What drug to add to maximal metformin therapy for diabetes?

Metformin is the recommended initial drug therapy for patients with type 2 diabetes mellitus (DM). However, the optimal second-line drug when metformin monotherapy fails is unclear.

All noninsulin antidiabetic drugs were associated with similar HbA1c reductions but differed in their associations with weight gain and risk of hypoglycemia.

The different classes of drugs were associated with similar HbA1c reductions (range, 0.64%-0.97%) compared with placebo.

Noninsulin antidiabetic drugs and their effect on body weight:

- thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg)

- glucagon-like peptide-1 analogs, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change

Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo.

References:

Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes. JAMA. 2010;303(14):1410-1418. doi: 10.1001/jama.2010.405

Insulin treatment for type 2 diabetes: When to start, which to use - The Cleveland Clinic approach

Image source: Metformin. Wikipedia, public domain.

Promise of Prevention: Effects of 4 Risk Factors on U.S. Life Expectancy and Disparities

This analysis included 4 preventable risk factors:

- smoking

- high blood pressure

- elevated blood glucose

- adiposity

The researchers estimated the effects of these 4 preventable risk factors on national life expectancy and on disparities in life expectancy and disease-specific mortality among 8 subgroups of the US population (the “Eight Americas”). The groups were defined on the basis of race, location and socioeconomic characteristics of county of residence, in 2005.

Who has the lowest number of risk factors?

Asians had the lowest mean body mass index, fasting plasma glucose, and smoking; whites had the lowest systolic blood pressure (SBP).

Who has the highest number of risk factors?

Systolic blood pressure (SBP) was highest in blacks, especially in the rural South - 5-7 mmHg higher than whites. The other three risk factors were highest in Western Native Americans, Southern low-income rural blacks, and/or low-income whites in Appalachia and the Mississippi Valley.

How much shorter is life expectancy if you have the risk factors?

These 4 risk factors reduced life expectancy at birth by 5 years in men and 4 years in women.

Life expectancy effects were smallest in Asians (M, 4.1 y; F, 3.6 y) and largest in Southern rural blacks (M, 6.7 y; F, 5.7 y).

Smoking and high blood pressure had the largest effect on life expectancy disparities.

Disparities in the 4 risk factors (smoking, blood pressure, blood glucose, and adiposity) explain a significant proportion of disparities in mortality from cardiovascular diseases and cancers. They also explain some of the life expectancy disparities in the US.

References:

Danaei G, Rimm EB, Oza S, Kulkarni SC, Murray CJL, et al. (2010). The Promise of Prevention: The Effects of Four Preventable Risk Factors on National Life Expectancy and Life Expectancy Disparities by Race and County in the United States. PLoS Med 7(3): e1000248. doi:10.1371/journal.pmed.1000248

Image source: Wikipedia, public domain.

Vitamin D receptor activation with paricalcitol decreases albuminuria in type 2 diabetes

Despite treatment with renin—angiotensin—aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria.

281 patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were enrolled in this study.

Patients were assigned to receive 24 weeks' treatment with:

- placebo
- 1 μg/day paricalcitol
- 2 μg/day paricalcitol

Paricalcitol (trade name Zemplar, Abbott Laboratories) is an analog of calcitriol, the active form of vitamin D.

The primary endpoint was the percentage change in mean urinary albumin-to-creatinine ratio (UACR).

The change in urinary albumin-to-creatinine ratio (UACR) was: −14% in the 1 μg paricalcitol group, and −20% in the 2 μg paricalcitol group.

The addition of 2 μg/day paricalcitol to RAAS inhibition safely lowers albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower renal risk in diabetes.

References:
Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. The Lancet, Volume 376, Issue 9752, Pages 1543 - 1551, 6 November 2010.

Image source: Paricalcitol, Wikipedia, public domain.

Liraglutide (Victoza) superior to sitagliptin (Januvia) for reduction of HbA1c in diabetics

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, increase GLP-1 levels by blocking the enzyme which inactivates GLP-1. The enzyme is called DPP-4 (dipeptidyl peptidase-4). They act similarly to Byetta (see figure above) but have the big advantage to be available in oral form (pills). Gliptins used for treatment of DM2 include sitagliptin (Januvia) and vildagliptin (Galvus).

What is Liraglutide?

Liraglutide (Victoza) is a long-acting glucagon-like peptide-1 (GLP-1) analog that was 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.

