Wednesday, November 13, 2013

PCOS and Diabetes: Glucose-Lowering Medication Options

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. Today, let's discuss the use of glucose-lowering medication options for those who have developed diabetes.

So far we've talked about PCOS's definition and symptoms, how it presents, its testing and diagnosis, and its possible causes. Now we are discussing common treatment protocols for PCOS, and the pros and cons of each.

We've already discussed insulin-sensitizing medications like metformin, the TZDs, and inositol.

Now let's chat about medication options for lowering blood sugar for those women with PCOS who have already developed diabetes. These drugs are not to treat PCOS per se, but to treat diabetes, which many women with PCOS develop at some point as they age.
Disclaimer: I am not a medical health-care professional. While the following information is based on my best understanding of the research, always do your own research. This information is not a complete explanation of all the risks and benefits of a particular medication, nor is it medical advice about a health condition or treatment. Consult your healthcare provider before making any decisions about your care plan.
Trigger Warning: Passing mention of the possible weight effects of several medications, and a mention of the emphasis on weight loss in typical diabetes treatment.

How different blood sugar medications affect the body
It is an unfortunate truth that many women with PCOS will probably develop full-blown diabetes at some point in their lives. As a result, women with PCOS often need to inform themselves about diabetes medication choices. This post is designed to help with that process.

For a long time, doctors had few choices for medicines to treat Type 2 diabetes. In the past 20 years, however, their choices have greatly expanded. Now there are so many choices, it's hard to know which is the best choice for any one person. Negotiating this maze can be confusing for care providers, let alone consumers.

But basically, diabetes medications attempt to address the two main problems of type 2 diabetes:
  1. Insulin Resistance, which makes it hard for the body to utilize its own insulin optimally
  2. Pancreatic Beta Cell Defects, which makes it hard for the body to produce enough insulin for its needs
Most diabetes medications reduce blood sugar by either reducing insulin resistance, stimulating the body's own insulin secretion, or by delaying carbohydrate absorption.

Remember, diabetes is usually a progressive condition. What works at first to control blood sugar will gradually become less effective. Treatment must change over time to reflect the needs of the patient.

Lifestyle changes can be helpful for some at first, but eventually most diabetics need medication. This post will discuss diabetes drug options, including some of the newer medications. However, it is not meant to be a complete discussion of these options; rather, it is an introduction to some of the more common options out there.

The most common medications used to control high blood sugar include:
  • Insulin Sensitizers - medications to lessen insulin resistance 
  • Secretagogues - medications to force the pancreas to secrete more insulin 
  • Alpha-Glucosidase Inhibitors - medications to delay carbohydrate digestion
  • Incretin Mimetics - synthetic gut hormones to increase insulin production, but only in response to high blood sugar (technically also a secretagogue, but by a different means)
There are other drugs that control blood sugar in other ways, but they are less common and will not be covered in this post.

Because each person has unique needs, conditions, and reactions to medications, it's very important to consult closely with your care provider when developing your care plan.

If you find your care provider is not listening to you or treats you poorly because of your size or PCOS status, then vote with your feet and find a new care provider. The last thing you should do is go without care or put up with suboptimal care.

Managing diabetes is not an easy task, but it is critical to your long-term health. Therefore it's important that you have a care provider you can trust, who truly has your best interests at heart, and who listens to your input. Keep searching till you find one of these.

Insulin Sensitizers

Over time, many people become resistant to their own insulin, causing the body to try to crank out more and more insulin to compensate. Eventually, the pancreas can no longer produce enough of its own insulin to keep blood sugar normal. Blood sugar rises and complications start to develop.

Rather than keep on adding more insulin to the mix, one of the most logical diabetes treatments is to encourage the body to use its own insulin more efficiently.

Exercise is one of the best ways to improve insulin sensitivity, so regular exercise (both aerobic and weight training) is one of the rock-solid pillars of diabetes treatment. Research shows that exercise alone can lower blood sugar significantly, sometimes by 0.5 - 1% of the HbA1c reading. This is as good as some diabetes medications.

