New Developments in Treatment of Diabetes Type 2

From The Lancet theme issue on diabetes:

Diabetes confers a two-fold excess risk for a wide range of vascular diseases - heart disease and stroke. Adjusted HRs with diabetes were: 2·00 for coronary heart disease; 2·27 for ischaemic stroke; 1·56 for haemorrhagic stroke; 1·84 for unclassified stroke; and 1·73 for the aggregate of other vascular deaths. http://goo.gl/ucF0

Increased occurrence of cough and change in pulmonary function in the group receiving inhaled insulin - Lancet http://goo.gl/ve3G

Once weekly exenatide is an important therapeutic option for patients with type 2 diabetes http://goo.gl/UL3e

Dapagliflozin, sodium-glucose cotransporter-2 inhibitor (SGLT2 inhibitor), provides a new therapeutic option for type 2 diabetes http://goo.gl/FqIM

18% tax on pizza and soda can decrease U.S. adults' weight by 5 pounds (2 kg) per year

Nearly a third of American children are overweight or obese. In our inner cities a prevalence of obesity of more than 50% is not uncommon. Too many calories in, too little energy out.

With two-thirds of Americans either overweight or obese, policymakers are increasingly looking at taxing as a way to address obesity on a population level.

The tobacco experience showed that education is not enough: regulation, litigation, and legislation are needed too. Increasing taxes on cigarettes has been the single most effective strategy in reducing smoking.

An important part of the obesity story is clearly the huge increase in consumption of sugar sweetened beverages (SSBs): carbonated sodas, sweet teas, energy drinks, flavoured water, and sports drinks. Their use has more than doubled in recent years.

"Sadly, we are currently subsidizing the wrong things including the product of corn, which makes the corn syrup in sweetened beverages so inexpensive."

Instead, the agricultural subsidies should be used to make healthful foods such as locally grown vegetables, fruits and whole grains less expensive.

Danish government imposed 25% tax on ice cream, chocolate, sweets, and will increase taxes on soft drinks, tobacco, alcohols to combat obesity, heart disease, and other illnesses. BMJ. http://goo.gl/ixc0

 Some pizzas are 'saltier than the sea' (NHS blog).

References:
Tax soda, pizza to cut obesity, researchers say | Reuters.

The case of the sugar sweetened beverage tax. BMJ 2010;341:c3719.

'To Burn Off Calories in This Soda, Walk 5 Miles' - new label http://buff.ly/1vzbCKH

Image source: Soft drinks, Wikipedia, public domain.

Diabetic Patients on Low-Carbohydrate Mediterranean Diet Avoided Medication, Lost More Weight, and Decreased Coronary Risk Factors

From the Annals of Internal Medicine:

In this trial, the authors compared the effects of a Mediterranean diet versus a typical low-fat diet for diabetes management.

Researchers randomly assigned 215 patients to follow either a low carbohydrate, Mediterranean-style diet or a low-fat diet for four years.

After four years, 44% of patients in the Mediterranean-style diet group required antihyperglycemic drug therapy compared to 70% in the low-fat diet group.

Patients in the Mediterranean diet group also experienced greater weight loss and an improvement in some coronary risk factors.


Video.

Related:
Effects of a Mediterranean-Style Diet on the Need for Antihyperglycemic Drug Therapy in Patients With Newly Diagnosed Type 2 Diabetes. Katherine Esposito, MD, PhD; Maria Ida Maiorino, MD; Miryam Ciotola, MD; Carmen Di Palo, MD; Paola Scognamiglio, MD; Maurizio Gicchino, MD; Michela Petrizzo, MD; Franco Saccomanno, MD; Flora Beneduce, MD; Antonio Ceriello, MD; and Dario Giugliano, MD, PhD. Ann Int Med, 1 September 2009 | Volume 151 Issue 5 | Pages 306-314.
Mediterranean Diet Seems to Improve Cardiovascular Risk Factors After Just 3 Months
Mediterranean diet can protect children from asthma
Mediterranean Diet May Decrease Diabetes Risk

Why to Eat Like a Greek http://goo.gl/Chpwf - Mediterranean diet improves heart risk factors http://goo.gl/DkPhF
Image source: Olive oil, Wikipedia.

