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.

Diabetes talk: SGLT-2 inhibitor: On God’s ingenious design and the evolving concept of the disease

I gave a talk at the Taiwanese Bible Study last Saturday; one of the topics was “What’s new on diabetes?”  Of the many families/classes of diabetes drugs (12 in all), the newest arrival is sodium glucose co-transporter (SGLT-2) inhibitor, which includes Invokana (canagliflozin), Forxiga (dapagliflozin) and Jardiance (empagliflozin). These agents prevent the filtered glucose from being re-absorbed back to the circulation in the kidney, thus lowering blood sugar.

There are a few interesting things about SGLT-2 inhibitors worthy talking about in my blog.

Reabsorption of glucose is God’s ingenious design
The Figure (below) shows the renal tubules, parts of a nephron, of which there are about one million in each kidney.  The main function of the kidney, through its nephrons, is to get rid of the waste by filtering them into the renal tubules, excreting in the urine. 

The problem is that glucose also filters from blood into renal tubules, which was not God’s intention as glucose (“fuel of life”) is good stuff; it is supposed to enter cells to be burnt to produce ATP (energy).  He therefore designed an ingenious way to have almost all filtered glucose (about 180 grams a day) reabsorbed back to circulation.

The task is not easy as it is against the sodium gradient, it involves sodium/potassium ATPase pumps (ATPase means the pump is powered by ATP), energy must be spent to conserve the precious stuff (glucose); it uses the sodium glucose co-transporter (SGLT), a protein, to transport glucose back to circulation.

There are two different types of SGLT: SGLT-1 and SGLT-2.  90% of glucose is transported by SGLT-2 from renal tubules back to circulation; the rest (10%) is by SGLT-1.  This is why SGLT-2 is targeted.  These new drugs (Invokana, Forxiga, and Jardiance) inhibit and disable the SGLT-2 transporter, the glucose remains in the renal tubules, excreting into urine, thus lowering blood sugar.

One may wonder if glucose is so good a stuff, why not make it un-filterable, so there will be no need to spend the energy to get it back.  The dilemma is that glomerular filtration goes by size, and glucose molecule is small enough to filter.  To modify the filtration apparatus to prevent glucose from being filtered, may lead to many wastes the size of glucose or larger staying in the body.

So His solution is let the glucose filter and then find a way to get it back.  This way of thinking about medicine may not be entirely inappropriate as the talk was given in a Bible Study class.

The concept about diabetes evolved over the years for Chinese and American medicine alike
Diabetes is called 糖尿病 in Chinese, meaning “the disease of having sugar in the urine”.  It implies having sugar in the urine is the root of the problem.

Chinese were not alone having this concept, so were American medicine men.  There was an article in October 1923 Scientific American with a title of “The Attack Upon Diabetes”, in which it described losing glucose in the urine and “cannot be burnt in the body” and that is why diabetes is “such a dread disease”.

We now know this kind of concept about diabetes is all wrong.  What is dreaded about diabetes is hyperglycemia (high blood sugar) leads to microvascular (kidney, eyes and nervous system) and macrovascular (heart attack and stroke) complications in the long run, not because having sugar in the urine.  In fact, the new way to treat diabetes is to increase the amount of sugar in the urine.

Reabsorption of glucose to prevent the loss in the urine makes sense evolutionary.  Our ancestors needed to conserve every bit of energy (burn glucose to produce ATP—energy) when one didn’t know when and where the next meal will be (no refrigerator in the caves).

Unfortunately this ingenious design (reabsorption of glucose) to increase survival in days of scarcity becomes a burden in the age of abundance.  Diabetes is indeed a disease of civilization.

The expected adverse effects of SGLT-2 inhibitors
There is no medicine without adverse effects; SGLT-2 inhibitors are no exception.  We like sweets, so do germs and yeasts.

-          Polyuria (~5%)

-          Urinary tract infection (4-6%)

-          Genital infection (~4-6%)

-          Hypovolemia ~3%

  

The urinary tract and genital infection occur more frequently in women.  Sugar cannot come out alone, it has to ‘drag’ the water (urine) along with it, thus leads to hypovolemia (too low a blood volume).

The unexpected disturbing adverse effects of SGLT-2 inhibitors: FDA’s warning and lawyers are chasing the ambulance

FDA warned on 5/15/15 that SGLT-2 inhibitors may cause ketoacidosis.  There are 20 cases reported during the period of 3/2013 to 6/6/2014.  FDA continues to investigate.  Kidney failure was also reported.

Diabetic ketoacidosis, typically occurs in type 1 diabetes, tends to have very high blood sugar, whereas the blood sugar is only slightly high in ketoacidosis seen in those taking SGLT-2 inhibitors.  The trigger factors appear to be major illness, reduced food and fluid intake, and reduced insulin dose.

I don’t know whether the impaired kidney function is a contributing factor or not; nevertheless patients with renal insufficiency shouldn’t take SGLT-2 inhibitors.

No sooner did the FDA’s warning came out on May 15, 2015, than the lawyers’ sensational advertisements showed up on internet, who says the “Diabetes Lawyers” are not keeping up with medicine?  The lawyers are chasing the ambulance even before the doctors have chance to see the patients.

Why insulin analog is the way to go in medicine and in business/investment

I have said “insulin is where money is”, in this post I’ll explain why insulin analog (analogue) is the way to go in medicine and in business/investment.

Insulin analog modifies the nature insulin so as to change the onset of absorption, the peak and duration of action.

Human insulin is a simple protein that is composed of 51 amino acids, having two chains (30 and 21 amino acids) connected by two S-S bonds.   

