Jaslok Hospital and Research Centre,
When you first go to see your doctor with your diabetes problem, he will most probably ask you to follow a diet and exercise program. Some of you will be controlled with this and your doctor will then ask you to continue with your diet and exercise. He will, of course, keep monitoring your diabetes regularly.
Some of you may not show an adequate response to the diet and exercise, or the initial control may deteriorate so that your doctor will then add some medications. Whilst this may be insulin, in most instances since you have Type 2 diabetes, it will be a tablet.
It is not absolutely necessary that all patients first be given a trial with diet and exercise. Even at first, if your blood glucose levels are very high, you have severe symptoms usually associated with a high blood glucose, or are feeling very weak and have lost a lot of weight, the doctor may start you with a medication along with diet and exercise.
Later, it may be that you are able to get off the tablets, but that will depend on your response to the treatment and what your doctor judges to be good control.
At the same time, it is a fact that most people with Type 2 diabetes will sooner or later need some oral medications, which may even be in combination with insulin injections.
A word of caution here.
Many people feel that now that they are on medications, there is no need for them to diet or exercise. This is absolutely wrong. Diet and exercise will always be central to your management. The tablets and if necessary, insulin injections, are always in addition to the diet and exercise prescribed to you.
Many of you must already be on tablets for your diabetes and some of you may soon need to take tablets for your diabetes. It is important for you to understand how these tablets work to decrease the blood glucose levels, as well as the doses, how the tablets should be taken and other aspects such as their side effects and interactions with any other medication which you may be taking.
Previously, we have already discussed how the body regulates the blood glucose levels to within normal values. Insulin plays a key role in this. When the food that we eat is digested and enters the blood stream, the pancreas secretes insulin which allows the glucose to be taken up by the cells of the body and also by the liver. It also stops the liver from manufacturing "new" glucose and since the secretion of insulin is closely linked to the blood glucose levels, it maintains the se levels within normal limits.
We have also discussed the reasons for the increase in blood glucose levels in Type 2 diabetes.
Very simply, the following factors play a role in the increase in the blood glucose levels seen in diabetes:
a) The secretion of the insulin from the pancreas is less than that which is necessary to control the blood glucose levels.
b) Even the insulin which is secreted by the pancreas is delayed, so that the blood glucose after eating rises and the insulin then is secreted later and not closely linked to the rising blood glucose levels. This often leads to very high post food glucose levels.
c) There is insulin resistance. Whatever insulin is secreted cannot show its action on the other cells as these cells are "resistant" to the actions of insulin. Thus, the cells cannot utilize glucose and the liver continues to manufacture "new" glucose, leading to high blood glucose levels at all times.
It is a combination of these three factors which are mainly responsible for the increase in the blood glucose levels seen in diabetes. In some people one of the factors may be more important and in some others, the other factors. But simply put, it all comes down to an interplay between these three factors.
Once this is understood, then one can easily understand where the tablets that you take for diabetes work.
They may increase the amount of insulin secreted by the pancreas, or decrease the time lag between the rise of glucose in the blood and the insulin secretion from the pancreas. The tablets may also act by reducing the insulin resistance.
First introduced in the U.S. in 1954, sulfonylureas stimulate the beta cells to produce more insulin. They will not work in anyone with Type 1 diabetes nor in anyone whose beta cells can no longer make insulin. This class of drugs helps only those who have some beta cell function and are able to produce sufficient amounts of insulin, which in turn reduces hepatic glucose output and increases peripheral glucose disposal.
The sulfonylureas are often classified as belonging to the first or second generation. The first generation drugs are rarely used and not available in most places.
|Target organ: Pancreas|
|Action: Increase insulin release|
|Lowers HbA1c by 1% to 2%|
|Taken: With food||Drug||Duration of Action||Daily Dose Range||Risk of Low BG|
|1st Gen.||Tolbutamide||6-10 hrs.||500-3000 mg||<1%|
|Chlorpropamide||24-72 hrs.||100-500 mg||4-6%|
|Glipizide||12-24 hrs.||2.5-20 mg|
|2nd Gen.||Glibeclamide||18-24 hrs.||1.25-20 mg||4-6%|
|Glicazide||6-10 hrs.||80-240 mg||<2%|
|Glimepiride||24 hrs.||1-8 mg||<2%|
Side Effects: low blood sugar; bloating, heartburn, nausea 1% to 3%; anemia, metallic taste or change in taste.
Some sulfonylureas work all day, so you take them only once. Others are taken twice each day. Your doctor will tell you how many times a day you should be taking yours.