Liraglutide as initial pharmacological therapy for type 2 diabetes mellitus

New treatments for type 2 diabetes mellitus are needed to retain insulin—glucose coupling and lower the risk of weight gain and hypoglycemia.

What is Liraglutide?

Liraglutide, which if approved, will be marketed under the brand-name "Victoza", is a long-acting glucagon-like peptide-1 (GLP-1) analog that is being developed by Novo Nordisk for the treatment of type 2 diabetes. Liraglutide has a half-life after subcutaneous injection of 11–15 hours, making it suitable for once-daily dosing (in contrast to Byetta's twice daily).


Liraglutide. Image source: Wikipedia, public domain.


Figure 1. Action of DPP-4 inhibitors. Note that DPP-4 normally inactivates GLP-1. DPP-4 inhibitors block DPP-4 which in turn leaves GLP-1 active.
Click to enlarge the figure. Created with Gliffy.

What is Glucagon-like peptide-1 (GLP-1)?

Glucagon-like peptide-1 (GLP-1) is a GI peptide that stimulates insulin secretion (similar to sulfonylureas). GLP-1 also inhibits glucagon release, gastric emptying and food absorption. GLP-1 and another similar peptide are called incretins. As noted above, incretins have a dual action which leads to lowering blood glucose:

1. Stimulate insulin release

2. Inhibit glucagon release

Exenatide (Byetta) is a GLP-1 receptor agonist approved for adjunctive therapy for patients with DM 2 who are not well controlled on oral agents. It is available only as injections and has to be administered twice daily.

DPP-4 inhibitors or gliptins

Two new medications increase GLP-1 levels by blocking the enzyme which inactivates GLP-1. The enzyme is called DPP-4 (dipeptidyl peptidase-4) and the new medications are called DPP-4 inhibitors or gliptins.

They act similarly to Byetta (see figure above) but have the big advantage to be available in oral form (pills). These 2 new medications for treatment of DM2 are:

- Sitagliptin (Januvia) is taken once a day and it costs about $ 4.50 per pill

- Vildagliptin (Galvus) is waiting for FDA approval but it is already speculated to be at a competitive disadvantage to Januvia because it has to be taken twice a day

New Liraglutide Study

In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide or glimepiride 8 mg for 1 year.

HbA1c decreased by 0·51% with glimepiride, compared with 0·84% with liraglutide 1·2 mg and 1·14% with liraglutide 1·8 mg. Six patients in the liraglutide groups discontinued treatment because of vomiting.

The authors conclude that liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA1c, weight, hypoglycaemia, and blood pressure than does glimepiride.

References:
Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. The Lancet, Volume 373, Issue 9662, Pages 473 - 481, 7 February 2009.
Liraglutide, from Wikipedia, the free encyclopedia.
DPP-4 Inhibitors for Treatment of Diabetes

Bret Michaels, Poison's lead singer has had diabetes since age 6, "rocks diabetes world"

Rockstar Bret Michaels on diabetes type I Speaking about rock music, I like Deep Purple better than Bret Michaels and Poison but you have to respect Bret for the encouragement he gives young people with diabetes type I. Anything seems possible with the current medical advancements and sensible lifestyle, including being a rock star. According to Diabetes Health: "Bret Michaels was only six years old when he was diagnosed with type 1 diabetes. Now 44 years old, he's a twenty-year veteran of the rock and roll scene as the lead singer of the eighties band "Poison." Now Bret takes three injections a day, at breakfast, again at dinner, and then a little bit at night. Bret runs around a lot on stage, so he doesn't eat like to eat much before a concert and takes very little insulin before performing. The band has deliberately built two breaks into the show, a guitar solo and a drum solo, just so that Bret can go to the dressing room under the stage and check his blood sugar. Bret's Stats: Age: 44 Years with Diabetes: 38 Injections: 55,328 Blood Tests: 110,960 Albums Sold: 25 million" Smoke on the water by Deep Purple. Why aging rock stars still tour: "Once the lights go down and the crowds roar, something magical happens. All your aches and pains go" http://buff.ly/1hfxi3x References: Bret Michaels, Diabetic Lead Singer of "Poison," Lives Life Large. Diabetes Health, 2007. Bret Michaels rocks the diabetes world. USA Today, 2002.

