Diabetes
Screening for diabetes is absolutely the most important thing that people on the front lines can do, and then we will talk about treatment for the rest of the time, focusing on the oral agents in particular, and I am talking about type II diabetes, type I diabetes is something that I think, first of all it’s the minority of diabetes and most people will feel more comfortable sending those people to internists or endocrinologists. We will focus on the definition of diabetes because they actually have changed over the last couple of years, the recommendations for screening which are also relatively new. The risk factors that should alert you to screen somebody for diabetes to begin with and then what we use for goals of treatment and how you can actually achieve some of those goals.
First to tell you why screening is so important, I don’t have to tell you that diabetes is a terrible disease, it causes a lot of problems, but just to give you some numbers, it causes 30 times the rate of blindness and is the most preventable cause of blindness in this country, one of the most preventable causes, twice at least the rate of heart disease, these are people who are dying of heart disease and stroke at a huge rate over the general or nondiabetic population, 17 times the rate of renal failure and a huge increase in the rate of amputations and it’s the leading cause of nontraumatic amputations.
Text continued belowSo these are huge increases in risks for things that are largely preventable. There is recent epidemiologic data to suggest that we are still doing a terrible job at identifying diabetics, 5% of the general know they have diabetes, this is about 10 million people, 5 million people, however, have diabetes and have actually no idea they have it, these are people who are walking around with blood sugars 200, 300, 400 and they have no idea, they probably don’t feel well, but they are also developing risks for blindness, amputation and heart disease and stroke and they have no idea, they have no way of reducing their risk because they are ignorant at that point. Unfortunately, this is a group that we continue to under recognize, most people when they are diagnosed with diabetes have probably had it for five or 10 years and they have been accumulating risk factors for the complications of diabetes for at least those five or 10 years or maybe before.
There is also a category of people who doesn’t get talked about very much and these are people who have impaired fasting glucose, also related to a category called impaired glucose tolerance, some people call that a prediabetic state, it’s certainly a risk factor for getting diabetes but more importantly, this is a group of people who die from heart disease and stroke at least two times the rate of the general population. So they have the same risk for heart disease and stroke which is nearly equal to that of a diabetic. So this is a group of people that is important to identify for several reasons, one because they need to be screened actively, probably every year for diabetes and also because they need a lot more aggressive management of hypertension and hyperlipidemia which these people tend to also have. So this is again, 13,000,000 people that were currently not identified.
These are the criteria, I call them new because they are new in the last couple of years, it used to be that diabetes was defined by a fasting blood sugar of 140, this has been recognized to be a kind of a ridiculous number so now the fasting blood sugar of 125 or greater on two occasions satisfies criteria for diabetes. The reason this was changed from 140 to 125 or 126 is that the incidence of complications, specifically related to diabetes like retinopathy, nephropathy, neuropathy begins to increase sharply when the blood sugar reaches this level, this is a level a lot of people are comfortable leaving people at, and if you have seen diabetes and seen blood sugars and most of you have, the4se are numbers that don’t sound like they are very bad, but in fact, these are people who are actively getting complications and people who show up with blood sugars of 125 in the morning, many of them already have retinopathy. So this is a group we have to be more aggressive about. If someone does an oral glucose tolerance test and this is the 75 gram oral glucose tolerance test, the same older criteria apply which is that after two hours, if the blood sugar is greater than 200, that is also diabetes, also if someone is obviously symptomatic with polyuria, polydipsia, appears diabetic, and has a blood sugar of greater than 200, that is also good enough to diagnose diabetes. Then the impaired glucose tolerance, there are two categories, one is this fasting blood sugar, the other is the two hour blood sugar during an oral glucose tolerance test. If the fasting blood sugar is greater than 110, that person has impaired fasting glucose, that person has at least a 5 to 10% chance per year of developing full blown diabetes which needs to be treated, so that person needs to be watched carefully, I think this person needs to have a fasting blood sugar every year after that, they need to be told they have a very high risk for diabetes and that person also has these other risk factors for heart disease and stroke which are twice the general population, so that person also needs to be screened for cholesterol elevation and hypertension which can be treated at this time. The two hour level, greater than 140, if you do an oral glucose tolerance test also meets the criteria.
