November 6, 2011 · 8:32 PM

Severe Carb Restriction in Type 2 Diabetes

U.K. researchers found major metabolic improvements in obese type 2 diabetics following a very low-carbohydrate diet, compared to a low-fat portion-controlled diet.  The latter is a standard recommendation in the U.S. for overweight type 2 diabetics.
 
This study is an oldie (2005) but a goodie.
 
Methodology
 
The investigators randomly assigned 102 poorly controlled diabetics to follow one of the two diets for three months.  Participants had average weights of 224 pounds (102 kg),  body mass index 36, age 58, hemoglobin A1c’s of 9%.  Half of them were men.  About 40% of the diabetics in both groups were on unspecified oral diabetic drugs; 20% were on insulin and 40% were using a combination of the two.  Sulfonylurea was mentioned, but not metformin. 
 
Participants were randomly assigned to either a low-fat portion-controlled weight-loss diet or a low-carbohydrate diet.  The goal with the low-carb diet was “up to 70 g of carbohydrate per day,” including at least a half a pint of milk and one piece of fruit.  (Is a UK pint the same as in the US?).  Increased physical activity was recommended to both groups. 
 
Only 79 of the 102 participants made it through the three-month diet intervention.  Drop-out rate was the same for both groups.
 
What Did They Find?
 
(Differences are statistically significant unless otherwise noted.)
Weight loss for the low-carb group was 3.55 kg (7.8 lb) compared to only 0.92 kg (2 lb) for the low-fat cohort.
 
The total/HDL cholesterol ratio improved for the low-carb group (absolute decrease of 0.48 versus 0.10). 
 
Hemoglobin A1c and systolic blood pressure tended to decrease more for the low-carb group, but did not reach statistical significance.  For instance, HgbA1c dropped 0.55% (in absolute terms) for the low-carb group, and 0.23% for the low-fat group.  Lower HgbA1c indicates improved blood sugar control.
 
Caloric intake was not different between the groups (about 1350 cals/day by diet recall method).
 
The low-carb group reduced carbs to 109 g/day compared to 168 g in the  low-fat cohort.
 
The low-carb group consumed 33% of energy as carbs compared to 45% for the low-fat group.
 
The low-carb group consumed 40% of energy as fat compared to 33% in the low-fat cohort.
 
Protein intake was 26% of energy for the low-carbers compared to 21% for the low-fatters.
 
Absolute saturated fatty acid intake was higher for the low-carbers, but still considered moderate.
 
Insulin dose was reduced in about 85% of the insulin users in the low-carb group but in only 22% of the low-fat group.  Oral diabetic pill use was unchanged in both groups.
 
Comments
 
This is a classic research report that I cited in Conquer Diabetes and Prediabetes: The Low-Carb Mediterranean Diet.
 
The improved total/HDL cholesterol ratio in the low-carbers may reduce risk of heart and vascular disease.  These investigators didn’t look at LDL particle size.  Other studies have found that low-carb eating tends to shift LDL cholesterol (bad stuff) from small dense particles to light fluffy particles, which are thought to be less harmful to arteries.
 
The authors considered reduction of carbs to 109 grams a day to be “severe.”  That compares to 275 grams a day eating by the typical U.S. citizen.  I agree that a reduction of carbs by two-thirds is major restriction.  Dr. Richard Bernstein and I consider severe restriction to be 20–30 grams, or perhaps up to 50 g.
 
I suspect the improved metabolic numbers in the low-carbers would have been even more dramatic if they had reduced carbs well below 100 grams a day.  The Ketogenic Mediterranean Diet reduces digestible carbs to 20–30 grams daily.  Many diabetics start losing control of their blood sugars when daily carbs exceed 60–80 grams.
 
Low-carb diets often yield better weight loss than low-fat calorie-restricted diets, as was seen here.  This is often attributed to lower calorie consumption on the low-carb diets.  These investigators didn’t see that here.
 
Low-carb diets are often criticized as being hard to stick with.  The low-carbers here didn’t have any more drop-outs than the low-fat group.  Granted, it was only a three-month study.
 
Based on what we know today, the reduced need for insulin in these patients was entirely predictable. 
 
The authors had some concern about the higher relative saturated fatty acid consumption in the low-carbers.  In 2011, we know that’s not much, if any, cause for concern.
 
