The Doctor Weighs In

William Bestermann, MD

The intensive glucose lowering arm of the ACCORD trial was just shut down because of an increased number of deaths in that portion of the study.  That finding has created a great deal of confusion on the long-held belief that aggressive treatment of blood sugar should protect patients from vascular events and death.  That belief, like many that prevailed in the practice of medicine, made perfect sense.  Virtually all of the bad things that happen to diabetics are the result of vascular disease.  Blindness, kidney failure, and nerve injury are the result of small vessel disease.  Heart attack, stroke and amputation are the result of large vessel disease.  For a long time, we have known that lower sugar reduces the damage to small vessels.  Very aggressive care should therefore lower heart attacks and strokes due to large vessel disease.

Glucose lowering-per se-does not prevent heart attack, stroke, or death.  I think the ACCORD trial did establish that fact, but this finding is now commonplace in vascular medicine.  Let not your heart be troubled.  There is a place for aggressive glucose control in optimal medical therapy for disease of the large vessels.  We have learned that certain drugs lower the risk factor, but do not protect the patient from events or death.  ACCORD is no different.  Treating hypertension  prevents heart attack and stroke.  Alpha blockers lower blood pressure.  Alpha blockers are inferior to other treatments in preventing events.  Rosiglitazone lowers blood sugar.  Rosiglitazone is associated with increased cardiovascular events.  The very first trial that looked at glucose lowering using tolbutamide was shut down early because of an increased death rate.  For decades estrogen was prescribed for its cardioprotective effects.  That practice ended when a controlled clinical trial showed that estrogens combined with progesterone were associated with increased numbers of heart attacks.  We have known for decades that higher HDL lowers vascular risk-yet a clinical trial for a medication that dramatically raised HDL had to be shut down because of increased events.  In fact, our whole system functions as if bypass surgery and angioplasty are the ultimate answer in heart attack prevention.  These treatments do nothing to prevent heart attack in the stable patient.  There is therefore, a long list of treatments that make sense but when subjected to clinical trials offer no benefit or actually cause harm.

The ACCORD trial was not a vascular trial but a sugar trial.  The trial was designed to test the hypothesis that lowering the sugar, taking precedence above all other considerations would lower events.  The interventions section from the ACCORD protocol states: “Both the intensive and the standard therapy groups will utilize all currently available glucose-lowering therapies.  The two treatment groups will have different glycemic targets and will have different thresholds of glycemic control at which therapeutic changes will be considered.

To achieve these glycemic targets, participants  will require self-management education and dietary and lifestyle interventions, as well as pharmacologic therapy.  They will also require different drug choices and treatment intensities.  For example, within 6 months of randomization, most intensive group participants will likely be on 3 or more injections of insulin a day in addition to two or 3 oral agents.  Conversely, standard therapy participants are less likely to be on insulin, will be on less than or equal to 2 injections per day if insulin is used, and will be taking fewer oral agents.  Moreover, the frequency with which self-management behavior is applied and participants are contacted will vary between the two levels of glycemic control.”  Later, in the Dietary and Lifestyle Interventions section there is the following guidance for investigators: “All participants will be provided with the same dietary and lifestyle recommendations to optimize their glucose control.  These will include : a) advice that blood glucose control may be more critical than weight control in reducing the risk of complications of diabetes.”
The investigators could use metformin, thiazolidinediones (TZDs), insulins, sulfonylureas, exanatide, and acarbose.  

There have been serious questions raised in the past about the adverse effects of certain drugs for diabetes on vascular events and survival.  These questions have been raised for rosiglitazone and sulfonylureas.  Diabetes is itself a weight-related illness.  Most type 2 diabetics have blood pressure and cholesterol problems that are both made worse by increased weight.  All diabetic treatments except for metformin, exanatide, and acarbose are associated with weight gain.  If you compare twice daily insulin with metformin and a single long-acting insulin shot, the metformin-insulin people gain no weight and the twice daily insulin patients gain an average of 10 pounds in one year.  This is no small matter in a weight-driven illness.  The ACCORD trial allowed a number of medical interventions that would be expected to produce weight gain.

On the very same day that the intensive glucose-lowering arm of ACCORD was shut down, the Steno-2 investigators reported their 13 year follow-up for aggressive treatment of high-risk type 2 diabetic patients.  They found that early intensive intervention with multiple drug combinations and behavior modification leads to reduced rates of death and cardiovascular disorders.  There was a 20% absolute risk reduction in the primary end-point of  all-cause mortality.  There was also a 13% absolute risk reduction for cardiovascular death.   In Steno-2, cholesterol, hypertension, glucose were all treated in an intensive and structured way.  The conservatively treated patients in the Steno-2 trial had a 50% death rate over 13 years-a shocking mortality rate.