Survivor: After hemorrhagic stroke, followed by TIA, Bret Michaels, who has diabetes type 1, returns to stage with vigor. CNN, 2010, http://goo.gl/NB18

Bret Michaels on being "a really active dad": "Listen kids, hurry up, man. I may lose another organ" http://goo.gl/tkmQ

Updated: 06/20/2010

Mediterranean Diet May Decrease Diabetes Risk

A Mediterranean diet, already known to protect against heart disease, also appears to decrease risk of developing diabetes according to a prospective study of 13,380 Spanish university graduates without diabetes at baseline followed up for 4.4 years.

Mediterranean diet was defined by features such as a high intake of fibre, a high intake of vegetable fat, a low intake of trans fatty acids, and a moderate intake of alcohol.

People who adhered closely to the diet were 83 percent less likely to develop type 2 diabetes than those who did not. The researchers admit they did not expect such a large reduction.

According to other studies, Mediterranean diet seems to improve cardiovascular risk factors after just 3 months and protect against asthma in childhood.

I try to follow a variant of the Mediterranean/DASH diet as much as possible. After adding 2-3 tablespoons of flax seed flower in the morning, my LDL decreased by 33% (from 136 mg/dL to 91 mg/dL).

My limited experience pales in comparison to John Halamka, the CIO of Beth Israel, Harvard, who literally became a new man by changing his diet and lifestyle. Read more in A Vegan Thanksgiving and check out his medical records available online.

References:
Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study. BMJ.
Mediterranean diet may also help stop diabetes. Reuters.

Related:
Mediterranean diet during childhood may protect against asthma
Mediterranean Diet Seems to Improve Cardiovascular Risk Factors After Just 3 Months

Why to Eat Like a Greek http://goo.gl/Chpwf - Mediterranean diet improves heart risk factors http://goo.gl/DkPhF
Diet Guidelines: No more than 1.5 gm of sodium/day, get off your "SoFAS" - Solid Fats and Added Sugars
Image source: Olive oil, Wikipedia.

Diabulimia (Skipping Insulin to Slim Down) Increases Morbidity and Mortality

CNN first mentioned “diabulimia” last June:

"Like many teenage girls, Lee Ann Thill was obsessed with her appearance. Then one day at a camp for diabetic teens, she heard counselors chew out two girls for practicing “diabulimia” — not taking their insulin so they could lose weight, one of the consequences of uncontrolled diabetes..."

Not surprisingly, a study published in Diabetes Care shows that women who restrict insulin face higher mortality and morbidity. The study authors also proposed a screening question for diabulimia asking patients to answer true or false to the statement, “I take less insulin than I should.”

In the world of medical journals, Web 2.0 is here to stay -- Diabetes Care prominently features several social bookmarking tools with each articles. A comment section is still missing however.

References:
Morbidity and Mortality in Women with Type 1 Diabetes. Ann E. Goebel-Fabbri et al. Diabetes Care.
Diabulimia: Skipping Insulin to Slim Down. Clinical Cases and Images - Blog.
Women who restrict insulin face higher mortality, morbidity. ACP Internist Weekly.
Image source: Wikipedia, public domain.

Attending rounds: How to start insulin therapy in diabetes mellitus type 2?

See Figure 3. Algorithm for the management of type 2 diabetes from AFP (http://www.aafp.org/afp/20040801/489.html).

For patients who have been inadequately controlled on oral antidiabetic medications , the initial dose is typically 10 units/day or 0.1 to 0.2 units/kg/day. Initially, basal therapies are usually administered as a single dose in the evening. Where necessary, NPH insulin also may be given in 2 doses: 1 dose in the morning and 1 dose in the evening. The dose can be titrated in 1-, 2-, or 3-unit increments until target FPG levels are achieved. When initiating insulin, it is best to start low and increase the dose gradually until the target is reached (http://www.ispub.com).