 
 
 
Reference: Daly, M.E., et al.  Short-term effects of severe dietary carbohydrate-restriction advice in Type 2 diabetes—a randomized controlled trial.  Diabetic Medicine, 23 (2006): 15-20.  doi: 10.1111/j.1464-5491.2005.01760.x

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November 5, 2011 · 2:00 AM

Drug Review: GLP-1 Analogues (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide)

GLP-1 analogues available in the U.S. are exenatide (sold as Byetta and Bydureon), liraglutide (sold as Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and lixisenatide (Adlyxin).  They are sometimes referred to as GLP-1 receptor agonists.  They are not considered first-choice drugs, but instead are typically used in combination with other drugs, in conjuction with diet and exercise.

Remember that drug names vary by country and manufacturer.  This is a brief review only; consult your physician or pharmacist for full details.

Fun Fact for the diabetic version of  Trivial Pursuit:

Exenatide  (Byetta and Bydureon) is a synthesized version of a protein initially discovered in the saliva of a lizard, the Gila monster.

How do they work?

It’s complicated.

First off, you need to know that a small intestine hormone, glucagon-like peptide-1 (GLP-1), is produced in response to a meal.  This hormone increases insulin secretion by pancreas beta cells, suppresses glucagon after meals, inhibits emptying of the stomach, and inhibits appetite. Other effects are suppression of glucose production by the liver, and improved glucose uptake by tissues outside the liver.  All this tends to lower blood sugar levels after meals.

The problem is that GLP-1 is quickly destroyed by an enzyme called DPP-4.  We have available to us now chemicals similar to GLP-1, called GLP-1 analogues, that bind to the GLP-1 receptors and are resistant to degradation by the enzyme DPP-4.  They essentially act like GLP-1, and they hang around longer.

GLP-1 levels, by the way, are decreased in type 2 diabetes.

The action of GLP-1 is dependent on blood sugar levels.  If blood glucose is not elevated, GLP-1 doesn’t go to work.  From a practical viewpoint, this means that GLP-1-based therapies rarely cause hypoglycemia.

We know little about long-term outcomes with these drugs, such as diabetic complications, health-related quality of life, or mortality.

Uses

Exenatide (Byetta)  is FDA-approved for adults with type 2 diabetes who are not adequately controlled with metformin, sulfonylurea, or a thiazolidinedione (or a combination of these agents).  So it’s an add-on drug, not approved for use by itself.  In October, 2011, the FDA extended approval as an add-on therapy to insulin glargine (for example, Lantus in the U.S.), with or without metformin and/or a thiazolidinedione (TZD), in conjunction with diet and exercise for adults with type 2 diabetes who are not achieving adequate glycemic control on insulin glargine alone.

Once-weely exenatide (Bydureon) was FDA-approved in January, 2012.  Use with insulin has not been studied and is not recommended.  Don’t use along with Byetta.  Surprisingly, I found nothing in the drug package insert Feb.2, 2012, regarding whether it can be used with other diabetes drugs.  See comments in the preceding paragraph regarding standard twice-daily exenatide.  I suspect Bydureon can be used with metformin, sulfonylurea, thiazolidinedione, and insulin glargine (Lantus), but the package insert is not at all clear.

Liraglutide is FDA-approved for treatment of type 2 diabetes but is not recommended as initial therapy, although it does seem to be approved for use by itself.  It has been used alone and also in combination with metformin, sulfonylurea, and/or thiazolidinediones.  It’s not approved for use with insulin therapy.

Albiglutide is a once-weekly subcutaneous injection for type 2 diabetes. It was FDA-approved in 2014. It’s not recommended as initial drug therapy, although it is approved for use by itself. It can be used in combination with metformin, sulfonylurea, thiazolidinediones, and/or insulin.

Dulaglutide is also a once-weekly injection for adults with type 2 diabetes, approved by the FDA in2014.  It’s not a first-line drug, but can be used by itself or with metformin, glimiperide (and presumably other sulfonylureas), pioglitazone, and insulin lisper (e.g., Humalog, a rapid-acting insulin).

Lixisenatide is a daily injection for adults with type 2 diabetes. It can be used alone or in combination with metformin, sulfonylurea, thiazolidinedione (e.g., pioglitazone), or long-acting insulin (insulin glargine). Clinical trials did not include short-acting insulin.

You can assume none of these have been tested for safety in pregnant or nursing mothers.

Dosing

They are available only as subcutaneous injections.  Exenatide is twice daily, starting at 5 mcg within 60 minutes prior to a meal.  After one month, the dose may be increased to 10 mcg twice daily.

Extended-release exenatide (Bydureon): 2 mg subcutaneous injection every seven days.

Liraglutide is a once daily subcutaneous injection starting at 0.6 mg, increasing to 1.2 mg after one week.  It is given without regard to meals.  Maximum dose is 1.8 mg/day.

Albiglutide is started at 30 mg subcutaneously every seven days and may be increased to 50 mg if needed.

