Diabetes Talk: Questions & Answers

Question 1

Eli Lilly made the first insulin in 1923, sulfonylurea was approved in 1946.  There had been a long dry spell, nothing came out until 1995 when Metformin was approved.  The market has been inundated with the innovated new class of diabetes drugs over the past 10-20 years.  There were two classes (insulin and sulfonylurea) when I began my practice in 1975; there are twelves now.  Why?

Answer

Worldwide persons with diabetes more than doubled since 1980; 350 million as of 2008.  The figure came from an estimate by checking blood sugar of more than 2.7 million adults of 25 years or older in 199 countries.  It was 153 million in 1980.  The same is also true for Americans.

The pharmaceutical companies must have known this before we did.  Realizing the rapidly growing potential market, the pharmaceutical companies have mobilized their resource on R&D for diabetes drugs the past 10-20 years.  They go after the money and at the same time benefit the patients.

The companies heavily invested on developing diabetes drugs are Novo-Nordisk, Sanofi-Aventis, and Eli-Lilly, partnering with Boehringer Ingelheim.  Bristol-Myers spent nearly $6 billion to buy Amylin, which developed Byetta/Bydureon, and Sanofi-Aventis paid $3 billion to co-market it.

Question 2

In treating diabetes the American Diabetes Association (ADA) has a goal of HbA1c 7% whereas the goal is 6.5% for American Endocrine Society, which goal shall I follow?

Answer

It has been well established that better blood sugar control improves the risk of microvascular complications (eye, kidney and nervous system) in patient with type 2 diabetes.  Some argue that this can be achieved with HbA1c ≤ 7%. But every 1 percent drop in HbA1c is associated with improved outcomes with no threshold effect.

However the benefits have to be weighed against an increased risk of hypoglycemia associated with intensive or overzealous therapy.  So the HbA1c goal should be tailored to the individual, balancing the preventing microvascular complications with the risk of hypoglycemia.

My advice is that if one reaches 7% for HbA1c and never or rarely experienced hypoglycemia, then one can aim even higher to bring it further down to 6.5% or even 6%.

It is discouraging to notice that only one randomized clinical trial has demonstrated benefits on macrovascular (heart attack or stroke) outcome.

Question 4

Why are so many diabetes pill combined with metformin?

Answer

The first drug of choice in treating diabetes is metformin unless there are good reasons of not using it, such as impaired kidney function and diarrhea.  There is no controversy about it.

Diabetes is a progressive disease, the efficacy of metformin may not sustain for many years, sooner or later the second medicine will be needed.  Many diabetes drugs vie for being the second drug.  The advantage of combining with metformin is convenient (one less pill to take) and economical (one co-pay for two drugs).

Diabetes drugs combined with metformin include Invokamet (Invokana + metformin), Xigduo XR (Farxiga + metformin), Janumet (Januvia + metformin), Kombiglyze XR (Onglyza + metformin), Jentadueto (Tradjenta + metformin), Actoplus (Actos + metformin), and Avandamet (Avandia + metformin).

Question 5

My diabetes had been well controlled for some years, but my HbA1c has been creeping up of late; my doctor said I need the second drug, which one shall I take?

Answer:

Reading this long answer, you’ll be able to make a better informed decision.  There was an article in New York Times in May 2011, “For those with diabetes, older drugs are often best”.  It can be true for many patients, but “one size fits all” approach is not the best option.  It faults on being too opinionated.  Let’s work together to search for the “ideal” (if there is such a thing) second drug for you.  Please refer to the Table (below) as we go along.

Glucophage (metformin) decreases glucose production by the liver, decreasing intestinal absorption of glucose and improves insulin sensitivity.

Lactic acidosis is a rare, but potentially fatal (up to 50%) complication, which almost always occurs in the setting of impaired kidney function; it should be avoided if serum creatinine ≥ 1.5 (for men) or ≥ 1.4 (for women).

Sulfonylurea is the ‘oldest” diabetes drug; there is nothing wrong to use it; it is time tested and cheap.  The old saying of “Do not be the first to try the new medicine or the last to abandon old medicine” doesn’t apply here.  But, hypoglycemia is the issue, especially the longer-acting one (glyburide and chlorpropamide), which should be avoided.  Choose shorter-acting glipizide (Glucotrol) or glimepiride (Amaryl).

The drawback of sulfonylurea is that it tends to lose its efficacy over time, say 3 to 5 or 6 years at most.

Meglitinide is structurally different from sulfonylurea and binds to different receptors, but the mechanism of stimulating pancreas to produce more insulin is the same.  They should be treated the same as sulfonylurea, except may be less likely to cause hypoglycemia; they used to be more expensive than sulfonylurea.  Two drugs available: Prandin (repaglinide) and Starlix (nateglinide).