The correct time to take these medications varies. If you take the medication once a day, you will probably take it just before breakfast. If you take it twice each day, you will probably take the first pill before breakfast and the second one just before dinner. Take the medications at the same times each day. Your doctor can tell you when to take your medication, depending on the type of sulfonylurea prescribed.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Although many text books list a large number of side effects, the main ones are a low blood glucose level, stomach upsets, a metallic taste in the mouth, a skin rash and itching and weight gain which in some cases may be due to fluid retention.
There are many drugs which interact with sulfonylureas either making the body more sensitive to the sulfonylureas or interfering with their action. It is absolutely essential that you tell your doctor all the medications which you are taking. This interaction can also be with some drugs which we commonly use for minor problems and one should preferably clear all such use with your doctor.
The biguanides were introduced in 1957. Both phenformin and metformin have been widely used here, although in recent times, the use of phenformin has decreased significantly and most people now use metformin when a biguanide is to be used.
Metformin is a chemical cousin to the French lilac plant, which was noted to lower blood sugars in the early 1900s. However, French lilac turned out to be too toxic for use in humans.
Initially it was felt that metformin acted by reducing the appetite and thus decreasing food intake. It also decreases the absorption of food from the small intestines. Now we know that main site of action of metformin is the liver. Metformin lowers blood glucose levels by increasing the sensitivity of the liver cells ( and some muscle cells, too) to insulin. This leads to an increased uptake of the raised blood glucose levels in the immediate post food period and a decrease in the production of "new" glucose by the liver at a later time.
|Target organ: Liver, with secondary effects on muscle and fat.|
|Action: Lowers glucose production by liver, increases insulin receptors on muscle and fat cells.|
|Lowers HbA1c by 1% to 2%.|
|Time to reach maximum effect: 2-4 hrs.|
|Taken: With meals||Drug||Duration of Action||Daily Dose Range||Risk of Low BG|
|Metformin||8 hrs.||500-2500 mg||<1%|
|Side Effects: Bloating, fullness, nausea, cramping, diarrhea, vit B12 deficiency, headache, metallic taste, agitation, lactic acidosis.|
|Contraindications: DKA, alcoholism, binge drinking, kidney or liver disease, congestive heart failure.|
Metformin is usually taken two to three times each day with a meal. Your doctor will tell you which meals to take it with. Once daily doses of metformin are available in the market, but are still not widely accepted by most doctors.
a) Lower blood sugars, especially after eating, with no risk of hypoglycemia.
b) Improved lipid levels with total cholesterol and LDL levels dropping about 10 percent, triglycerides by as much as 50 percent, while protective HDL levels rise about 10 percent.
c) Mild reductions in weight and blood pressure.
There are drugs which interact with metformin. It is absolutely essential that you tell your doctor all the medications which you are taking.
Acarbose is an alpha-glucosidase inhibitor that slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose. AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption. Delaying the absorption of carbohydrates is a unique mechanism among oral diabetic medications for lowering HgbA1c levels. The effectiveness of this mechanism is one of the physiologic characteristics of type 2 diabetes. Patients with type 2 diabetes demonstrate a delayed or sluggish insulin response from the pancreas to a glucose (a meal) load. By delaying the absorption of glucose, the insulin response is more matched to the serum glucose, resulting in less postprandial hyperglycemia and a lowering of the HbA1c. The AGIs also demonstrate a lowering of total insulin output of the pancreas, increased insulin sensitivity, a variable but mild decrease in triglycerides, with no effect on patient weight.
|Target organ: Intestine.|
|Action: Slows breakdown of carbohydrates.|
|Lowers HbA1c by 0.5% to 1%.|
|Time to reach maximum effect: 1 hr.|
|Taken: With first bite or food||Drug||Duration of Action||Daily Dose Range||Risk of Low BG|
|Acarbose||4 hrs.||12.5-100mg before each meal||none|
|Side Effects: bloating, diarrhea, nausea, excess gas, abdominal pain|
|Contraindications: liver disease, bowel or intestinal disease, intestinal obstruction.|
Acarbose is taken three times daily, at meals, although your doctor might ask you to take the medication less often at first One disadvantage with the use of acarbose is that it is to be taken along with the first bite of a meal. Moreover, it has to be taken three times daily with meals. These factors often lead to non compliance and a decrease in the efficacy of the drug.
The way in which these drugs work is also the major source of their side effects. Although these drugs are very safe, their side effects can be annoying. If digestion is greatly inhibited, this may cause abdominal bloating, gas and diarrhea. The alpha glucosidase inhibitors should always be started on a minimal dose, often half of the smallest tablet, and then gradually increased over time. This greatly minimizes gastric side effects; side effects also tend to decrease over time.