Liraglutide (Victoza) superior to sitagliptin (Januvia) for reduction of HbA1c in diabetics

This Lancet study assessed the efficacy and safety of the human GLP-1 analogue liraglutide versus the DPP-4 inhibitor sitagliptin, as adjunct treatments to metformin, in individuals with type 2 diabetes who did not achieve adequate glycaemic control with metformin alone.

More than 600 participants (aged 18—80 years) with type 2 diabetes mellitus who had inadequate glycaemic control (glycosylated haemoglobin [HbA1c] 7·5—10·0%) on metformin (more than 1500 mg daily) were enrolled.

Participants were randomly allocated to receive 26 weeks' treatment with 1·2 mg or 1·8 mg subcutaneous liraglutide once daily, or 100 mg oral sitagliptin once daily.

Greater lowering of mean HbA1c (8·5% at baseline) was achieved with 1·8 mg liraglutide (−1·50%) and 1·2 mg liraglutide (−1·24%) than with sitagliptin (−0·90%).

Nausea was more common with liraglutide (27%) on 1·8 mg. Minor hypoglycaemia was recorded in about 5% of participants in each treatment group.

Liraglutide was superior to sitagliptin for reduction of HbA1c, and was well tolerated with minimum risk of hypoglycaemia. These findings support the use of liraglutide as an effective GLP-1 agent to add to metformin.

References:

Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. The Lancet, Volume 375, Issue 9724, Pages 1447 - 1456, 24 April 2010.

Diabetic retinopathy is identified in a third of people with diabetes

Diabetic retinopathy is a common microvascular complication of diabetes, and remains the leading cause of preventable blindness in working-aged people. It is identified in a third of people with diabetes and associated with increased risk of life-threatening systemic vascular complications, including stroke, coronary heart disease, and heart failure.

Optimum control of blood glucose, blood pressure, and possibly blood lipids remains the foundation for reduction of risk of retinopathy development and progression.

Timely laser therapy is effective for preservation of sight in proliferative retinopathy and macular oedema, but its ability to reverse visual loss is poor.

Vitrectomy surgery might occasionally be needed for advanced retinopathy.

New therapies, such as intraocular injection of steroids and antivascular endothelial growth-factor agents, are less destructive to the retina than are older therapies, and could be useful in patients who respond poorly to conventional therapy.

Future treatment modalities include inhibition of other angiogenic factors, regenerative therapy, and topical therapy.

References:
Diabetic retinopathy [Seminar]. Ning Cheung, Paul Mitchell, Tien Yin Wong. Lancet, 2010.

Intensifying glucose control and adding fenofibrate to simvastatin each reduced progression of retinopathy in DM2 http://goo.gl/htHIK

Ophthalmology Self-Guided Study Activity - ACP 2011 .

Metformin increases risk of vitamin B-12 deficiency

As many as 22% of people with type 2 diabetes could have vitamin B-12 deficiency.

This BMJ study evaluated the effects of metformin on the incidence of vitamin B-12 deficiency (lower than 150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin.

Compared with placebo, metformin treatment was associated with a decrease in vitamin B-12 concentration of -19%.

The absolute risk of vitamin B-12 deficiency (lower than 150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group with a number needed to harm of 13.8 per 4.3 years.

Long term treatment with metformin may increase the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, regular measurement of vitamin B-12 concentrations during long term metformin treatment should be considered.

References:
BMJ 2010; 340:c2181

BMJ 2010; 340:c2198

Image source: Metformin. Wikipedia, public domain.

People who get less than 6 hours sleep per night have an increased risk of dying prematurely

People who get less than 6 hours sleep per night had an increased risk of dying prematurely in a recent study. Those who slept for less than that amount of time were 12% more likely to die early, though researchers also found a link between sleeping more than 9 hours and premature death.

The study aggregated decade-long studies from around the world involving more than 1.3 million people and found "unequivocal evidence of the direct link" between lack of sleep and premature death.

Just one sleepless night can hamper the body's ability to use insulin to process sugar in the bloodstream. Insulin sensitivity is not fixed in healthy people, but depends on the duration of sleep in the preceding night.

"Society pushes us to sleep less and less," one of the study investigators said, adding that about 20% of the population in the United States and Britain sleeps less than 5 hours.

Adults typically need between 7 and 9 hours sleep a night. If you sleep little, you can develop diabetes, obesity, hypertension and high cholesterol.