The big difference in the glucose management compared with ACCORD was that Steno-2 provided an evidence-based protocol consistent with best practice.  Overweight diabetics in Steno 2 were given metformin.  Gliclazide was added to the medical therapy of obese patients who did not achieve goal glucose reduction.  If the glicazide-metformin combination did not result in reduction of A1c to 7.0, then gliclazide was dropped and long-acting insulin added to the metformin.  This is a critical difference.

The insulin-metformin regimen does not cause weight gain.  Metformin is the only diabetic drug with powerful evidence of reduction of incidence of myocardial infarction (39%) and all cause mortality (42%) compared with diet and exercise.  Pioglitazone has some evidence of a less potent effect in this regard.  If metformin fails, it is because the patient is not making enough insulin and so simply replacing the insulin that the patient cannot make should result in preservation of the protective effects of metformin regarding heart attack and death.  Steno 2 seems to bear that out.

Metformin is a drug that has powerful vascular effects on a par with a statin or ACE inhibitor.  Metformin is associated with modest weight loss, decreased total cholesterol, decreased triglycerides, decreased LDL cholesterol, improved endothelial function (increased ability of the artery to dilate) and positive effects on the increased tendency to clot formation found in diabetics.  Metformin cuts to the center of the metabolic syndrome and diabetes by upregulating AMPK-its only site of action.  A study abstract that has just been published by David Lefer’s group shows that a single dose of metformin reduces myocardial infarction size in lab animals by 50% by upregulating AMPK and nitric oxide activity.  A single dose of statin does the same thing.  These are powerful effects.  The National Registry of Myocardial Infarction showed that  the patient entering an emergency room with a heart attack was one third as likely to develop CHF or die if a statin was started in the ER and continued during the hospitalization.  These effects are due most likely to a reduction in myocardial infarction size.

These two studies, ACCORD and Steno 2 teach us a great deal about the way that we should manage the epidemic of type 2 diabetes.  It is not about the sugar.  Simply driving the sugar lower may well be harmful.  The Institute of Medicine in 2001 recommended evidence-based protocols consistent with best practices in the treatment of chronic conditions.  Steno 2 fits that recommendation and ACCORD clearly does not.  Steno 2 should provide us with the model of the future- that is a coordinated-integrated attack on global cardiovascular risk using medications that have been shown to reduce the risk of heart attack and death.  ACCORD has shown us that aggressive care using any modality that lowers the risk factor may be dangerous and a premium should be placed on medications that have been shown to reduce events and death.  The ADA treatment guidelines say that metformin should be started at diagnosis in the absence of contraindication and these results underscore that recommendation.  Long-acting insulin should be used sooner as in Steno 2 rather than later.  

Over a 10-year period in South Carolina ending in 2007, I personally treated 450 type 2 diabetic patients with an average age of 65 and multiple comorbidities.  By using metformin, a self-adjusted long-acting insulin shot and the South Beach diet, I was able to maintain an A1c in that patient population that ranged from 6.8-7.0 over a the entire 10-year period.  These patients did very well with nothing approaching a 50% mortality.  Most of these patients had hypertension and cholesterol problems.  They were treated in a systematic protocol-driven manner.  Pharmaceutical interventions were chosen using the following cascade of priorities. 

1. event reduction
2. effect on weight
3. beneficial effects on other risk factors
4. effects on endothelial function and arterial structure
5. convenience
6. side effect profile
7. reduction of insulin resistance

The basic protocol used looked like this:

Most of these drugs are now available at Walmart for $4 a month.  Most of the patients actually lost weight and kept it off.  The patients could be seen at a reasonable rate of speed and for relatively little cost.  Aggressive diabetes management can be an important part of vascular risk reduction.

The last message anyone should take away from the ACCORD shut-down is that aggressive treatment is a bad idea.  Evidence of event reduction is king and other treatments should only be used when the patient cannot take the evidence-based therapy.

Dr. Bestermann leads the Center for Cardiovascular and Diabetes Management at the Holston Medical Group in Kingsport TN. He is a regular contributor to The Doctor Weighs In.

Bill Bestermann

Do you remember the guy on the cigarette commercial—the ruggedly handsome, cool cowboy with the hat and the sheepskin jacket?  The message was clear—smoke a cigarette and you can be like me!  Well, there is one way you would not want to be like this gentleman-he is a prime candidate for erectile dysfunction.

