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.

Diabetes Mellitus: Questions & Answers

Question 1

Eli Lilly made the first insulin in 1923, sulfonylurea was approved in 1946, nothing until 1995 when Metformin was approved.  There have been close to 10 families/classes (numerous drugs) of diabetes medicines came to the market the past 20 years; why?

 

 

Hepatitis B: Dr. Baruch Blumberg: a great scientist and a great man

It would be an inexcusable omission if I do not mention Dr. Baruch Blumberg while talking about hepatitis B.  He discovered Australia antigen, later proved to be hepatitis B surface antigen (HBsAg), the origin of hepatitis B infection in mid-1960s, leading to the Nobel Prize in Medicine in 1976.

Blumbergs celebrating Nobel Prize in 1976

Dr. Baruch Blumberg died on April 5, 2011 (a Tuesday), we read NY Times obituary next day, but LA Times obituary showed up three days later (April 8).  The delay is embarrassing either uninformed or unprepared.  Blumberg is not household name; it took even LA Times three days to come up with an obituary.

Blumberg was a towering figure in medicine, whose study on polymorphism led to the discovery of Australia Antigen (hepatitis B virus).  He helped develop the test to detect the HbsAg to ensure the safety of blood transfusion; he also developed the first hepatitis B vaccine (first used in Taiwan)—truly the first cancer vaccine as preventing hepatitis B also prevents liver cancer.

The detailed story of how the genetic polymorphism research led to the discovery of hepatitis B surface antigen is beyond the scope of this writing.  Dr. Blumberg noticed that a hemophilic patient whose blood reacted with a stuff in the blood of an Australian aborigine; the “stuff” was then called Australia antigen.

D

Dr. Barusch Blumberg

r. Blumberg and his team observed that there was a high prevalence of positive Australia antigen among the institutionalized Down syndrome patients.  They documented a mentally retarded patient, James Bair, who developed hepatitis when his Australia antigen turned from negative to positive, strongly suggested hepatitis (it was then called serum hepatitis) is infectious and Australia antigen is the culprit.

James Bair’s parents allowed, in fact, encouraged Dr. Blumberg to use his real name, as they’re pleased their son had played an important role in the discovery of hepatitis B virus and infection.

Dr. Blumberg wrote a paper about this finding and submitted it to the Annals of Internal Medicine (the official publication of the American College of Physicians to which both Dr. Blumberg and I belong.  I on purposely put Dr. Blumberg and I in the same sentence, how about that :- ); the paper was rejected as it was felt this was just one of the many claims that HBV had been found.  The Annals editor later admitted the rejection was the biggest blunder the journal had made.

The term ‘serendipity” has been used in describing this story, implying “fortunate happening” and “pleasant surprise”.  But, Australia antigen and hepatitis B couldn’t be put together without Dr. Blumberg’s keen insight, relentless pursuit for the answer and intense intellectual passion.  After graduating from Columbia University Medical School, he obtained a PhD in biochemistry from Balliol College, Oxford University.  He studied physics and math before entering the medical school.

Reading his memoir (The Hunt for a killer virus Hepatitis B), I found Dr. Blumberg was such a kind and humble person.  He was as humble as James Watson was arrogant (he mellowed as he aged) and both are great scientists.

He was a co-owner of a farm in western Maryland that supplied beef for a local market. “Shoveling manure for a day is an excellent counterbalance to intellectual work,” he said.

One can only imagine how many millions of lives he saved or will save for generations to come by discovering Australia antigen (HBsAg).   His obituary in NY Times ended like this.

“Well, it is something I always wanted to do,” he said. “This is what drew me to medicine. There is, in Jewish thought, this idea that if you save a single life, you save the whole world, and that affected me.”

It may be a cliché the say many of the great scientists are Jewish.  Blumberg, Richard Feynman and Burton Richter, all came from Far Rockaway High School, a Jewish neighborhood in New York City (borough of Queens).  It is unprecedented that one high school produced 3 Nobel laureates. In fact, two were honored in 1976 (Blumberg and Richter).  Sadly Bernard Madoff was also an alumnus; sadly the school was closed in 2011.