However, as diabetes progresses, exercise alone may not be enough. Insulin-sensitizing medications can help. It used to be that these were only prescribed once a trial of diet and exercise had failed to keep blood sugar normal. Now, however, the standard of care is to start an insulin-sensitizing medication along with diet and exercise as soon as diabetes is diagnosed. Outcomes seem to be better by starting multiple modes of care at once.

[Note ─ "diet" in this context does not have to mean a low-calorie or reducing diet, but rather a way of managing food intake that keeps the blood sugar as normal and as stable as possible. This has more to do with timing, choice, and combination of foods than anything else.]

Of course, Insulin Resistance (IR) is not just a problem of diabetes; it is also one of the primary problems in PCOS. Most women with PCOS have hyperinsulinemia (too much insulin), probably caused by problems with insulin signaling pathways or insulin receptor defects. The theory is that by encouraging the body to use its own insulin better, some of the hormonal imbalances of PCOS may be lessened.

As a result, insulin-sensitizing drugs are a cornerstone of therapy for both women with PCOS and Type 2 Diabetics.

As we've mentioned before, there are two main drug classes used to improve insulin sensitivity, the biguanides and the thiazolidinediones (also known as glitazones or TZDs).

The primary insulin-sensitivity drugs on the market today are the biguanide Glucophage (metformin) and two TZDs, Avandia (rosiglitazone) and Actos (pioglitazone). Because these drug classes have been extensively discussed in previous posts, they will only be briefly summarized here.

Metformin is the first-line treatment of choice in diabetes. It works primarily by decreasing glucose output by the liver, but also improves insulin sensitivity elsewhere in the body.

Its long record of safety and efficacy makes metformin an excellent choice for most diabetics, despite the G.I. side effects that some people experience. It is inexpensive and extremely effective, lowering A1c blood sugar on by about 1-2% on average. It has been shown to improve not only clinical risk factors, but also long-term outcomes (endpoints like cardiovascular events and death). This is a huge advantage that no other diabetes drug can claim at this time.

Because of its effectiveness against insulin resistance, many care providers also prescribe metformin for women with PCOS. Although not every care provider agrees, many care providers see metformin as the drug of choice for PCOS, regardless of glucose status. Certainly, in pre-diabetic and diabetic women with PCOS, it is the first drug that should be tried.

Another effective insulin-sensitizer is the family of TZDs (glitzaones). TZDs also are extremely effective at reducing blood sugar, also around 1-2% A1c on average, and improve symptoms of PCOS. They often work in people who are resistant to metformin.

TZDs improve glucose uptake and insulin sensitivity in muscle and fat tissue in the body. They work by stimulating peroxisome proliferator-activated receptors (PPARs); most of the current generation of TZDs stimulate the PPAR-gamma receptor. Future generations of TZDs may stimulate other PPAR receptors (or multiple receptors).

Unfortunately, the current generation of TZDs have been associated with increased cardiovascular risk or liver toxicity; Rezulin (troglitazone) was pulled from the market, and Avandia (rosiglitazone) has been restricted in some countries. On the other hand, Actos (pioglitazone) so far seems to have fewer side effects and is still in regular use.

In addition to metformin and the TZDs, an emerging class of insulin-sensitizers are the inositols (myo-inositold-chiro inositol). Inositols work by improving insulin signaling, which helps the body use its own insulin more effectively. They seem particularly effective for women with PCOS. They received a lot of buzz at first and are now experiencing a resurgence of interest, but research is still emerging on their safety and efficacy.

Metformin, TZDs, and inositols are all used in women with PCOS, although their use in those who still have normal blood sugar is controversial. Some care providers feel they should be reserved only for those who have developed diabetes, while others feel that they should be utilized long before diabetes develops in order to help prevent or delay it, as well as to minimize symptoms of PCOS.

Regardless, insulin sensitizers are one of the most important medications for both PCOS and diabetes, because they help the body use its own insulin more efficiently. This is the first and most important goal for clinicians to address.

Insulin Secretagogues: Increasing Insulin Production

There are several classes of drugs commonly used to lower blood sugar in diabetics. One of the oldest is the secretagogues, including sulfonylureas and meglitinides. These work in a different way than the insulin-sensitizing drugs.