Start dulaglutide at 0.75 mg weekly, increasing to 1.5 mg weekly if needed.

Lixisenatide starts at 10 mcg daily for 14 days then increases to 20 mcg daily.

Side Effects

GLP-1 analogues tend to cause nausea, vomiting, and diarrhea in as many as four in 10 users.  The nausea typically improves over time.  Compared with Byetta, Bydureon seems to cause less nausea.  They tend to cause weight loss.  These drugs might cause pancreatitis, which is life-threatening.  When used with insulin or an insulin secretagogue (like sulfonylureas or meglitinides), hypoglycemia may occur.

Hypoglycemia is rare when GLP-1 analogues are used as the sole diabetes drug, but still possible (0-5% risk?). When it happens, it’s rarely severe.

Liraglutide, albiglutide, and dulaglutide might cause thyroid cancer or thyroid tumors.   

Don’t use if you have . . .

… severe kidney impairment (exenatide), end-stage renal disease (lixisenatide),Multiple Endocrine Neoplasia syndrome (liraglutide), Multiple Endocrine Neoplasia syndrome type 2 (albiglutide, dulaglutide), or family history of medullary thyroid cancer (liraglutide, albiglutide, dulaglutide), or personal history or medullary thyroid cancer (albiglutide, dulaglutide).

Use GLP-1 analogues with caution or avoid entirely if you have a history of pancreatitis or gastroparesis. Don’t use dulaglutide if you have pre-existing severe gastrointestinal disease.

Use liraglutide with caution in patients with kidney or liver impairment. Dulaglutide is risky in the setting of liver impairment.

Don’t use any of these to treat diabetic ketoacidosis.

Steve Parker, M.D.

Last modification date: July 29, 2016

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November 2, 2011 · 4:20 AM

What IS Process Cheese Food?

I’ve seen “process cheese food” on packages of apparent cheese or listed with other ingredients on food labels.  Why don’t they just call it “cheese”?

If you’re curious, see what Vitruvius the Sagacious Iconoclast has to say about cheese production.  It’s all processed to some degree.  From the introduction:

I was recently involved in a discussion in which some folks were attempting to distinguish between what they were calling “processed” cheese and other (presumably non-processed) cheese, without defining what they mean by “processed” cheese. As I think that’s a less than optimal approach, I’d like to take a moment to sketch out why that is so; perhaps increasing, in the process, your enjoyment of cheese forever.

It’s a moderately lengthy article, but well worth it for the amusement and erudition.  You’ll learn how cheese is made, starting with the photons.

Cheese is a time-honored component of the traditional Mediterranean diet.  That’s one reason I left it in the Ketogenic Mediterranean Diet.  If you don’t like cheese but still desire the health benefits of the Mediterranean diet, don’t fret.  I’ve not found any important nutrients in cheese that you can’t get elsewhere.

Steve Parker, M.D.

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October 28, 2011 · 6:21 AM

Does Loss of Excess Weight Improve Longevity?

High WHR

Intentional weight loss didn’t have any effect either way on risk of death, according to recent research out of Baltimore.  Surprising, huh?

Obesity tends to shorten lifespan, mostly due to higher rates of cancer and cardiovascular disease like heart attacks and strokes.  Doctors and dietitians all day long recommend loss of excess weight, figuring it will reduce the risk of obesity-related death and disease.  Many of them are unaware that’s not necessarily the case.  It’s called the “obesity paradox“: some types of overweight and obese patients actually seem to do better (e.g., live longer) if they’re above the so-called healthy body mass index of 18.5 to 24.9.  For instance: those with heart failure, coronary artery disease, and advanced kidney disease.

It’s never really been clear whether the average obese person (body mass index over 30) improves his longevity by losing some excess weight.  That’s what the study at hand is about.

Methodology

Baltimore-based investigators followed the health status of 585 overweight or obese older adults over the course of 12 years.  Half of them were randomized to an intentional weight loss intervention.  All of them had a high blood pressure diagnosis.  Average age was 66.  Average body mass index was 31.  Details of the weight-loss intervention are unclear, but it was probably along the lines of “eat less, exercise more.”

What Did They Find?

The weight-loss group lost and maintained an average of 4.4 kg (9.7 lb) over the 12 years of the study.  This is about 5% of initial body weight, the minimal amount thought to be helpful for improvement in weight-related medical and metabolic problems.  Most of the weight loss was over the first three years.

The men assigned to the weight-loss program had about half the risk of dying over the course of the study, compared to the men not assigned to weight loss.  The authors don’t seem to put much stock in it, however, stating that “…no significant difference overall was found in all-cause mortality between older overweight and obese adults who were randomly assigned to an intentional weight-loss intervention and those who were not.” 