If intermediate insulin is chosen, the amount can be calculated by dividing a patient's body weight in kilograms by four and using that number to determine the starting dose (resulting in one fourth of the regular dose) or by figuring the dose according to a ratio of 0.5 U/kg and using 25% to 30% of that amount as the initial dose. Patients who have insulin resistance often need between 0.75 and 1 U/kg and tend to tolerate the larger increases (http://www.postgradmed.com/issues/2003/06_03/3cooppan.htm)

In subjects with type 2 diabetes who are poorly controlled on oral antidiabetic medications, initiating insulin therapy with twice-daily BIAsp 70/30 was more effective in achieving HbA1c targets than once-daily glargine (Lantus), especially in subjects with HbA1c >8.5% (http://care.diabetesjournals.org/cgi/content/abstract/28/2/260).

The INITIATE (INITiation of Insulin to reach A1c TargEt) study provides guidelines for twice-daily initiation of insulin (aspart premix 70/30). Begin with 6 units twice a day if the FPG is 180 mg/dL or greater, and 5 units twice a day if the FPG is less than 180 mg/dL (http://www.medscape.com/viewarticle/567952).

References listed in the text above.
Image source: Wikipedia, public domain.

Dangers of Intrabdominal Fat on YouTube

A video by the Portuguese Cardiology Foundation graphically conveys the danger of intrabadominal fat for "big belly people."



According to Harvard Medical School, "it’s appropriate to think of fat as an endocrine organ or gland, producing hormones and other substances that can profoundly affect our health. Scientists are also learning that visceral fat pumps out immune system chemicals called cytokines — for example, tumor necrosis factor and interleukin-6 — that can increase the risk of cardiovascular disease."

Calling patients (or anybody) fat or "big belly" is not advisable though. A New Hampshire doctor was recently reprimanded by the state medical board because he “told a fat woman she was obese.” Dr. Bennett says, “I tried to get her attention. I told her, 'You need to get on a program, join a group of like-minded people and peel off the weight that is going to kill you.'"

References:
Abdominal fat and what to do about it. Harvard Medical School Family Health Guide.
Doctor in trouble for calling patient obese. MSNBC.
Boomeritis, Man Flu & Salad Dodging Down Under. WSJ Health Blog, 01, 2008.
Link via Dr. Wes.
Belly Fat, Also Called Visceral Fat, Boosts Inflammation and Atherosclerosis, Say Scientists Studying Mice. WebMD, 01/2008.

Updated: 01/29/2008

Diabulimia: Skipping Insulin to Slim Down

According to CNN:

"Like many teenage girls, Lee Ann Thill was obsessed with her appearance. Then one day at a camp for diabetic teens, she heard counselors chew out two girls for practicing “diabulimia” — not taking their insulin so they could lose weight, one of the consequences of uncontrolled diabetes..."

I learned about 2 new diseases this month: first, wiitis, and now, diabulimia.

References:
‘Diabulimics’ skipping insulin to slim down. MSNBC, 06/2007.
Diabetics risk health to feed obsession with thinness. CNN, 06/2007.
CNN Video: Skipping insulin to stay thin, 08/2007.
Image source: Wikipedia, public domain.

Updated: 08/17/2007

DPP-4 Inhibitors for Treatment of Diabetes

Glucagon-like peptide-1 (GLP-1) is a GI peptide that stimulates insulin secretion (similar to sulfonylureas). GLP-1 also inhibits glucagon release, gastric emptying and food absorption. GLP-1 and another similar peptide are called incretins. As noted above, incretins have a dual action which leads to lowering blood glucose:

1. Stimulate insulin release

2. Inhibit glucagon release


Figure 1. Action of DPP-4 inhibitors. Note that DPP-4 normally inactivates GLP-1. DPP-4 inhibitors block DPP-4 which in turn leaves GLP-1 active. Click to enlarge the figure. Created with Gliffy. The diagram Action of DPP-4 inhibitors is now on Wikipedia.