An epic game in PNC Park

There is no good sport writing unless there is a good game and I can unabashedly say this is good sport writing.

When St. Louis Cardinals came to town (the Steel City) July 9, Pirates treated it with the utmost respect as this is the best MLB team; I refrained from calling it a little bird or two little birds.  They took the first of the 4-game series.  Pirates remained calm and evened the series for Game 2, setting the stage for fierce competition; fierce is an understatement; the Game 3 turned out to be an epic game.

It has every element to be called an epic game: lengthy (a bit over 5 hours with no rain delay), full of heroes (McCutchen, Burnett, Alvarez, Kang, Walker, just to name a few), walk off homer and played in grand style.

After going into extra innings, the Cardinals led twice, only to have Pirates tie it in no less dramatic way, sending waves of roller coaster emotions of the nearly 38,000 frenzy Pirates fans.  Why do we need the seats in PNC Park when our heroes got us off the seats again and again.

AJ Burnett

Pirates was swept by the Cardinals (the dreaded “Meet me in St Louis” theme) on May 1-3; Pirates was able to take the series when Cardinals came to town on May 8-10.  A lot have happened since; the two teams have established themselves as the best two teams in the National League or MLB as far as I am concerned. 

The pitcher, A.J. Burnett, took the matter into his own hand to help himself when Pirates was shut down by John Lackey (Cardinals pitcher), trailing 0 to 3 at the bottom of 5^th inning, Burnett hit a homer, the 4^th in his 17-year career as a pitcher, the first since July 24, 2005, nearly 10 years ago.  “You get lucky once in a while”, Burnett said; I said it was a “divine intervention”. 

Burnett’s homer sent the PNC Park into a roar, but didn’t wake up the sleeping lion; Pirates was still trailing 1 to 3 going into the bottom of 8^th inning.  Jung Ho Kang’s and Pedro Alvarez’s RBI single tied for the first time.

Cardinals Mark Reynold’s second homer of the night and Peralta put St. Louis on top twice in the extra innings.  Pirates returned the favor in kind to tie it.

The final climax came at the bottom of 14^th inning (passed the midnight).  Neil Walker (Pittsburgh native) had a lead off single followed by McCutchen’s walk off homer, sending the frenzy 37,318 fans into heaven; who said there is no heaven?

Cardinals and Pirates are not the two best MLB teams for no reason.  Let’s paraphrase Churchill that never in the field of American baseball has so much been owed, by so many, to so few.

The following is from today’s comic strip, Marvin: Marvin and his dad were watching baseball, which put Marvin to sleep; Marvin’s dad was wondering when football season starts.  They obviously didn’t watch the epic game at PNC Park.

Kang

McCutchen

 

Alvarez

The peril of gardening: Potential disaster in the making

On May 17 I had a post of “The joy of gardening: Beauty in the making” (http://doctorjytsai.blogspot.com/2015/05/the-joy-of-gardening-beauty-in-making.html); little did I know that nearly two months later I have to post this “disaster in the making”.

There hardly a day or two went by without raining the past six weeks or so.  What’s even worse is that there was no sun during the rain and overcast before and after the rain.  All the flowers and veggies are “starving” (no sun, no food, no eating) while their roots are submerging in the water at all time; many wither and were practically drowned to death.  They lost the luster, then color and life.

We gardeners believe in tomorrow, but tomorrow forecast is 40% rain; it rained even the rain forecast was only 10%.  Tomorrow will come, so will be the rain.

The other day I learned that Sean has been doing the Rain Dance for the benefit of our garden.  Sean’s dance may not be as graceful and elegant as Gabby’s, but it is certainly effective.  No more rain dance; decree has been issued.

News had it that Rachel Rohanna and her cousin, Robert Rohanna, accepted the Rain Day hat bet.  (When I read Rachel news not in the sport section, I know she is now a celebrity.)  Let’s Go Rachel! I now cheer Rachel in and out of Golf course.  I am hoping she will win the hat bet (it used to be not if, but when to rain); enough is enough, no more rain in Waynesburg, not even on Rain Day.