Remember, in Type 2 diabetes, the problem is usually both insulin resistance and a relative shortfall of insulin relative to the body's needs. It's not just the body's resistance to its own insulin, but also that the pancreas cannot produce enough to compensate, either because of an inborn beta cell defect or because the pancreas has exhausted itself.

The secretagogues work on this problem by forcing the pancreas to produce more insulin, which in turn, helps to lower blood sugar. If there is enough pancreatic beta cell reserve, these drugs can work quite well. If there is not enough pancreatic beta cell reserve, however, these medicines don't work very well.

Use of secretagogues is controversial in women with PCOS. These drugs do not reduce the hyperinsulinemia of PCOS and may actually worsen outcomes because they force the pancreas to produce more insulin. However, because high blood sugar causes so much damage in the body, they are often still used with diabetics (PCOS or not) if normal blood sugar cannot be achieved on metformin or a TZD alone.

Sulfonylureas are the most common secretagogue and were the first widely-used oral anti-diabetes medication. Modern versions include drugs like glimepiride, gliclazide, glibenclamide (glyburide), and glipizide. An older version that is still sometimes used is tolbutamide.

The advantages of sulfonylureas are that they are extremely effective at lowering blood sugar and are available in generic forms so they are very affordable. They work quickly, are taken orally, and are easy to dose.

The side effects of sulfonylureas nearly always include some weight gain and periodic episodes of low blood sugar (hypoglycemia) as a result of the increased insulin. Hypoglycemic episodes can be dangerous, so this is a serious side effect that must be watched for carefully. A regular meal schedule is important, and meals should not be delayed or skipped.

Sulfonylureas are often quite effective at lowering blood sugar at first but lose their efficacy over time as the pancreas exhausts itself from producing more and more insulin. They may also increase the risk of poor long-term outcomes like cardiovascular disease and cancer-related mortality compared to treatment with metformin. This is a serious disadvantage, but the risk may vary strongly by which sulfonylurea is used.

Meglitinides are another medication that make the pancreas produce more insulin. These drugs include repaglinide (Prandin) and nateglinide (Starlix). They are similar to sulfonylureas but work on a different binding site in the pancreatic beta cells. They also differ in how they are excreted and how long their effects last.

Meglitinides have side effects similar to the sulfonylureas, including weight gain and low blood sugar episodes. However, the side effects are usually less severe than with the sulfonylureas. They are taken shortly before meals, have a quick effect on insulin production, and are particularly helpful in lowering postprandial blood sugar (the rise in blood sugar after eating). This can be a key advantage for people who have normal fastings but significantly raised postprandial readings.

Repaglinide has been shown to be effective in lowering blood sugar, even in elderly patients and in those with kidney disease. It is usually used in combination with metformin and has been shown to be more effective than metformin alone. However, its disadvantage is that it is expensive and can result in low blood sugar episodes.

Obviously, medications that increase insulin production are not ideal for most women with PCOS, since they already produce far too much insulin. These medications can temporarily improve blood sugar but may worsen PCOS symptoms. This is why the first-choice drugs for diabetic women with PCOS are usually insulin-sensitizers.

However, sulfonylureas and meglitinides are very effective at lowering blood sugar long-term, and are usually fairly well tolerated. Thus, they are often part of diabetes treatment, even in women with PCOS, because as diabetes progresses, keeping blood sugars as normal as possible will hopefully help prevent the most serious complications of diabetes, like heart disease, stroke, neuropathy, or eye damage. This may be worth the trade-off of possibly worsening PCOS symptoms.

Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors are another medication option for diabetics.

This group includes acarbose (Precose) and miglitol (Glyset). These are oral medications and should be taken with the first bite of each meal. They inhibit the production of alpha-glucosidase enzymes, which are intestinal enzymes needed to digest carbohydrates.

These medications act by delaying carbohydrate absorption, which can help lower blood sugar. They also lower insulin levels somewhat. They primarily affect post-meal blood sugar levels because they inhibit the enzymes close to the stomach and delay carbohydrate digestion to lower in the intestines. Blood sugar will still go up, but much more slowly and evenly, which will also help blunt the insulin surge the body produces in response to a quick rise in blood sugar.