The ability to achieve and maintain an erection is fundamentally a vascular event.  The firmness is produced by opening the inflow of blood into the penis and shutting down or reducing the blood that is leaving that organ.  Of course the inflow of blood depends on the condition of the arterial supply to the penis and so erectile dysfunction becomes an early warning signal for arterial disease.  This is a great topic to help understand the central role of nitric oxide in the arterial system.

Nitric oxide is produced in the endothelium- a thin sheet of cells that lines every artery in the body.  The entire mass of endothelium is a very large organ that produces a number of substances that affect the structure and function of the artery.  Nitric oxide is a powerful artery dilator and it is produced in every artery in the body-from your hair roots to your toenails.  It is the active ingredient in nitroglycerine.  When you place a nitroglycerine tablet under your tongue, the nitric oxide level in the blood stream is increased and all arteries dilate.  Nitric oxide is anti-inflammatory, anti-proliferative (interfering with thickening and narrowing ), anti-coagulant, and vasodilating.  In short, nitric oxide does almost everything that you would like to see done in promoting arterial health.  Very interestingly, all risk factors for arterial disease are associated with diminished endothelial function and thereby decreased nitric oxide production—and erectile dysfunction.  

Endothelial dysfunction occurs very early in vascular disease.  It precedes the development of high blood pressure.  It occurs in the very earliest stages of atherosclerosis.  The first stage of atherosclerotic disease of the artery is the fatty streak.  Young soldiers who were killed in action in Korea and  Vietnam were found to have fatty streaks in the artery.  These were men in their late teens and twenties.  These youngsters with fatty streaks had diminished nitric oxide activity.  Nitric oxide production is predictably reduced in patients with hypertension, high cholesterol, high triglycerides, metabolic syndrome, diabetes, and cigarette smoking.   In fact, spending 30 minutes in a smoky bar can produce a measurable decline in arterial dilation.  When endothelial dysfunction becomes sufficiently advanced, erectile dysfunction occurs. Erectile dysfunction is a very good early indicator of endothelial dysfunction.  The endothelium, and nitric oxide production, play such a central role in the cardio-metabolic underpinnings of vascular disease that many physicians who are specialists in this area consider themselves endotheliologists.  They select their medical therapies specifically to enhance nitric oxide production and improve the endothelial function in the patient with arterial disease or vascular risk factors.

Now things start to get really interesting.  When the development of Viagra started, the researchers involved were looking for a way to increase nitric oxide levels in the artery and to improve arterial structure and function.  Nitric oxide is like a faint mist in a wind storm.  It is degraded in seconds.  Viagra works by slowing the breakdown of nitric oxide and causing it to accumulate in the circulation.  The researchers found that Viagra did not have much benefit as a cardiac drug—and then they noticed that amazing side effect and the rest is history.  This is a case where serendipity produced a blockbuster drug.

Viagra improves nitric oxide levels very quickly, but there are other medications used in the medical treatment of arterial disease that have that same effect.  ACE inhibitors, angiotensin-receptor blockers (ARBs), and amlodipine are important medications in the treatment of hypertension and they rapidly improve nitric oxide activity.  Nitric oxide and angiotensin II are a kind of yin-yang in vascular disease.  When angiotensin II activity is high, nitric oxide activity is reduced and vice versa.  Angiotensin II is a bad actor in the artery.  ACE (angiotensin converting enzyme) inhibitors and ARBs work specifically by reducing the effect of angiotensin II.  Losartan, an angiotensin receptor blocker, has been proven over the course of a year to improve arterial function (dilation related to nitric oxide) and structure (reduction of the abnormal thickness of the artery.)  Not surprisingly, there are reports in the medical literature that treatment with losartan improves erectile function.  Statin drugs for cholesterol and metformin for diabetes also improve endothelial function very rapidly and there are reports of improved erectile function related to these medications.  The TZD drugs for diabetes increase nitric oxide levels.  Some medications used for high blood pressure may cause problems with sexual activity, but the best drugs improve arterial structure and function, reduce the incidence of stroke, heart attack, and diabetes, and may—over time—improve erectile function.  

High blood pressure is not a disease.  It is a measurement.  The elevation of the blood pressure tells use that the artery is abnormal in structure and function.  Erectile dysfunction is like an early warning system.  It tells us that the arterial system has enough disease that it does not work properly.  If you have that problem, you may want to see a medical specialist rather than a urologist for a vascular evaluation.  You want to see someone who is very well-versed in the medical management of vascular disease.  And—while you are at it—you just might want to buy yourself a cowboy hat and a sheepskin jacket.

by Bill Besterman

The underpinning for much of the death and disability from arterial vascular disease in this country is the metabolic syndrome. One of the real authorities on the metabolic syndrome is a Dr. Ralph DeFronzo.  I particularly like his description of this collection of disorders as a “complex metabolic web.” 