Frederick Sanger

Frederick Sanger was the one figuring this out; his 1958 Nobel Lecture is “Chemistry of Insulin”.  He figured out the sequence of amino acids in insulin.  He got another Nobel Prize in 1980 for deciphering the sequence of nucleic acids of DNA. He is truly “a man of sequence” and “a man of consequence” (重要人物)

Levemir (insulin detemir) is made by deleting the amino acid (threonine) at position 30 in B chain and adding a C14 fatty acid to it.  The end result is that it takes time to be absorbed and lasts nearly 20-24 hours mimicking the basal insulin that represents about half of our daily insulin secretion.

Levemir

Novolog (insulin aspart) is made by replacing proline (at position 28 in B chain) with an aspartic acid.  The end result is that it is absorbed rather quickly within 5 to 15 minutes of injection and lasts for 2-4 hours only, whereas the natural short-acting insulin may last 5-8 hours.

Novolog

The short-acting insulin is given before each meal to cover the surging blood sugar level as we eat.  The shorter duration of insulin analog is also advantageous as it may decrease the incidence of hypoglycemic (low blood sugar) reaction.  For example, if one has insulin analog injection before breakfast, its action will be completely gone when another injection given before lunch.  In case of short-acting insulin (not analog), the lingering effect (with 5-8 hours duration of action) of the morning injection may potentially increase the chance of hypoglycemia.

The long-acting insulin analog (Levemir or Lantus) serves as basal insulin and short-acting insulin analog to cover the blood sugar surge after meals, thus mimicking the physiological state of normal individual.     

Insulin is where money is: All eyes on Novo Nordisk

Banting and Best

I gave a talk about diabetes mellitus in the Taiwanese Bible Study last week.  In talking about the history of insulin, I said “insulin is where money is”, which is true in every sense, not trying to belittle the importance in clinical medicine.

There are three phases of making insulin.  Banting and Best discovered insulin in 1921 (Nobel Prize to Best 2 years later) and for the next 60 years (the first phase) insulin was made from bovine (牛) or porcine (豬) pancreas; the Eli Lilly got them from the slaughter houses.

The recombinant DNA technology made the making of human insulin possible and that is the second phase.  It was a fascinating story of the race of making human insulin by Genentech and Biogen in 1970s (Genentech won the race).  The discovery of restriction enzyme (so that DNA can be ‘cut’ open) by Stanley Cohen and Herbert Boyer paved the way for Paul Berg to develop recombinant DNA technology.  Genentech was founded on the knowledge of the discovery of restriction enzyme and recombinant DNA technology.  Herbert Boyer and Robert Swanson (the venture capitalist) were the cofounders.

Somehow Stanley Cohen didn’t participate, losing the chance to make a fortune when La Roche bought Genentech for 46.8 billion in 2009.  Stanley Cohen went on to get his Nobel Prize for the discovery of growth factor in 1986; he shared with Rita Levi-Montalcini, who will be 103 years of age in April.  James Watson said the discovery of restriction enzyme should be a Nobel Prize work.

Human insulin is the first biological, which is the drug that is made by living cells.  It is made by inserting human insulin-making gene into the DNA of E-coli, which then makes human insulin dutifully.

The third phase arrived in 1990s when the insulin analog (analogue) was developed.  Insulin analog modifies the nature insulin so as to change the onset of absorption, the peak and duration of action; that is there is to it.  The insulin analogs have been outselling, and I predict, will eventually replace human insulins; the trend is inexorable.

Pay attention to Novo Nordisk (a Danish pharmaceutical giant) if one is interested in long-term investment.  It thrives on products to treat diabetes; the blockbusters abound.  The sales of the insulin analogs (Levemir and Novolog) will be around $29 billion for 2011 and that of human insulins will be around $11 billion.  Victoza (liraglutide—a GLP-1 receptor agonist) was just released last year, some analysts predict the peak sales may reach $5-6 billion a year.  Novo Nordisk is also developing degludec (an insulin analog that can have 3 times a week injection) which has a favorable report on the Phase 2 trial (photo below).  Another popular oral diabetes drug (Prandin) is also their product.

It was announced 1 out 4 of U.S. adults is diabetic (probably including prediabetes) in the 71^st American Diabetes Association meeting last year.  There are 150 million diabetics worldwide in 1980 and 347 million in 2008; it is estimated there will be 472 million in 2030.  With that many insulin analogs and Victoza under their belt; more are on the way, Novo Nordisk is well positioned to make you well and make itself a fortune.      

糖尿病 (Diabete Mellitus) is no longer a good term in describing the disease

I gave a talk about diabetes mellitus in the Taiwanese Bible Study last week, pointing out糖尿病 (the disease of having sugar in the urine) is no longer a good term.  We no longer test sugar in the urine to diagnose the disease or monitor the treatment.  Besides, a new drug under development aims to lower blood sugar (glucose) level by causing sugar loss in the urine, thus having lots of sugar in the urine is the goal of the treatment, not pathogenic of the disease.

AstraZeneca and Bristol-Myers Squibb have spent hundreds of millions in developing dapaglifozin, which is a sodium-glucose transporter-2 inhibitor.  Normally the majority of glucose filtered through the glomerulus (the basic unit of the kidney) are reabsorbed back by way of the sodium-glucose transporter, inhibition of which will prevent its reabsorption, causing the loss of glucose in the urine.

FDA rejects it on February 11 citing the concern of higher rate of breast and bladder cancer in the treatment arm.  This is not a surprise, given the FDA expert panel also didn’t recommend it in July 2011.  Like many newer agents, dapaglifozin is not a potent diabetic drug, it only lowers HbA1c by 0.5%; nevertheless, it is a novel approach; a newer class (we have 10 classes of diabetic drugs so far).  I believe this is just a temporary setback.

“Mellitus” means sweet or honey in Latin/Greek, thus Diabetes Mellitus is a better term than 糖尿病.