However, these medications don't lower blood sugar all that much. Some sources state that they lower the HbA1c only by 0.5 - 0.8%. They have little effect on lipids or bodyweight. The effect, if any, on mortality or cardiovascular events is unclear.

The good news is that this medication does not increase insulin secretion in the pancreas, so it should not add to hyperinsulinemia problems in women with PCOS. Because it doesn't increase insulin production, it doesn't usually cause low blood sugar episodes or weight gain unless combined with a sulfonylurea or meglitinide. Another advantage is that acarbose has been on the market since 1995 and an affordable generic form is available.

The bad news is that because it delays carbohydrate absorption, it has lots of G.I. side effects, including diarrhea and gas/bloating. In one study, as many as 50% of people who took these medications experienced significant G.I. symptoms, although this number decreased to 14% over time.

More is not better; high doses result in more G.I. side effects without an increase in efficacy. If you are prescribed acarbose, slowly increasing the medication dosage over time and reducing the amount of carbohydrate in a meal may help reduce G.I. side effects.

Because of the G.I. side effects, it should not be prescribed to people with Inflammatory Bowel Disease or Crohn's Disease. Hepatitis may also occur, so liver enzymes must be monitored while on this drug.

Because it offers only mild advantages in exchange for significant side effects, this medication is not used as much as other diabetes medications, but it can be used in combination with them to improve blood sugar via multiple pathways.

It seems most useful for those who are recently diagnosed with diabetes and those who have normal fasting blood sugars and only mildly-elevated post-meal readings.

Incretin Mimetics

Image from Gallwitz 2010
A fairly new but much-heralded class of anti-diabetes drugs includes the incretin mimetics.

Incretins are G.I. hormones like glucagon-like peptide (GLP-1) that are produced by your own body. They help your body respond to glucose production from food. They are responsible for much of your insulin response to food intake.

Incretin mimetics are a man-made version of these G.I. hormones, synthesized from other substances. They are designed to work like your body's own incretins, but to have a longer-lasting effect.

Technically, incretin mimetics are also a secretagogue because they help the body produce more insulin, but are generally discussed separately from sulfonylureas and meglitinides because they act only in response to raised blood sugar. 

Once your blood sugar is normal, the action of incretin mimetics shuts off, making low blood sugar episodes less likely. Sulfonylureas, on the other hand, cause your pancreas to keep churning out insulin no matter what your blood sugar is doing, making low blood sugar episodes more likely. This is a very important distinction.

Your own gut incretins work by causing your pancreatic beta cells to release more insulin, by inhibiting glucagon release from pancreatic alpha cells (thereby keeping your liver from dumping its stored glucose into your body), and by slowing absorption of nutrients into the blood stream by reducing gastric emptying.

Incretins also increase pancreatic beta cell proliferation, lessen beta cell death, and improve first-phase insulin release. 

In other words, they help the pancreas work more quickly and efficiently, and they help preserve pancreatic function longer. This is a huge benefit. They are the only medication that is thought to help keep or even improve beta cell function, which may delay or keep diabetes from progressing so quickly.

The problem with your own body's incretins is that their effect doesn't last long; they work for just a few minutes and then they are blocked by DPP-4 enzymes. So for a long time, incretins really weren't that useful for helping to control blood sugar in diabetics; you'd have to receive a continuous infusion for them to help.

But now there are incretin mimetics, synthesized from other sources, that are similar to your own incretins but changed just enough to be effective. They are called "mimetics" because they mimic the action of your own G.I. incretin hormones, but are not quite the same because they make the effect last longer. Incretin mimetics include:
  • GLP-1 receptor agonists
  • GLP-1 analogs
  • DPP-4 inhibitors
GLP-1 Receptor Agonists are the most common form of incretin mimetics. They are a protein, so if they were taken orally, they would be digested. Therefore, they must be injected in order to be effective.

Byetta (exenatide) is a synthetic version of a substance found in the saliva of Gila monster lizards. It is a GLP-1 receptor agonist that is just different enough from your own body's GLP-1 that it is absorbed more slowly. It can lower A1c numbers by up to 1.5%, which is quite significant.