These are the current recommendations for screening and these are very aggressive, I don’t think that we are close at all to implementing these in primary care. Basically my bottom line on this is that you look for any excuse to screen someone for diabetes. Age itself is a risk factor. The incidence of diabetes goes up sharply with age. So anyone over the age of 45 regardless of any other risk factors should be screened at least every three years with a fasting blood sugar, because it’s a very easy and cheap test to do. Then you look for any other reason, obesity, greater than 20% above the ideal body weight, you would be surprised how many people meet that criteria. It doesn’t take much to get somebody to a body mass index of 27, you look at a person, you don’t think they are terribly overweight, but especially if they have the abdominal obesity which tends to bet hidden very well, this people can meet a body index of 27 very easily. If they have a first degree relative with diabetes, their rate of diabetes is increased dramatically. If they have a high risk ethnic group, I have another side which delineates those, these are a rapidly growing and highly representative group of people, certainly in major cities and all over the country which are developing diabetes at huge rates. History of gestational diabetes or large babies, hypertension, dysmetabolic syndrome which I will mention a little bit later, low HDL or high triglyceride, people with hypertension, dyslipidemia are at high risk for diabetes, and certainly impaired glucose tolerance or impaired fasting glucose if you found that before.
These are the high risk ethnic groups just to give you some numbers here; African Americans have at least twice the rate of diabetes as whites, Mexican and Puerto Ricans have 2 ½ times the risk and Native Americans have up to five times the risk, this is an enormously increased risk group. I have actually been surprised at the number of Native Americans that you might find in your clinic who don’t look at all Native American, who don’t live on a reservation in Minnesota or Arizona, but have Native American ancestry and those people have a much higher risk for diabetes than you might imagine.
There is another group not on here which are the Pacific Islanders or Asians who have moved here. Japanese people have a much higher risk of diabetes once they have lived here for some time at much lower body mass index than we have partly because they have an abdominal distribution of the way they carry their fat and that fat happens to me a little more metabolically active and predisposes people to cholesterol abnormalities and risk factors for diabetes. These are the targets for glycemic control once you are treating a diabetic, and you will notice they are very similar to the numbers we use for screening. So the fasting blood sugar needs to be around 80 to 120. If that seems like an aggressive goal, it is. We now know from very large studies, the main one being the United Kingdom perspective diabetes study or the UK PDS that aggressive control for type II diabetes is just as important as aggressive control for type I diabetes which we all now have accepted and the rates of complications are reduces dramatically even when modest improvements in blood sugar control. So these preprandial sugars and bed time sugars should be around 100, a little bit higher at night in case somebody has a risk for getting hypoglycemic at night, and then AIC control goals, these are unfortunately going to differ a little bit because everyone’s laboratory is a little bit different, but if the upper limit of your laboratory is 6%, then you want their hemoglobin A1C to be less than 7%, this is to remind you the hemoglobin A1C is really an indispensable tool in terms of monitoring average blood sugars over time, they should be done three to four times a year, this gives you a sense over the previous three month period of time what the average blood sugar is, and correlates very highly with the incidence of complications. So not to discount the fact that people should be doing home blood sugar monitoring and that’s actually one of the first things that should be implemented. This is an excellent tool to corroborate what patient’s are measuring at home, and to tell you how they sort of fit into overall diabetic control.
Also to mention that glucose control is not the only thing to pay attention to with diabetes, they need to have aggressive cholesterol control, we treat them as if they have already had a heart attack because in fact, a diabetic’s risk for having a heart attack is as great as someone who already has had one, so they are treated as aggressively as someone with established coronary disease with the need to get their LDLs less than 100 and aggressive blood pressure control, about 130/85, because blood pressure control is as or more important than glucose control in reducing the risks for all the complications of diabetes and these are the standard other things we implement, yearly eye exam, screening for nephropathy with spot urine to check for protein, looking at feet, and getting them to stop smoking.
