasoning. Diabetes is not a drug deficiency nor is heart disease due to a deficiency in statin agents. Granted rates of diabetes and CHD are rising but shouldn’t we focus on the reason rather than simply promoting more drugs? Realize that the fifth leading cause of death in the United States is prescription drugs taken as the doctor intended-more than 100,000 deaths per year.213 Lest you think you can simply prescribe medication with impunity rather than implement lifestyle changes-consider the following.


Hypoglycemic Agents

Standing before nearly 2,000 applauding diabetologists at the 1994 Annual European Association for the Study of Diabetes (EASD) Meeting, Thomas Chalmers proclaimed that, according to his opinion, the use of oral antidiabetic agents, outside randomized controlled trials, is unethical214. To this date none of the thousands of scientific studies and publications of pharmacologic interventions in diabetes have documented a benefit in the outcomes that truly matter. These are the prevention or improvement of macrovascular disease and the related complications of CHD events, strokes, limb amputations, and premature deaths214.

Each antidiabetic oral agent has untoward side-effects. Insulin itself is associated with exacerbating insulin resistance, increasing weight gain, and deteriorating lipid and coagulation profiles associated with worsening CHD risk.215-227 According to a retrospective population-based cohort study from an independent research organization, patients with type 2 diabetes treated with glitazone antidiabetic drugs (troglitazone, rosiglitazone, and pioglitazone) appear to be at greater risk of heart failure independent of age and other risk factors. After a mean follow-up of 8.5 months, patients receiving glitazones had a 4.5% risk of heart failure compared with 2.6% in controls.228

The most commonly prescribed branded diabetes medication in the United States is metformin. A recent retrospective chart review suggests that 25 percent of the time, metformin was prescribed to patients who had one or more absolute labeled contraindications (including renal dysfunction and CHF). 229

While hypoglycemia was the chief adverse event associated with intensive therapy in the Diabetes Control and Complications Trial DCCT, weight gain was also a problem.230 At five years, patients receiving intensive therapy had gained a mean of 4.6 kg more than patients receiving conventional therapy 230. The UKPDS findings show that a mean weight gain between 1 and 9 years after randomization of patients into treatment groups was 5 kg for patients on a sulfonylurea, 7 kg for patients on insulin, and 1 kg for those on metformin or diet alone231. In a similar study looking at the effect after six months of intensive insulin therapy in type 2 diabetes, Henry et al showed an average weight gain of 9.3 percent of the patient’s pretreatment body weight.232.

Antihypertensive Agents

Lowering BP with drugs has not been proven to prevent MIs and may exacerbate insulin resistance

Although high BP is a strong risk factor for MI, lowering BP with medications has not been shown to lower the risk. This concept is highlighted by the Hypertension Optimal Treatment (HOT) Study. In the HOT study there was no difference in the risk for MI whether a patient had a diastolic BP of 105 or 75, and they basically had the same risk whether they had a systolic BP of 170 or 120.233

As a group, patients with hypertension have the insulin resistance syndrome also known as syndrome X or the metabolic syndrome. According to DeFronzo, normalizing BP in hypertensives has never been shown to prevent MIs. “This paradox may be explained by the failure of antihypertensive therapy to reverse the basic underlying metabolic problem: insulin resistance with its compensatory hyperinsulinemia. In fact, most anti-hypertensive regimens exacerbate the existing insulin resistance /hyperinsulinemia and promote a more atherogenic plasma lipid profile. This is particularly true of beta adrenergic antagonists and diuretics.”234 Simply stated, because some BP-lowering drugs such as some beta blockers worsen endothelial dysfunction, insulin resistance, and elevate insulin levels,235 they may not protect against MIs long term.

Increased risk of diabetes with anti-hypertensives

Sowers et al followed 12,550 adults ages 45 to 64 and found that the risk of diabetes is 28 percent greater among patients receiving beta blockers than among those whose hypertension is untreated. The authors recommended against abandoning beta blockers, arguing that these drugs are proven to lower the risk of CHD. 236 Likewise an accompanying editorial concluded “…beta blockers will continue to have an important therapeutic role in patients with hypertension who have known coronary artery disease and in hypertensive patients who have diabetes, a population in which the prevalence of underlying coronary artery disease is high.” Does this seem logical? Would you willingly take a drug that increases risk for developing diabetes by almost 30 percent when other drugs or perhaps even dietary approaches may be effective and safer? In a number of studies, beta blocker use was consistently associated with lower HDL levels,237which is associated with endothelial dysfunction and CHD risk.