Byetta must be injected twice a day, preferably an hour before breakfast and dinner. It slows down the progression of food or medicines through the intestinal tract, so any oral medications should be taken an hour before Byetta is injected.

Like insulin, it should be kept out of hot temperatures and direct sunlight. The manufacturer recommends refrigerating it until it is first opened, then storing it in a cool area for up to 30 days.

Byetta's G.I. side effects include nausea, vomiting, and diarrhea. Many people report a feeling of fullness, stomach discomfort, and nausea when first starting the drug. These effects are reduced after a few weeks, but may recur periodically.

Byetta is excreted via the kidneys and so should not be used in people with severe kidney disease. It can sometimes cause headaches, sweating, acid reflux, or thyroid issues. It has been under close scrutiny for a possible increase in pancreatitis, and should not be prescribed to anyone with a history of pancreatic issues, alcohol abuse, or a family history of thyroid cancer.

Doctors like Byetta because it often results in a small weight loss (about 2-10 lbs.), and can be used in conjunction with metformin, TZDs, or sulfonylureas. The main disadvantage to Byetta is that it must be injected, and multiple times per day at that.

The drug companies have responded to this concern by creating a long-acting version (Bydureon); patients only have to inject it once a week instead of twice a day. So far, the long-acting version seems to improve blood sugar better and reduce some G.I. issues, but longer trials are needed.

Victoza (liraglutide) is a GLP-1 analog. It is structurally very close to the GLP-1 hormone that naturally occurs in the human body.

Its main advantages are that it only has to be injected once per day, without regard to time of day or mealtimes, and it has a low rate of low blood sugar episodes. It also improves triglyceride levels better than Byetta, although whether this has any long-term effect on cardiovascular events is unknown.

Its main side effect is mild nausea. Some studies suggest it may lower blood sugar even more than Byetta. It has also been shown to lower blood pressure and sometimes result in a small amount of weight loss. However, it is a newer drug (FDA-approved in 2010) and only time will tell how safe it is.

So far, the GLP-1 drugs do not seem to increase cardiovascular risk in the short term (and may help decrease blood pressure and cholesterol), but more research is needed to confirm this and to investigate its long-term effects.

Like Byetta, Victoza should not be prescribed to people with a history of pancreatitis or thyroid cancer. Caution should also be taken in people with a history of gallstones.

DPP-4 inhibitors act by inhibiting the enzyme that inactivates the body's own GLP-1, thus increasing your own GLP-1's length of effect in the body.

Januvia (sitagliptin) is the most famous of the DPP-4 inhibitors, although there are others as well (saxagliptin/Onglyza, vildagliptin/Galvus, and linagliptin/Tradjenta). Januvia was approved by the FDA in 2006.

The main advantage of DPP-4 inhibitors is that they can be taken orally, as opposed to the GLP-1 drugs which must be injected. DPP-4 inhibitors also result in less nausea and so are better tolerated by many patients.

However, they do not decrease blood sugar as well as GLP-1 drugs, and they are usually weight neutral (no gain but also no loss, which of course most doctors see as a disadvantage). Other side effects include an increased reporting of respiratory infections and cold-like symptoms with nearly all the DPP-4 inhibitors. Headaches may also be increased.

On the other hand, when combined with metformin, DPP-4 inhibitors improved post-meal blood sugars far better than metformin alone, which also improves long-term blood sugars (A1c) more efficiently.

One of the most exciting potential effects of DPP-4 inhibitors is that they are thought to preserve or even improve pancreatic function, thus maintaining the patient's own insulin function over time. Since the progression of diabetes involves declining pancreatic function, DPP-4 inhibitors are sometimes prescribed early on in the treatment of diabetes, either as a stand-alone therapy or in combination with metformin or TZDs, in order to delay the progression of diabetes and give the patient more time before drugs with more serious side effects are needed.

recent drug trial found that DPP-4 inhibitors did not increase the risks of heart attack, pancreatic inflammation or cancer, but may modestly increase the risk for heart failure. They should not be prescribed in conjunction with sulfonylureas but, as noted, may be prescribed with metformin or the TZDs.