This is an introduction to the pathophysiology of diabetes which helps me explain why we treat with the different medications we treat. It happens we have a medication to treat each part of the pathophysiology. So diabetes is not just an elevation in blood sugar, it used to be that we only had insulin or medications which increased insulin to get the blood sugars down, but it turns out there are actually a lot of components to diabetes which are helpful to understand when you choose an antidiabetic medication. So obviously, in diabetes, the pancreas has a relatively deficiency of insulin. Regardless of how much insulin that person needs, the pancreas is not keeping up, so there is always some degree of insulin deficiency and there is a huge spectrum, in type I diabetics or the juvenile onset diabetics, they have no insulin secretion but many of our older diabetics with standard type II diabetes make quite a bit of insulin, it’s just not enough for that particular person.
The other thing is insulin resistance which you have heard mentioned and this is inefficiency or impairment of the ability of insulin to act at it’s target tissue, one of it’s target tissues being the muscle. It is not as good taking glucose into the muscle to be used as it would be otherwise and this is something we see in obesity, aging, physical inactivity, and it’s a very common underlying problem which precipitates diabetes. The other thing is the liver makes too much glucose and this is the way that insulin resistance is manifested in the liver, insulin is not as efficient at lowering the rate at which the liver makes glucose. This is the source of elevated fasting blood sugar, many diabetics will come in and say, I didn’t eat anything since 8:00 last night how can my sugar be elevated? This is why, their liver has no ability to appropriately detect the fact that they already have high blood sugars and continues to make a lot of sugar and pours it into the circulation. These there things sort of converge to make hypoglycemia and as I go through the oral agents that are available, we have one that targets each part of this pathophysiology and similar to way we treat hypertension, we are not using them altogether to lower blood sugars and avoid insulin therapy. These are the modalities that we have available to us to treat diabetes, the first is diet, weight loss and exercise. Although I will talk about oral agents, these are actually by far the most effective things for diabetes and I tell all my patient’s that diet and exercise are more effective than any single drug we have, however, the person actually has to do it, and that doesn’t happen very often, so we need to bring out the other list of things we have available and I will go through each one of these individually. I am not going to talk about insulin today because that ends up getting more complicated, and that is sort of the last resort. I did put some information about insulin in hour handout if you want to look at it.
This is a very simplified version of how I think about the different agents or the different therapies that are available. Glipizide, Glyburide, Micronase, Glucotrol, the agents that have been around for a very long time stimulate the pancreas to make more insulin, so they actually raise insulin levels, just like insulin therapy does, and insulin, whether you take it by an injection or you make more of it, is a weight promoting therapy and so these people, if you want to think about diabetes as sort of a supply demand mismatch that people are not making as much insulin as they need, if you increase the supply, you are going to lower the blood sugars, but not without a side effect and that side effect is weight gain and weight gain promotes insulin resistance, so in some ways, these therapies really make the whole situation worse. They can lower the blood sugar, but over time, they are going to create more of a problem, and now that we have other therapies available, we try to use second line agents or even third line agents. Diet and exercise reduce the demand for insulin. If you eat less, you don’t need to make as much insulin, if you exercise, you can reduce insulin resistance and actually reduce the need for insulin, either your own or injected form of insulin. Then there are these relatively new medications. Metformin is a group of medications, since another one has been withdrawn from the market, it’s really the only one in a group called Biguanides, and the brand name for this is Glucophage, it’s been around for several years and this is a medication I think you should feel very comfortable using. It does have some restrictions to it which we will go through, but it’s extremely effective and the main advantage is there is no risk of hypoglycemia when you use it, it lowers hepatic glucose output so this is the medication we have that targets specifically the fact that the liver makes too much sugar, and it’s very easy to start, you will find that the fasting blood sugars come down tremendously with this agent. The advantages are there is no risk of hypoglycemia because it doesn’t stimulate insulin, it doesn’t stimulate the pancreas to make excess insulin.