Actos (pioglitazone) is a reasonable choice, but keep in mind that it may cause or exacerbate congestive heart failure in some patients.  Increased incidence of bone fracture has been reported in women taking Actos.  Clinical trial data suggest an increased risk of bladder cancer in patients taking Actos. Avoid it in those who have active or history of bladder cancer.  However the debate about the relationship between Actos and bladder cancer is not settled; conflicting reports continue to emerge.

Like Actos, Avandia (rosiglitazone) is another thiazolidinedione, which is an insulin sensitizer, which is supposed to be an ideal drug to treat type 2 diabetes with root of problem being insulin resistance.

Speaking of Avandia, one cannot think about the story of the flip-flop of FDA.  Avandia was approved in 1999.  It was taken off shelf with severe restriction in 2011 as it was allegedly associated with increased heart attack.  The meta analysis was done by Dr. Steven Nissen, the cardiologist at Cleveland Clinic.  Thanks to Dr. Nissen’s report, Vioxx was withdrawn from the market.  If Dr. Nissen sneezes, the big pharmaceuticals may catch cold.

FDA lifted the restriction in November 2013 after the independent review conducted by Duke University found no evidence that Avandia may cause heart attack.  It was said that “May be people will quit taking Steven Nissen too seriously”.

The two relatively new classes (DDP-4 inhibitors and GLP-1 receptor agonists) are related, working on the same system.  Incretin (of which GLP-1 is the major one) is the hormone secreted by intestine once food (carbohydrate) reaches there.  Incretin works by stimulating pancreas to produce more insulin. Unfortunately incretin is very short lived; it is quickly deactivated by an enzyme called DDP-4.

There are two approaches to keep the active incretin last longer.  One is to inhibit the enzyme (DDP-4) activity, so incretin will remain active to do its job.  The other one is to make something structurally similar to incretin (analogue), and yet cannot be deactivated by DDP-4, an incretin mimetic, that is.

As of now there are four DDP-4 inhibitors

-          Januvia (sitagliptin)

-          Onglyza (saxagliptin)—may cause heart failure; its fate is doomed.

-          Tradjenta (linagliptin)

-          Nesina (alogliptin)

and five (actually four) GLP-1 receptors or incretin mimetics.

-          Byetta and Bydureon (both are exenatide: Byetta is twice a day and Bydureon is once a week injection)

-          Victoza (liraglutide—once a day injection)

-          Tanzeum (albiglutide—once a week injection)

-          Trulicity (dulaglutide—once a week injection)

Comparing with DDP-4 inhibitors, GLP-1 receptors agonists are more effective (not by much, though) in bringing down HbA1c and cause more weight reduction, but pay the price of having more anorexia, nausea or even vomiting.  GLP-1 receptors agonists are given by subcutaneous injection (just like insulin) and DDP-4 inhibitors are taken orally.

GLP-1 receptor agonists and DDP-4 inhibitors have been implicated causing pancreatitis or even pancreas cancer, especially GLP-1 receptor agonists, all be it rarely.  Do not use them if one has history of pancreatitis.

Welchol (colesevelam) is a bile acid sequestrant that binds bile acids (cholesterol is the precursor of bile acids) in the intestine, preventing it from being reabsorbed back to circulation.  This increased excretion of bile acids results in an increased oxidation of cholesterol to bile acids, thus lowering serum cholesterol.  The mechanism by which it lowers blood sugar is unknown.

Welchol is not very popular treating diabetes.  The blood sugar-lowering effect is modest and taking 6 big tablets a day is not very appealing to many.

Welchol may raise triglyceride, especially in those who also takes insulin or sulfonylurea.  If serum triglyceride is above 500 mg/dL is a contra-indication as too high a triglyceride may induce pancreatitis.  Welchol may also cause constipation and should be avoided in those who had history of bowel obstruction.

Lowering LDL is of importance in ones with diabetes.  The main appeal of Welchol is it lowers both LDL and blood sugar; one stone two birds, so to speak.

They are two α-glucosidase inhibitors: Precose (acarbose) and Glyset (miglitol).  α-glucosidase is the enzyme that breakdown complex carbohydrate (a large molecule) to eventually glucose that is small enough to be absorbed.  Precose and Glyset inhibit this enzyme, so that complex carbohydrate cannot be absorbed, but one pay the price of having diarrhea, abd cramp and flatulence, etc.

The chance that you may use Amylin analogue or Bromocryptin (Cycloset) is extremely rare and will not be discussed here.

The newest class of the arsenal of diabetes dugs at your doctor’s disposal is SGLT-2 inhibitor.  Please refer to the following link for further discussion.

http://doctorjytsai.blogspot.com/2015/07/diabetes-talk-sglt-2-inhibitor-on-gods.html

Question 6
How about insulin?

Answer:
It calls for a session of "Questions & Answers" of its own; stay tuned.