The patients who have this diagnosis are burdened with multiple chronic conditions: hypertension, high LDL or bad cholesterol, high triglycerides, low HDL or good cholesterol, and high blood sugar ultimately resulting in type 2 diabetes. These patients routinely have vascular systems where the vessels are inflamed and the blood more likely to clot.

Early in the condition the arteries are thicker and less distensible than in people without the syndrome; progression of the arterial disease is the norm. Many of affected individuals also have gout. More recently, the metabolic syndrome has been called the cardiometabolic syndrome because this name underscores the impact of these conditions on the heart and the rest of the vascular system. Metabolic syndrome patients have an increased risk of coronary artery disease, cardiac enlargement and congestive heart failure.  Type 2 diabetes is the late stage of the syndrome

Dr. DeFronzo highlights a very important clinical reality in describing the cardiometabolic syndrome as a complex metabolic web. "Job one" of the clinicians who treat these patients is to unravel that complex web using every medical and lifestyle tool in the medical toolbox.

Only 7% of these patients have all of their risk factors (hypertension, blood sugar, and cholesterol) simultaneously controlled to the most conservative goals. For each risk factor that is controlled, using the proper interventions, the risk of all adverse outcomes is reduced by roughly 50%. So, the task of the clinician is not just to control hypertension or diabetes, but rather to control all risk factors to goal at the same time.

That is where the focus, skill and training of your provider come into play. The particular medical choices that are made are critical for success. For three decades now I have heard physicians blame patients for not being “compliant:”

 “Mrs. Brown is diabetic and she does not listen to a thing I tell her. She just stuffs herself with anything she wants and she continues to gain weight.”

Here is the reality. Every medication commonly used for the treatment of type 2 diabetes causes weight gain with the exception of metformin (Glucophage) and the Byetta-type medications. The new drug Januvia is weight neutral. Most patients do not have their sugar controlled to goal using a single medication. Most patients require multiple drugs and even then progressive loss of glucose control is the norm. Weight gain not only makes control of the sugar more difficult—the metabolic syndrome is itself worsened by increased abdominal weight—weight gain also makes controlling pressure, cholesterol, triglycerides and gout more difficult.

The patient that receives a prescription for two shots of NPH insulin a day will gain 10 pounds in a year. The patient that uses glyburide plus a single shot of NPH gains 9 pounds. The regimen combining  glyburide, metformin and a single shot of NPH, produces a similar weight gain. Metformin added to a single injection of NPH at bedtime produces no weight gain, the best control of the blood sugar and the least number of hypoglycemic attacks. The doctor with the prescription pad is producing this result—not the patient. These are impressive weight changes and they make a big difference over time. I have treated 450 type 2 diabetics for nearly 10 years with a regimen based on metformin and a long-acting insulin injection with durable control in most patients.

The treatment of high blood pressure hides the same kind of traps. Until very recently beta blockers like propranolol (Inderal), metoprolol (Toprol) and atenolol (Tenormin) were recommended as first line therapies for the treatment of hypertension.  Many patients continue to be on these medications for the one purpose of treating high blood pressure. These medications have important metabolic effects:

• Propranolol increases triglycerides by 25%, decreases HDL by 10%, increases total cholesterol by 9% and increases insulin resistance by 33%
• Metoprolol increases triglycerides by 30%, decreases HDL by 7%, decreases total cholesterol by 1%, and increases insulin resistance by 21%

Tricor (fenofibrate) is prescribed to treat the lipid or cholesterol abnormalities that go with the metabolic syndrome decreases triglycerides by 29%, increases HDL by 11%, and decreases total cholesterol by 18%.  When we prescribe propranolol and fenofibrate simultaneously, we have simply cancelled the lipid effect of two drugs.

The prescription of propranolol makes it 28% more likely that the patient will develop diabetes. Choosing an ACE inhibitor makes it 33% less likely that a patient will develop diabetes. These are critical metabolic issues. There is a newer beta blocker carvedilol, with dramatically improved metabolic effects relative to the older drugs.

The point of all this is that treatment of these patients is very complex if it is done properly. 95% of type 2 diabetes care is provided by primary care doctors who are under tremendous pressure to see patients at the rate of 5-6 per hour. They are required to be experts in the whole massive knowledge base of medical practice We need focused clinics of the type described by the Institute of Medicine to treat metabolic syndrome patients. The providers in these clinics will need to be very expert in the coordinated, integrated management of metabolic syndrome patients and the resulting complications. Until that happens, we will continue to produce the same poor levels of risk factor control and pay a terrible price in lives, disability and treasure.