All in all, the incretin mimetics seem to be a major advance in treating diabetes, especially when other treatment options (like metformin) aren't enough. They effectively lower blood sugar, and have modest beneficial effects on blood pressure, insulin sensitivity, cardiovascular risks, and other clinical goals. Many clinical guidelines now promote early use of incretin mimetics, rather than waiting until the diabetes has progressed.

However, they are a relatively young drug class, so more research is needed. They may raise the risk for thyroid cancer, for example. Since each drug presents its own unique profile of benefits and risks, careful clinical judgment is needed to individualize their usage appropriately.

The other major disadvantage of the incretin mimetics is that they are very expensive (several hundred dollars a month, usually), and many insurance plans do not cover them.

Combination Drugs

Image from Medscape (link in references)
Diabetes treatment these days often combines two or more drugs together. Rather than using an ever-increasing dose of one drug, care providers often prescribe two drugs instead to work on blood sugar in different ways and therefore lower blood sugar more effectively.

This combination therapy offers a distinct advantage in that it targets not only insulin resistance, but also pancreatic beta cell function and hepatic (liver) glucose production.

Combination therapy often has better results than monotherapy. Research shows that more patients reach blood sugar target ranges when two drugs are used than when one drug is used at a higher dose.

Combining two medications into one pill also makes it simpler and more convenient for the consumer, making them more willing to take the drugs as needed. Furthermore, the drug company is able to hold onto exclusive patent use longer for the drugs, thus prolonging their profit margins.

Time will tell if these combination therapies truly improve long-term outcomes better than monotherapy, but so far results seem promising. Here are some common combination drugs:
  • Metaglip is a combination of metformin and the sulfonylurea glipizide (a generic form is available)
  • Glucovance is a combination of metformin and the sulfonylurea glyburide (a generic form is available)
  • Janumet is a combination of metformin and the DPP-4 inhibitor sitagliptin/Januvia
The Importance of Reducing Stigma

The bottom line is that women with PCOS are profoundly vulnerable to developing Type 2 diabetes at some point in their lives and thus need good information about the latest diabetes drug choices.

It should be pointed out that this tendency towards diabetes does not reflect a lack of willpower or a poor lifestyle, but rather the underlying metabolic issues of PCOS. This cannot be emphasized enough.

In our society, there is far too much shaming and blaming around the development of Type 2 Diabetes. This leads many people to put off or avoid medical treatment until their blood sugar is very high or they have developed significant complications.

It also blames people for developing something that may have far more to do with an inborn metabolic defect than with their habits. Although poor habits can impact health and personal responsibility is important, there are many people with very poor habits who never develop diabetes, and some people with very reasonable habits who do develop diabetes. It's rarely related to only lifestyle, but more to a combination of factors, some of which are modifiable and some of which are not.

In the case of PCOS, there is almost certainly some sort of underlying metabolic defect that predisposes these patients to diabetes. Combine that with low pancreatic beta cell reserve, and you get early-onset diabetes that has nothing to do with habits or personal responsibility.

Careful attention to nutrition and exercise and use of some medications may help prevent or delay some cases but many women with PCOS will develop diabetes despite their best efforts. Therefore it's important to reduce the stigma of this diagnosis so it can be diagnosed quickly and treated effectively.

Finding diabetes early on can help delay the progression of diabetes, and may even prevent some of the more serious complications. It's important that women with PCOS feel comfortable in getting yearly blood sugar tests to make sure any problems are caught quickly, and that those who do develop diabetes get treatment that does not shame them or inhibit their willingness to pursue treatment. Yet far too many receive scoldings and blame and reluctance to prescribe any help except dieting.

The scoldings, shaming, and emphasis on weight loss at any cost causes many fat people to avoid or delay seeing a doctor. It should be pointed out that although weight loss is sometimes helpful to blood sugar in the short term, it often leads to regain and a higher weight than the patient began with. In addition, recent research suggests that it does not decrease cardiovascular events.

Care providers need to take a more nuanced view of weight loss as the foundation of diabetes prevention and treatment. While some patients will want to pursue weight loss, others will not because they do not want to risk rebound weight cycling or because they are concerned about developing disordered eating patterns. Opting out of weight loss treatment can be a legitimate choice and should be respected by care providers.