References:
Bad night's sleep can hamper body's insulin use. Reuters.

Image source: A halo around the Moon. Wikipedia, GNU Free Documentation License.

Glycated hemoglobin as a diagnostic test for diabetes predicts mortality more accurately than fasting glucose

Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose.

The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes.

For glycated hemoglobin, values of less than 5.0%, 5.0-5.5%, 5.5-6.0%, 6.0-6.5%, and 6.5% or greater, the hazard ratios for diagnosed diabetes were 0.52, 1.00, 1.86, 4.48, and 16.47, respectively.

For coronary heart disease, the hazard ratios were 0.96, 1.00, 1.23, 1.78, and 1.95, respectively. The hazard ratios for stroke were similar.

In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve.

The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant.

In this community-based population of nondiabetic adults, glycated hemoglobin was associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.

References:

Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults. NEJM, 2010.

Image source: OpenClipArt.org, public domain.

Start metformin early when diabetes type II is first diagnosed

Initiating metformin soon after diabetes diagnosis and while A1C is low might preserve β-cell function, prolong the effectiveness of metformin, reduce lifetime glycemic burden, and prevent diabetes complications.

These findings support the current treatment algorithm for hyperglycemia management that recommends metformin initiation when diabetes is first diagnosed.

References:

Secondary Failure of Metformin Monotherapy in Clinical Practice. Diabetes Care March 2010 vol. 33 no. 3 501-506.

Contact lenses change color when blood glucose increases in diabetics

In the future, diabetics may be able to wear contact lenses that continuously alert them to variations in their glucose levels by changing colors - potentially replacing the need to routinely draw blood throughout the day.

The non-invasive technology, developed by Chemical and Biochemical Engineering professor Jin Zhang at The University of Western Ontario, uses extremely small nanoparticles embedded into the hydrogel lenses. These engineered nanoparticles react with glucose molecules found in tears, causing a chemical reaction that changes their color.

References:
Nanocomposites could change diabetes treatment. The University of Western Ontario, 2010.

Image source: OpenClipArt.org.

Preventing diabetes, biological passport for athletes and more from the Lancet

Low-dose combination therapy with rosiglitazone and metformin was highly effective in prevention of type 2 diabetes in patients with impaired glucose tolerance, with little effect on the clinically relevant adverse events of these two drugs.

Preventing type 2 diabetes with low-dose combinations: Lifestyle interventions aimed at reducing bodyweight, and use of metformin, thiazolidinediones, acarbose, and orlistat, reduce the risk of diabetes by 25—60% over 3—6 years

The biological passport and doping in athletics: A biological passport monitors an athlete's blood and body chemistry values over time to assess whether there has been a deviation from an established baseline, thus indirectly detecting illegal manipulation.

A long look at obesity: Even with their primitive understanding of nutrition, our neolithic forebears somehow made the “right choices”, thriving on a wholesome diet of nuts, seeds, and fruits with the occasional piece of meat. And what is more, their rare intake of animal protein could only have been obtained through vigorous exercise, which they would, of course, indulge in every day.

Former FDA commissioner on the killer combination of salt, fat and sugar - our food

David A Kessler, former commissioner of the FDA (the US Food and Drug Administration):

"Our favourite foods are making us fat, yet we can't resist, because eating them is changing our minds as well as bodies

For example, KFC's approach to battering its food results in "an optimised fat pick-up system". With its flour, salt, MSG, maltodextrin, sugar, corn syrup and spice, the fried coating imparts flavour that touches on all three points of the compass while giving the consumer the perception of a bargain – a big plate of food at a good price."

The ranks of overweight adults and children continue to increase. For the first time in history, overweight persons actually outnumber those who are malnourished. Obesity now kills more men and women in developed nations than war, terrorist attacks, or climate changes. On average, obese individuals forfeit about 9 years of life.

More on the same topic in the video below:



"Fake foods are more affordable. It's enticing people to eat more because they think they're saving money when they're really just buying heart disease." 10 Questions for Jillian Michaels. TIME, 2010.

References:
Obesity: The killer combination of salt, fat and sugar | David A Kessler. Guardian.

JAMA - Fat, Gluttony and Sloth: Obesity in Literature, Art and Medicine, July 7, 2010, Miksanek 304 (1): 101 http://goo.gl/eEos

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

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

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

Image source: Soft drinks, Wikipedia, public domain.

Updated: 07/16/2010

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.