Comments

With regards to the men losing weight, we’re only talking about 100-150 test subjects, a relatively small number.  So I understand why the researchers didn’t make a big deal of the lower mortality: it may not be reproducible.

This same research group did a similar study of 318 arthritis patients and intentional weight loss, finding a 50% lower death rate over eight years.

The authors reviewed many similar studies done by other teams, noting increased death rates from weight loss in some studies, and lesser death rates in others. 

When the studies are all over the place like this, it usually means there’s no strong association either way.  Nearly all the pertinent studies were done on relatively healthy, middle-aged and older folks.  The most reliable thing you can say about the issue is that loss of excess fat weight doesn’t increase your odds of premature death. 

 Remember that patients with coronary heart disease, congestive heart failure, or advanced kidney disease tend to live longer if they’re overweight or at least mildly obese.  It’s the obesity paradox.  Will they live longer or die earlier if they go on a weight-loss program?  We don’t know.

We do know that intentional weight loss helps:

  • prevent type 2 diabetes
  • maintain reasonable blood pressures (avoiding high blood pressure)
  • improves lower limb functional ability

Maybe that’s enough.

Steve Parker, M.D.

Reference: Shea, M.K., et al.  The effect of intentional weight loss on all-cause mortality in older adults: results of a randomized controlled weight-loss trial.  American Journal of Clinical Nutrition, 94 (2011): 839-846.

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October 23, 2011 · 7:30 AM

Nasal Insulin Slows Dementia?

 

Insulin administered via the nasal passages slowed or stabilized mental functioning and functional abilities in a pilot study of people with Alzheimer disease and mild cognitive impairment, according to Seattle-based investigators.

As you probably know, dementia is a huge problem for our aging population, and Alzheimers is the most common form of dementia.  The Mediterranean diet is associated with lower risk of mild cognitive impairment and has long been linked to lower risk of dementia as well as slower mental decline in existing Alzheimer dementia patients.  The Mediterranean diet also seems to prolong life in Alzheimer patients.  So I’m always interested in ways to prevent and treat Alzheimers.  Mild cognitive impairment is often a precursor to Alzhiemer disease.

Methodology

The study involved 104 non-diabetic participants with Alzheimer disease (40) or amnestic mild cognitive impairment (64).  They were randomly assigned to one of three groups: placebo (control group), nasal insulin 20 IU twice daily, or nasal insulin 40 IU twice daily. 

Insulin was delivered through a ViaNase device which releases the insulin in to a chamber covering the nose; the participant breathes regularly for two minutes to pick up the dose.  This insulin goes directly to the central nervous system without affecting blood insulin levels or blood sugar levels.

Mental and functional abilities (for example, activities of daily living) were measured at baseline, then again 2, 4, and six months later.  Some of the participants (23) underwent lumbar puncture (for dementia biomarker analysis) and PET brain scans (18).

Comments

This was a well-designed pilot study.

Nasal insulin was well-tolerated.  It’s not commercially available in the U.S.

ResearchBlogging.orgRegarding the placebo group, I was surprised that the researchers could document mental and functional deterioration over this relatively short-term study (4–6 months).  I’m impressed with the need to treat age-related cognitive decline early and aggressively, when we have something that works.

How would nasal insulin work?  We don’t know for sure, but it seems to relate to insulin’s effect on

  • the ability of neurons (brain cells) to communicate with each other through synapses
  • modulaton of blood sugar metabolism in the hippocampus and other brain areas
  • facilitation of memory
  • ß-amyloid peptide

In case you’re wondering, standard subcutaneous injections of insulin can’t be used in studies like this because of the risk of low blood sugar.

I agree wholeheartedly with study authors that “these promising results provide an impetus for longer-term trials of intranasal insulin therapy in adults with amnestic mild cognitive impairment or Alzheimers disease.”

Psychiatrist Emily Deans blogged about this study at Evolutionary Psychiatry September 21, 2001.  Please see her cogent remarks.

Steve Parker, M.D.

Reference:  Craft, S., Baker, L., Montine, T., Minoshima, S., Watson, G., Claxton, A., Arbuckle, M., Callaghan, M., Tsai, E., Plymate, S., Green, P., Leverenz, J., Cross, D., & Gerton, B. (2011). Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial Archives of Neurology DOI: 10.1001/archneurol.2011.233

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October 18, 2011 · 1:42 AM

LADA Awareness Week

"Who can tell us about LADA?"