Since the drugs cause intestinal discomfort, they should not be taken by anyone who already has medical problems with digestion or absorption.
The thiazolidinedione (TZD) class of oral hypoglycemics ( popularly known as glitazones) was developed in 1997 and offers a new mechanism for treatment of type 2 diabetes. The first, troglitazone was taken off the market in 1999 because of its association with hepatic toxicity. Rosiglitazone and pioglitazone have been available since 1999.
The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake. The TZDs have some effect on hepatic glucose uptake and sensitivity to a lesser degree. They do not stimulate the pancreas to produce more insulin.
The glitazones work well only when the major factor is insulin resistance. If you have excess abdominal weight ( high waist to hip ratio), low HDL, high triglycerides, or high blood pressure, these would be good indicators that the glitazones would be good for you possibly in association with metformin, or by themselves.
Because they work on insulin resistance, they have their greatest effect on the blood glucose after eating rather than the blood glucose upon waking. These drugs are better absorbed when taken with a meal. They can be dosed once daily, although rosiglitazone works better with twice-daily dosing.
With use of glitazones, patience is required. Blood sugar levels may show a significant reduction statistically in as little as two to four weeks, but the maximum effects are not seen until two or three months have passed.
|Target organ: Muscle, fat, and liver.|
|Action: improves receptivity in insulin receptors.|
|Lowers HbA1c by 1% to 1.5%.|
|Time to reach maximum effect: 2-4 hrs.|
|Taken: With or without food||Drug||Duration of Action||Daily Dose Range||Risk of Low BG|
|Pioglitazone||24 hours||15-45 mg||<2%|
|Rosiglitazone||12 hours||2-8 mg||<2%|
|Side Effects: Upper respiratory tract infections ,headaches, muscle aches, tooth aches, sore throat, fluid retention, liver dysfunction.|
|Contraindications: Kidney or liver disease, enlarged heart, swelling, pregnancy.|
Although they normally do not cause hypoglycemia when used by themselves, if used in combination with a sulfonylurea or insulin, low blood sugars may occur. Less insulin is required to control blood sugars when glitazones are used so your doctor may reduce the doses of any other diabetes tablets or insulin which you may be taking.
The glitazones are associated with side effects such as water retention and swelling of the ankles, especially in older people. Other possible side effects include weight gain, muscle weakness, and fatigue. Although they have not been shown to cause liver damage, your doctor may ask that you check your liver functions regularly. Call your doctor right away if you have any signs of liver disease, which include nausea, vomiting, stomach pain, lack of appetite, tiredness, yellowing of the skin or whites of the eyes, or dark-colored urine.
If you take birth control pills, glitazones might make your birth control pills less effective in preventing pregnancy.
Glitazones have additional benefits. Besides their effect in lowering the blood glucose levels, both drugs also have notable effects on lipids. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favorable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Rosiglitazone has a favorable effect on HDL cholesterol levels but a negative effect on LDL cholesterol levels. They also lead to a slight reduction in the high blood pressure levels.
Repaglinide and nateglinide are the two drugs which are used in this, the meglitinide group of drugs.
Their action is similar to that of sulfonylureas in the sense that they increase the secretion of insulin from the pancreas and are ineffective if the pancreas does not have enough capacity to secrete insulin.
We discussed before that one of the problems in Type 2 diabetes was that there was a lag period between the increase in the blood glucose levels following a meal and the release of insulin from the pancreas. This caused the immediate post meal blood glucose to be very high and also could possibly lead to late hypoglycemia.
The meglitinides are different from the sulfonylureas in that they raise the insulin levels acting on the pancreas but through a different mechanism. This allows more insulin to be secreted earlier, removing the lag period between the rise in the blood glucose levels and the rise in the insulin levels in the blood. They act over a short period of time by increasing first-phase insulin release from the pancreas. They respond to the glucose level, so hypoglycemia is milder and less frequent than with sulfonylureas.
Their peak action of an hour and short duration of action of about three hours is ideal for matching meals.
They are ideally taken 10 to 15 minutes before meals, the dose should be skipped if a meal is skipped.
Meglitinides, first phase insulin releasers
|Target organ: Pancreas.|
|Action:Increases first phase insulin release, glucose driven, lowers after-meal glucose.|
|Lowers HbA1c by 0.5% to 0.7%.|
|Time to reach maximum effect: 1 hr.|
|Taken: 15 to 30 minutes befor meals||Drug||Duration of Action||Daily Dose Range||Risk of Low BG|
|Repaglinide||3 hrs.||0.5-4 mg before each meal||<1%|
|Nateglinide||3 hrs.||60-120 mg before each meal||<2.5%|
|Side Effects: Low blood sugar, nausea, vomiting, diarrhea, muscle aches, upper respiratory infection, cold- and flu-like symptoms, headache, joint aches, and back pain.|
|Contraindications: Type 1 diabetes, DKA, liver disease.|
They can cause low blood sugars, but because they stimulate insulin production only if the blood sugar is high, the risk of lows is reduced. Like sulfonylureas, they do not work in Type 1 diabetes and require beta cells capable of producing insulin. If sulfonylureas have failed to control your blood glucose levels, the meglitinides would rarely be effective.