Exenatide (Byetta) is a GLP-1 receptor agonist approved for adjunctive therapy for patients with DM 2 who are not well controlled on oral agents. It is available only as injections and has to be administered twice daily.

Two new medications increase GLP-1 levels by blocking the enzyme which inactivates GLP-1. The enzymes is called DPP-4 (dipeptidyl peptidase-4) and the new medications are called DPP-4 inhibitors or gliptins.

They act similarly to Byetta (see figure above) but have the big advantage to be available in oral form (pills). These 2 new medications for treatment of DM2 are:

- Sitagliptin (Januvia) is taken once a day and it costs about $ 4.50 per pill

- Vildagliptin (Galvus) is waiting for FDA approval but it is already speculated to be at a competitive disadvantage to Januvia because it has to be taken twice a day

References:
New Medications
Merck Wins U.S. Approval for a New Diabetes Drug. NYTimes.
Sitagliptin: First DPP-4 Inhibitor for Type 2 Diabetes. Resident and Staff Physician, 04/2007.
Merck Diabetes Drug Could Face Competition from Takeda. WSJ Health Blog, 01/2008.

Related:
Lilly, Amylin Disclose More Cases of Byetta-Related Pancreatitis. WSJ Health Blog, 08/2008.
FDA Issues Warning for Diabetes Drug Byetta about possible kidney problems, including renal failure http://bit.ly/1UOjwB

Updated: 11/03/2009

Does Avandia Prevent Diabetes?

As Medpundit points out, sometimes, unfortunately, the thought process with pharmaceutical company-sponsored studies is like that: "well, we did the study, how can we spin the results now?"

I am not saying that this is the case with the recently publicized research that Avandia "cut the risk of developing Type 2 diabetes by more than half" but at least one doctor has doubts: "It is giving the impression that it prevents diabetes, when really what it is doing is delaying the diagnosis for one year," said Dr. Jim Wright, managing director of the B.C. Therapeutics Initiative."

Update 05/21/2007:
Avandia (Rosiglitazone) May Increase Risk of Cardiovascular Death

References:
Let Us Now Praise Expensive Drugs. Medpundit.
The DREAM study, Are we preventing or just delaying diabetes? Retired doc's thoughts.
Image source: Rosiglitazone, from Wikipedia, the free encyclopedia.

New Medications

Diabetes Type 2

Exenatide (marketed as Byetta)

Glucagon-like peptide-1 (GLP-1) is a GI peptide that stimulates glucose-dependent insulin secretion (similar to sulfonylureas). GLP-1 also inhibits glucagon release, gastric emptying and food absorption.

Byetta is a GLP-1 receptor agonist approved for adjunctive therapy for patients with DM 2 who are not well controlled on oral agents.

Byetta is administered SQ BID, just like NPH insulin. Nausea is a common side effect occurring in 40% percent of patients.

The advantge of using Byetta instead of insulin is the weight loss which can be significant. The NYTimes reported that Byetta is sometimes prescribed off-label to nondiabetic patients to induce weight loss. This use of the medications is discouraged by the manufacturer. Click here for FDA Patient Information Sheet for Byetta.

Another GLP-1 agonist is Liraglutide which is longer acting than Byetta and can be injected once a day.

FDA recently approved an inhaled insulin called Exubera which will surely be preferred by patients over any injectable diabetes drug. Exubera seems poised for an exuberant growth in its market share after its launch.

Related:
Wrong prediction -- Exubera was taken off the market in the second half of 2007.
Lilly Ends Effort to Develop an Inhaled Insulin Product. NYTimes, 03/2008.
Lilly, Amylin Disclose More Cases of Byetta-Related Pancreatitis. WSJ Health Blog, 08/2008.
FDA Issues Warning for Diabetes Drug Byetta about possible kidney problems, including renal failure http://bit.ly/1UOjwB

References:
Diabetes drugs that modify the intestinal absorption of food. UpToDate (paid subscription required)
GLP-1 and extra-islet effects. Horm Metab Res. 2004 Nov-Dec;36(11-12):842-5.
A Ray of Hope for Diabetics. NYTimes.
Novo Nordisk Shelves Inhaled Insulin. WSJ Health Blog, 01/2008.
Image source: Byetta.com

Alcohol Abuse

Acamprosate (marketed as Campral)

Campral is a structural analog of GABA, which can reduce the relapse rate in alcohol abuse. In a RCT, the rate of abstinence was higher with Campral (18 %) than placebo(7%).