When you use it by itself, people don’t get hypoglycemia. If you start it on a particular day, you will start to notice an effect within a couple of days. It has a very quick onset of action, and this is the only agent of any of the pills we use for diabetes that has been shown to have good blood sugar control without weight gain. That is a huge advantage, even in larger studies this has been shown to be true many times over. The mechanism for that is not completely clear but there are some GI side effects to metformin and it could be the appetite reduction is part of that lack of gaining weight, but it doesn’t really matter because the fact they don’t gain weight is a huge advantage. The disadvantages are that there are some gastrointestinal side effects and for some people they are prohibitive. Maybe about 5% of people actually can’t take this medication for a long period of time because there are some GI side effects, these are not harmful to the patient’s but they are bothersome enough that they want to stop the medication and it’s usually nausea, sometimes vomiting, loose stools and I always tell people that when you start that medication to expect these side effects for the first few days, but they will go away over time, and most people if we start with a very low dosage, tolerate this medication fine, and of course it’s more expensive than the older drugs, although my understanding is that this medication will become generic, I think actually this year.
The precautions, and if you have a well informed patient who comes back and says, but I read in the product information sheet about this lactic acidosis, what is that, I would feel very comfortable that this is not going to happen if you choose your patient carefully. So lactic acidosis is a build up of lactate, it’s related to the mechanism of action of the drug. It’s caused by a failure of the kidneys or liver to excrete lactate. When these patient’s are studied and many many studies have not been done in patient’s who have had lactic acidosis, they found that everyone who has had this problem has had a specific risk factor for having it, and if you simply know who to give it to and who not to give it and who not to give to they won’t get and the people who have had problems or were the ones in whom it was inappropriately started to begin with. Remember, the kidney, the liver and the heart. So basically major organ failure. These are people who are potentially treated by other physicians anyway who will potentially manage their diabetes, but people with renal insufficiency shouldn’t get this drug, people with known liver disease who are active alcoholics or who binge drink even periodically shouldn’t get this drug and people with congestive heart failure. Occasionally, people with congestive heart failure will have an episode of decompensation, not perfuse their kidneys well and that’s the origin of this recommendation because there is potential for kidney failure, also with IV contrast agents such as you give in an infused CT scan those can also precipitate temporary renal insufficiency and so the medications should be stopped just during that period of time, usually about 24 to 48 hours. So the vast majority of people actually don’t fall into this category. Most people have normal renal function, normal liver function and if you screen them ahead of time, and start this medication on in people who don’t have these contraindications, there is really no risk for lactic acidosis whatever, and they actually don’t need to be monitored over time either. This is the dosing that I tend to use starting at very low doses and working up and this is also in your handout, to minimize the side effects and encourage tolerance.
The other thing I will mention which I think is actually of practical importance here is that actos is metabolized through cytochrome P450 and there are potential drug interactions, and particularly with oral contraceptives, this has not been studied but oral contraceptives are also metabolized through P450 and theocratically they would be less effective and I think you can’t assure somebody that OCPs would be effective in someone taking one of these drugs because we just don’t know that yet. Both of these medications have adverse effects on cholesterol, and particularly LDL. Precose, this is a mediation you take with each meal, it inhibits the ability of the intestine to break down sugars, complex sugars into absorbable units. So the sugar stays in the intestinal tract, so that it doesn’t get absorbed which is the benefit, but it doesn’t get absorbed which causes a lot of symptoms and many people come back saying they can’t tolerate the symptoms, there is a tremendous amount of flatulence with this medication sometimes, the families of people will come back and ask us to stop it, and it’s also not terribly effective, even at the maximum dose, which is associated with about 100% incidence of side effects has a maximum A1C reduction of about half percent which is not great and it’s also expensive so I think there is not a great reason to use this particular drug.
Initially when you see a diabetic, you have done a screening test, you found the blood sugar was 160 or the hemoglobin A1C was elevated, basically, my rule of thumb is if you pick one pill except carbos, you will get an average reduction in the fasting blood sugar of about 50 points, so a lot of people are afraid, what is going to happen if I start Glyburide a certain dose, they are going to end up in the emergency room with hypoglycemia, they are not, if they have a blood sugar of 280 fasting and you give them one pill, they are not going to get hypoglycemic. They just don’t work that well. So you are going to get a lowering of about 50, if you add them together they are not completely additive but you can think of it as 50 points per pill just to keep it simple.