It's important for patients to know that lifestyle tweaks (like increasing exercise or lowering carbohydrate intake) can often improve blood sugar and other risk factors significantlyindependent of weight loss. Lifestyle tweaks do not have to involve weight loss to be effective. Care providers need to incorporate more Health At Every Size models that emphasize healthy habits and improving lab numbers instead of focusing only on the scale.

The current stigma around the diagnosis and treatment of Type 2 diabetes just adds to the disease burden felt by people with diabetes and PCOS, and may well backfire in trying to improve outcomes in this group.*

Summary of Diabetes Medication Options
Image from Medscape and Joslin Diabetes Center

The good news is that people with diabetes are living longer and with a better quality of life now, thanks to easier self-monitoring and better medication options.

However, it is very difficult to find the "perfect" diabetes drug because there are so many competing priorities. You need a drug that:
  • reduces insulin resistance
  • improves pancreatic beta cell function
  • reduces blood sugar, both fasting and after meals
  • reduces the average blood sugar over time (A1c)
  • does not cause low blood sugar episodes
  • does not have side effects (or only mild side effects)
  • does not cause weight gain
  • delays the progression of diabetes
  • is safe for people with kidney or liver impairment
  • does not have many drug interactions, especially with blood pressure or lipid drugs
  • is easy to take (preferably once daily)
  • is not too expensive
  • is covered by most insurance
Unfortunately, there is no drug that meets all of these criteria. All involve a trade-off of some sort. This is the challenge of treating diabetes, to find the "sweet spot" of treatment that involves the most benefits for the fewest risks.

What's most important is that blood sugar is lowered. That is the most important goal of diabetes treatment, and patients may have to accept some side effects or disadvantages in order to achieve this most basic goal. What side effects or trade-offs are acceptable, however, will differ from person to person.

Because of decreasing pancreatic function leads to diabetes progression, sooner or later nearly everyone with diabetes is going to need some sort of medication. 

Which drug is used will depend on how high your blood sugar is, what additional complications you may have developed, what other medications you may be on, the side effects you experience, and how you respond to the various options. An individualized treatment plan is important and will change over time in response to your condition.

The medication uniformly recommended as the first-line choice of therapy in diabetes is metformin. It is comparatively safe and well-tolerated, and is quite effective at lowering A1c levels. In addition, it works to increase insulin sensitivity, which in turn seems to improve long-term outcomes, including cardiovascular disease and death.

TZDs are another insulin-sensitizing medication which can be used in patients who do not tolerate metformin or who are metformin-resistant. Many people with severe diabetes are able to normalize their blood sugar with a combination of metformin and a TZD. However, TZDs come with significant risks, including edema, liver issues, and heart failure. They should only be used with caution.

The inositols are another option for lessening blood sugar and improving insulin sensitivity. D-chiro-inositol seems to be more effective for this than myo-inositol, and may be particularly effective for women with PCOS. However, studies so far are small and of uneven quality. It is also not clear how inositols may interact with other medications. Research is ongoing.

Secretagogues such as sulfonylureas and meglitinides can be used in addition to metformin or a TZD. They work by forcing the body to continually produce more insulin. They are extremely effective in lowering blood sugar in those people with significant pancreatic reserves. However, these drugs have substantial side effects, and they may increase the risk for cancer and cardiovascular issues. Because they increase insulin production and most women with PCOS already have too much insulin, their use in PCOS is more questionable but cannot be ruled out.

Alpha-glucosidase inhibitors like acarbose slow down digestion of carbohydrates enough to blunt post-meal blood sugars significantly. Although they do not lower blood sugar as much as some other medications, they can still be useful for some patients, especially early in the course of diabetes.

Incretin mimetics are a fairly new class of drugs and we are still learning about their risks and benefits. Thus far, they are a very promising addition to diabetes treatments but longer-term research is needed.

DPP-4 inhibitors are often prescribed to newly diagnosed diabetics nowadays because they are thought to preserve pancreatic function fairly effectively. However, they are not as effective at lowering blood sugar, so they are usually prescribed in conjunction with metformin or a TZD.