Campral is well tolerated and was approved by FDA in 2004 for relapse prevention in patients who have already stopped drinking. The dose is 666 mg TID for 6 to 12 months.

FDA Patient Information Sheet

References:
Treatment of alcohol abuse and dependence. UpToDate (paid subscription required)

Updated: 11/03/2009

Inhaled Insulin (Exubera) Coming Soon in 2005 -- 2008 Update: Exubera is Taken Off the Market

After a recent FDA decision, it looks like the inhaled insulin (called Exubera) may be on the market soon. Exubera is equivalent to injected insulin in controlling the glucose, but not superior.

Question of Lung Safety

Studies showed a small decline in lung function in patients using Exubera, which did not continue after several months and was not clinically significant.

Despite this, the FDA panel made up of endocrinologists and pulmonologists, recommended the use of inhaled insulin only by people with healthy lungs. Exubera is not for you if you have COPD, for example.

Only 10 percent of the inhaled insulin reaches the bloodstream. Smokers absorb several times as much drug through their lungs and they are also excluded for the potential users of Exubera.

Not Easy To Use

Nektar Therapeutics has developed a special delivery chamber for the inhaled insulin which looks like a spacer device for asthma inhalers.

The estimates are that Exubera sales could easily exceed $1 billion within 2-3 years. Other companies, like Eli Lilly and Novo Nordisk, are also developing inhaled insulin.

References:
F.D.A. Panel Endorses Inhaled Form of Insulin - NYT

Related:
Lilly Ends Effort to Develop an Inhaled Insulin Product. NYTimes, 03/2008.
Pfizer Warns of Inhaled Insulin Lung Cancer Risk. NYT, 04/2008.

Updated: 04/10/2008

Today's Medical News: Exubera and Natrecor

Inhaled Insulin Shown to be Effective but How About Its Long Term Safety?

According to Pfizer's studies with 200-300 patients, inhaled insulin (Exubera) seems just as effective as the injected one and, of course, patients like the inhaled version much better. FDA is likely to demand long-term studies, proving that there is no adverse lung effects after long-term administration.

Pfizer is not alone on the inhaled insulin turf, other drug companies (Eli Lilly among them) are developing their own inhaled insulins. Exubera seems to be poised for exuberant growth - sales of inhaled insulin are predicted to creach close to $2 billion by 2011. The maker of the inhaled device is named Nektar, which in the Greek mythology was the food of the gods (nectar), how is this for an ambitious name?

Reference:
Inhaled Insulin Is Effective, Pfizer Reports - NY Times

Related:
Pfizer Warns of Inhaled Insulin Lung Cancer Risk. NYT, 04/2008.


Natrecor not to be used for outpatient treatment of CHF

This was the recommendation of the panel led by Eugene Braunwald, the chief editor of Harrison's.

References:
Panel Urges Limits on Use of a Heart Drug. NY Times.
Nesiritide (Natrecor) for Acute Decompensated Heart Failure. AFP, Vol. 73/No. 4 (February 15, 2006).


More than one million Americans are living with HIV according to CDC

"Reaching the 1 million mark is "a sign of both victory and failure" (CNN).

Victory because the new anti-HIV medications have allowed patients to live longer. Failure because since the 1990s the rate of estimated new HIV infections has been 40,000 per year despite the CDC efforts to cut it in half. The government agency was not able to "break the back" of the AIDS epidemic.

As reported previously, the African American population is hit the hardest by the AIDS, the rates of AIDS cases are 58 per 100,000 African Americans, 10 per 100,000 Hispanics, 6 per 100,000 Caucasians. In total, African Americans account for 47 percent of HIV cases.

Reference:
CDC: 1 million living with HIV in U.S. - CNN
Blacks hardest hit by HIV in U.S. - report - Reuters