Antihypertensive drugs may increase morbidity and mortality in patients with diabetes

For treating hypertension, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure encourages prescribing thiazide diuretics and beta blocker medication because they effectively lower BP and relatively inexpensive. Yet these agents increase insulin resistance, insulin secretion238, and may increase mortality. In a study of 759 diabetic patients at the Joslin Clinic treated with thiazide diuretics, mortality from CHD increased nearly four-fold239. Similar results occurred in the Wisconsin Epidemiologic Study of Diabetic Retinopathy,240 while elderly hypertensive patients in Finland who were treated with thiazide diuretics and/or beta blockers had twice the risk for developing diabetes than did other hypertensive subjects not receiving these agents.241 These effects were similar whether the subjects had impaired or normal glucose tolerance at baseline.

Other studies also suggest that subjects on beta-blockers and/or thiazides have an increased risk of diabetes. The recent UKPDS showed those given atenolol gained more weight and had a greater increase in glycated hemoglobin concentrations (HGA1C).242 Yet, clinicians are falsely reassured when they see blood pressure reduced despite the worsening of endothelial function and insulin resistance. Likewise are they reassured when HgbA1C is lowered despite the concomitant deterioration of coagulation profiles and increased risk of a coronary event and death. 215, 217

Anthypertensives may increase CHD risk in non-diabetics

In a trial from the Copenhagen Male Study, 2,906 men were followed for eight years. In the men who had an elevated TG:HDL ratio, a common feature of the metabolic syndrome, their risk for MI was not related to BP level. What is perhaps most eye-catching is when the hypertensive men with high TG:HDL were treated with standard BP-lowering medications, they had the highest risk of MI! 243 It didn’t matter whether they used beta blockers, diuretics, calcium channel blockers, or any combination-67 percent used diuretics alone or in combination, and 6 percent used other forms of antihypertensive medication including calcium channel blockers. The authors raise the question, “Could it be possible that this observation (more MIs) was due to severe hypertension being treated with drugs that raise TG and lower HDL cholesterol?”243 They further suggest that in patients who have high BP and high TG:HDL, it may be more important to normalize TG:HDL and other components of syndrome X than to normalize BP. As with focusing on lowering blood glucose in diabetes, the point is to treat the problem-insulin resistance/endothelial dysfunction-and not one result of it—blood pressure.

The effects of different antihypertensive drugs on endothelial function can vary. 244, 245Cardiovascular drugs that affect the lipid profile include diuretics, alpha and beta-blocking agents and, in some instances, angiotensin converting enzyme (ACE) inhibitors.237Thiazide and loop diuretics increase serum total cholesterol and LDL levels by up to 5 to 10 percent and triglyceride levels by 5 to 15 percent which increase with higher drug dosages. While the effects of beta blockers on LDL are negligible, they increase triglycerides levels 10 to 40 percent and decrease HDL levels 5 to 20 percent.237 In patients with type 2 diabetes, ACE inhibitors may increase triglycerides levels. Also in these patients an increase in total cholesterol and LDL levels (5 and 7 percent, respectively) has been observed after ACE inhibitor therapy, although this has been suggested to be possibly due to declining albuminuria237, 246

Non-Drug Alternatives for hypertension

Changing to a “healthy” diet balanced in calories balanced with expenditure to maintain or achieve optimal body weight; low in salt; high in fruits, vegetables, legumes, and increases, in modest levels of physical activity (walking, etc.) would be expected to reduce blood pressure by between 2 and 4 mm Hg. This could have a substantial impact on population mortality patterns. 247 Significant reduction in blood pressure can be achieved and maintained for up to 16 hours in hypertensive patients after a single, 45-minute exercise session (70% VO2 max treadmill). 248

The Dietary Approaches to Stop Hypertension or DASH diet was studied at multiple centers. The DASH diet, which, by comparison to the typical American diet, emphasizes fruits, vegetables, and low fat dairy foods, includes whole grains, poultry, fish, and nuts, and is reduced in fats, red meat, sweets, and sugar-containing beverages. This balanced diet alone has been shown to modestly lower blood pressure249-251Hypertensive patients were able to halve their dose of antihypertensive medication by switching to a diet high in MUFA-rich olive oil.252 In addition to the MUFA, the extra-virgin olive oil consumed contains polyphenols, which are anti-oxidant compounds that may help endothelial cells dilate blood vessels thereby reducing blood pressure.

Supplementing with fish oil in hypertensive patients with and without diabetes has been shown to significantly lower their blood pressure (158.7/80.8 to 146/72.9 and from 157.6/83.2 to 141.9/75.6, respectively). The fish oil also dramatically reduced triglycerides levels from 159.2 to 108.0 and 208.7 to 153.1, respectively.253

Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-1997). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject.


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