Diabetes Part II—a multimodal approach to treatment

As an experiment on cross-blogging, I’m going to pick up where N.B. of Secundum Artem left off—the treatment of diabetes. We have learned quite a bit about how to treat diabetes over the last several years, thanks to large randomized controlled trials such as DCCT and UKPDS. Focusing on Type II diabetes (DM II), the most prevalent kind, our aims are to reduce morbidity and mortality due to microvascular and macrovascular disease (this is explained in tolerable detail here)…

Since the discovery insulin, diabetes lost its reputation as a death sentence. To touch on DM I briefly, without insulin, patients develop what is called ketoacidosis and die. Fast. The only way to prevent ketoacidosis is to starve—and die slowly.

DM II is a bit less dramatic in the short run, but just as devastating over the long term. The microvascular complications of DM II include blindness, kidney failure, and painful peripheral neuropathy, which can lead to amputations. Controlling blood sugars has been found to greatly reduce these complications. Some of the physiology behind this has been explained by N.B., although our understanding is incomplete.

Macrovascular complications, such as stroke and heart attack are trickier. These are the big killers. Controlling blood sugars alone does not greatly reduce the incidence of these problems. However, controlling blood pressure and cholesterol with certain medications has a dramatic effect in diabetics.

So when discussing treatment of diabetes, we can’t speak only of blood sugar. But that’s where it all starts.

Insulin is, of course, the model for controlling blood sugar. Give it, and you unlock the door for glucose to enter cells. Of course, this is entirely un-physiologic. In a healthy person, multiple feedback mechanisms exist that regulate glucose, insulin, glucagon, and many other chemicals. In a diabetic, these feedback loops are disordered. As a simple example, give too much insulin, and blood sugar levels can drop dangerously low, leading to seizures, coma, or heart attack.

Type II diabetics, unlike type I’s sometimes produce a great deal of insulin, but their cells are resistant to its effects. Weight loss and exercise can reduce insulin resistance, which is one of the underlying problems in many type II’s. Sometimes this is enough to control the disease, but not always.

One of the oldest classes if diabetic medications is the sulfonylureas. These basically act by telling the pancreas to secrete more insulin. This can lower blood sugar, but can also exhaust the pancreas, and increased insulin levels are not necessarily a good thing.

Metformin is an important medication, especially early in the disease. This drug acts primarily by reducing the liver’s secretion of glucose. It is especially good in obese patients, but it has its limitations.

Thiazolidinediones, such as Avandia and Actos, have multiple effects, but among these is the reduction of insulin resistance, one of the main problems in type II DM.

A minor class of medications are the alpha glucosidase inhibitors. These are not widely used.

A new path of investigation holds a great deal of promise. These medications, such as Byetta, Symilin, and Januvia act on the incretin pathway. These have multiple effects, including slowing food absorption, aiding in insulin release when it is actually needed (with food absorption), and lowering glucagon levels. These are still quite new, and we have a lot to learn.

Take home points

All of these medications and strategies help lower blood glucose. As we’ve discussed, this doesn’t necessarily lead to lower mortality from heart attack and stroke. What are we missing?

First, cholesterol and blood pressure are even more important in diabetics than in non-diabetics.

But there’s much more. Diabetics are different than other people. High insulin levels are a bad thing. Diabetics’ metabolism is different from normals. There are still many questions.

But we have learned much from outcome studies. Not only is glucose, blood pressure, and cholesterol control important. Other interventions, less obvious ones, are essential. Regular diabetic foot exams, a very simple intervention, helps prevent amputations. Screening of urine for protein and treating urine protein with certain medications slows kidney disease.

What do some of these outcome studies tell us? As stated in previous posts, macrovascular complications of diabetes, such as heart attack and stroke, are the big killers. Lowering blood sugar alone does not appear to be the answer. Is there evidence to guide us in the prevention of diabetic-related mortality? Thankfully, yes.

One example is a Danish study of type II diabetics. The study was small, but well-designed. Diabetics were assigned to “typical” therapy, or more intensive therapy that focused on controlling not only blood sugar, but also blood pressure and cholesterol (“multifactorial intervention”). The patients chosen not only had DMII but also microvascular complications, indicating significant disease.

Results were encouraging. Early results showed a reduction in micro- and macrovascular complications.¹ About fifteen years later, the researchers followed up on their patients to assess actual mortality.² The benefits of the multifactorial intervention endured, with an absolute risk reduction (for all cause mortality) of 20%. Some of the most effective interventions appeared to have been statin medications and blood pressure medications, followed by aspirin.

This reinforces the utility of our current approach to type II diabetes, which stresses not only blood glucose control, but also blood pressure and cholesterol control.

This is how medical science works. When a study measures useful outcomes (mortality, cardiac events), and looks at practical interventions, those of us on the front lines of clinical medicine get useful information that informs our practice, and helps our patients.

People devote their lives to the study of this one disease. So what are we missing? Why doesn’t lowering blood sugar reduce macrovascular disease? What are futue avenues of inquiry? More to come from N.B. of Secundum Artem in our experiment in cross-blogging.

Addendum: Given that there is actual clinical information in this post, I wish to remind people to read the disclaimer on the front page (right). Also, I will be a bit picky about comments purporting to give advice or making outrageous claims that might affect people’s treatment decisions. Please…refer questions to your doctor, not an anonymous blogger.

References:
1) Gaede, P., Vedel, P., et al, . (2003). Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. New England Journal of Medicine, 348(5), 383-393.
2) Gaede, P., Lund-Andersen, H., et al, . (2008). Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. New England Journal of Medicine, 358(6), 580-591.