This is the first ever LADA Awareness Week, organized by Diabetes Hands Foundation and dLife.  LADA stands for Latent Autoimmune Diabetes in Adults.  I think of it as type 1 diabetes that starts in adulthood, although there are some differences from typical juvenile-onset type 1 diabetes.

Seven-and-a-half to 10% of apparent type 2 adult diabetics have LADA.  It’s caused by the body attacking its own pancreas beta cells and thereby impairing insulin production; in other words, it’s an autoimmune thing.

Here are some generalities (with exceptions, of course) about LADA, compared to typical type 2 diabetes:

  • lower body mass index, often under 25
  • age at onset under 50
  • poorer response to dietary management
  • poorer response to oral diabetic medications
  • acute symptoms at time of diagnosis (e.g., weight loss, thirst, frequent urination, ketoacidosis, malaise, etc.)
  • higher risk of developing diabetic ketoacidosis
  • much more likely to need insulin

How Is LADA Diagnosed?

First of all, the doctor has to consider the possibility, based on the clinical factors above.  The autoimmune nature of the disease is reflected in islet-cell antiobodies (ICA) and antibodies to glutamic acid decarboxylase (anti-GAD).  These are testable in the blood.  One of the two may be enough.  If the disease is far enough along, blood levels of C-peptide will be low.  C-peptide reflects the body’s production of insulin.

For more information on LADA, talk to your doctor or visit this page at dLife.

Steve Parker, M.D.

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October 16, 2011 · 11:50 PM

Dr. Andreas Eenfeldt Explains LCHF Diet

LCHF Cheese

Dr. Eenfeldt of DietDoctor.com gave a talk at the recent Ancestral Health Symposium in California, on the rationale of the current low-carb, high-fat diet (LCHF) so popular in his home country of Sweden.  It’s very understandable to the general public and is a good introduction to low-carb eating.  The entire YouTube video is 55 minutes; if you’re pressed for time, skip the 10-minute Q&A at the end.

He also discusses the benefits of LCHF eating for his patients with diabetes.

If you reduce carbohydrate, you’re going to replace it with either protein, fat, or both.  As Dr. Eenfeldt recommends, the Ketogenic Mediterranean and Low-Carb Mediterranean Diets replace carbs more with fats than protein.

Steve Parker, M.D.

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October 14, 2011 · 2:09 AM

Coronary Heart Disease on Decline in U.S.

The U.S. Centers for Disease Control and Prevention reports this month that the prevalence of self-reported coronary heart disease declined from 6.7% of the population in 2006, to 6% in 2010.  Figures were obtained by telephone survey.  Coronary heart disease, the main cause of heart attacks, remains the No.1 cause of death in the U.S.

Self-reports of heart disease may not be terribly reliable.  However, I remember an autopsy study from Olmstead County, Minnesota, from a few years ago that confirmed a lower prevalence of coronary heart disease.  I wrote about that at my old NutritionData.com Heart Health Blog, but those posts are lost to posterity.

The CDC report mentioned also that mortality rates from coronary heart disease have been steadily declining for the last 50 years. 

Improved heart disease morbidity and mortality figures probably reflect better control of risk factors (e.g., smoking, high blood pressure), as well as improved treatments.  I’ve never seen an estimate of the effect of reduced trans fat consumption. 

Obesity is always mentioned as a risk factor for heart disease, yet obesity rates have skyrocketed over the last 40 years.  You’d guess heart disease prevalance to have risen, but you’d have guessed wrong.  In view of high obesity rates, some pundits have even suggested that the current generation of Americans wil be the first to see a decrease in average life span. 

The American Diabetes Association offers a free heart disease risk calculator, if you’re curious about your own odds.  My recollection is that the calculator works whether or not you have diabetes.

Steve Parker, M.D.

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October 12, 2011 · 12:52 AM

Avoid Drug Toxicity By Avoiding Drugs

David Mendosa over at Diabetes Developments writes about avoiding diabetes drug toxicity with low-carb eating.

Steve Parker, M.D.

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October 10, 2011 · 2:00 AM

“New” Drug for Diabetes

The U.S. Food and Drug Administration a few days ago announced its approval of Juvisync for treatment of type 2 diabetes.  It’s just a combination of sitagliptin and simvastatin, drugs that have been on the market for years.  Simvastatin isn’t a diabetes control drug at all; it’s a cholesterol-lowering drug in the statin class.

Better living through chemistry

I often see patients with potential drug side effects.  If they’re taking six drugs, the culprit is usually only one of the drugs.  So I tell the patient to put that one drug on hold and see what happens.  Combination drugs interfere with that strategy, so I tend to avoid them. 

Steve Parker, M.D.

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