GLP-1 agonists and analogs are injectable medications that mimic your own body's GLP-1 proteins but their effect lasts longer. Like sulfonylureas, they increase insulin secretion, but unlike sulfonylureas, they shut off when normal blood sugar is reached, decreasing the risk for low blood sugar episodes. They are often utilized when other medications start being less effective.

These are the main types of glucose-lowering medications on the market today. There are other types of glucose-lowering drugs (for example, SGLT-2 inhibitors, dual PPAR agonists, amylin agonist analogs), but those are much less commonly used or are very new to the market. In most cases, the drugs discussed earlier are the main diabetes medications you will encounter right now.

However, there are sure to be new drugs in the future, so it's important to keep on top of the latest research. When considering a new drug, remember that medications are always a work in progress. Serious side effects may not become apparent until population-wide use, like with some of the TZDs. So while many of these newer medications have great advantages, long-term use may turn up problems currently unknown to us.

And of course, even the best medications always have pros and cons, risks and benefits. The complete profile must be considered when deciding on a treatment plan. Sometimes a known risk is worth taking if the advantages of the medication are strong enough, but this trade-off can only be judged on an individual basis.

Another important point is that people respond differently to drugs. One woman may do extremely well on metformin with minimal side effects, while another cannot tolerate the G.I. side effects. Another may need metformin plus additional drugs in order to achieve normal blood sugar and reduce long-term complications. Still others may be able to achieve good results with only lifestyle, herbs, or alternative medicine options.

There is no one standardized treatment that is right for everyone. That's why it's so important to discuss the benefits and risks of all your treatment options with a trusted care provider. Do your research so you can become a partner in your own care.

Remember, a big limitation on our discussion here is that we do not have much information on the use of these drugs for women with PCOS. Most of the information we have on these drugs has been done on the type 2 diabetes population only, so their effect on diabetic women with PCOS is often speculative.

The bottom line is that data on the long-term efficacy and safety of these drugs in PCOS populations is urgently needed. 


*See the links in the post for many further references. Be aware that many of these references are very mainstream and so strongly promote weight loss as "the" treatment of choice.

Overview of Various Diabetes Medications

Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Mar. Report No.: 11-EHC038-EF.
AHRQ Comparative Effectiveness Reviews.  PMID: 21735563
...The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. RESULTS: The review included 140 randomized controlled trials and 26 observational studies..Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users...Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.
Links with Information on Various Diabetes Medications
Alpha-Glucosidase Inhibitors

Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003639. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. PMID: 15846673
BACKGROUND: Alpha-glucosidase inhibitors such as acarbose or miglitol, have the potential to improve glycemic control in type 2 diabetes mellitus. The true value of these agents, especially in relation to diabetes related mortality and morbidity, has never been investigated in a systematic literature review and meta-analysis...MAIN RESULTS: We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life...AUTHORS' CONCLUSIONS: It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated hemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.
Incretin Mimetics

Rev Diabet Stud. 2008 Summer;5(2):73-94. doi: 10.1900/RDS.2008.5.73. Epub 2008 Aug 10.
Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors. Pratley RE, Gilbert M. PMID: 18795210
...Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.
Am J Manag Care. 2010 Aug;16(7 Suppl):S187-94. Incretin-based therapies in the management of type 2 diabetes: rationale and reality in a managed care setting. Garber AJ. PMID: 20809667
...The recently introduced incretin-based therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving beta-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin. Earlier and more frequent use of these incretin-based therapies is recommended in the treatment of type 2 diabetes, based on their overall safety and ability to achieve the glycosylated hemoglobin level goal. As such, both the American Diabetes Association and the American Association of Clinical Endocrinologists/ American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naive and previously treated patients. The AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy.
Further studies/information on Incretin Mimetics:

*To the trolls: No, I do not have diabetes at this time. I write about this topic because I know that with PCOS, I am very likely to develop diabetes at some point. I also write about it because I have seen good friends treated so poorly by care providers that their diabetes went undiagnosed or under-treated for too long. I write about this because women need better and less-judgmental information in order to optimize their outcomes and quality of life.


Anonymous said...

Thank you so much for this beautiful round up!

superhumanradio said...

great blog thanks for keeping the awareness up. My whole family is diabetic and I am doing everything I can to prevent or prolong it .