One difficulty with these medications is identifying those who would benefit from them. Most people do not check their blood sugars after meals to see how high it is going. Those whose blood sugar are spiking more than 40 or 50 mg/dl after meals may benefit from these drugs, so post-meal testing is critical for identifying these individuals. They are ideal for people whose fasting blood sugar is not that high, but whose HbA1c is elevated and whose blood sugars spike after meals so testing at this time is critical.
A minor problem is that people treat when they eat, so doses are taken several times a day and has to use eating as a reminder for taking the medication. Conversely, they are very useful in people who show high post meal levels and also have a very erratic eating timings, as they can be taken just with a meal rather than one having to take the sulfonylurea tablet some time before the meal.
They have been used in combination with metformin and the glitazones with good results.
Your doctor may ask you to take more than one type of tablet to control your blood glucose levels.
It is usual to add a tablet from a group which acts differently from what you have been taking.
As we can see from this figure, the increase in the blood glucose level can be brought down by
a) Increasing the secretion of, and decreasing the lag period in the secretion of, insulin from the pancreas ( sulfonylureas, meglitinides);
b) Decreasing the rate of rise of the blood glucose level after a meal by decreasing the rate of absorption (alpha-glucosidase inhibitors, ?metformin);
c) Decreasing the resistance to the action of insulin ( glitazone, metformin);
You will see that adding drugs from a different group which has a different action makes sense. Thus, whilst, one could add a metformin to a sulfonylurea, it would not make sense to add another sulfonylurea or a meglitinide if you are already taking a sulfonylurea.
Metformin can be added to a glitazone, as although belonging to the same category, their main actions are on different types of cells which supplement the actions of each other and lower the blood glucose levels.
No matter what category the tablet belongs to, it is NOT insulin!
The sulfonylureas and meglitinides can only act is the pancreas still has the ability to secrete insulin. Metformin and the glitazones can only act in the presence of insulin.
Which is why they cannot be used by themselves to treat Type 1 diabetes in which a patient has practically no insulin in the body.
Even the picture in Type 2 diabetes is quite different from what one sees in the Western countries. In India, as is true for many other countries, nearly 40% of people with Type 2 diabetes, have a decreased capacity to secrete insulin. So whilst, they can push out some insulin from the pancreas, this is never going to be adequate to meet the requirements. There is limit to how much one would be able to push the pancreas to increase the secretion of insulin by using sulfonylureas or meglitinides. To give an analogy, no matter how much you "whip" a lame horse, he will not be able to run as fast as one would want!
In such circumstances, even the glitazones and metformin have their limitations. Yes, they can make your body more sensitive to insulin, but there must be enough insulin available to take advantage of this increase in the sensitivity. Going back to our analogy, you can make the gates of the winning post larger, but the horse still has to reach there and a lame horse will not be able to do it!
If you have this type of diabetes, your doctor may tell you to take insulin injections.
Even if the tablets have helped control your diabetes for many a year, many of you will reach a stage where the tablets, no matter in what combination, will not be able to adequately control you. Here once again, your doctor may prescribe insulin to you.
Firstly, starting insulin does not mean that you have reached end stage or a very critical stage and that death is only a few months away! Many patients feel like this and it is completely untrue. It is just that your body does not have enough insulin and this deficit has to be made up with injected insulin. It is as simple as that!
What tablets can be combined with insulin injections? If you are taking insulin injections, then "stressing" your pancreas more does not make sense and therefore, I believe that sulfonylureas and meglitinides would have no role to play once you are taking insulin.
Metformin and alpha-glucosidase inhibitors can be combined with insulin as their actions are complementary.
Although used often, the combination of a glitazone with insulin is still a little controversial as both insulin and the glitazones can lead to fluid retention. In some patients with heart problems, there is a fear that it could precipitate heart failure.
But this is something which your doctor would be in a better position to judge and the decision to use insulin along with which tablets, if any, must be made jointly by you and your doctor.
The main point is that you have to look at the addition of insulin as just another way to control your blood glucose and not as if you have reached a critical terminal phase of your life!
It is important that you know about the tablets which you may have to take for many a year.
Knowledge, it is said is Power………and Power is Control!