Today is World Diabetes Day


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Let today be the beginning of the end of your diabetes. Today being the World Diabetes Day, there is no better a day to take a new step for the awareness of the lifestyle disease, Diabetes. Every year, World Diabetes Day is co-ordinated by the International Diabetes Federation (IDF) with a particular theme; between 2009 and 2013 the theme has been ‘education and prevention’.

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Noninjectable Insulin Developers Make Progress


Diabetes sufferers may soon be able to avoid the needle.

Noninjectable Insulin Developers Make ProgressLessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. [AndrzejTokarski/Fotolia]

Whether famous like Tom Hanks or not, millions of people with diabetes for generations have had to take insulin by injection, just as a 14-year-old diabetic named Leonard Thompson did when he became the first patient successfully treated with the peptide hormone in 1922.

Nearly a century later, drug developers remain unable to market a noninjectable therapeutic. But of late, lessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. The companies see a growing market: An estimated 552 million people are expected to develop diabetes by 2030, up from 371 million in 2012, according to the International Diabetes Federation.

No Needles Required

MannKind earlier this month resubmitted to FDA its new drug application for Afrezza® (insulin human [rDNA origin]) Inhalation Powder for adults with type 1 or type 2 diabetes)—two years after the agency required two additional clinical studies comparing its current inhaler to its first-generation MedTone inhaler.

In August, MannKind released promising results from two Phase III trials. One study in type 1 patients compared Afrezza to insulin aspart; the other measured inhalable insulin in type 2 patients with inadequate diabetes control following metformin treatment, with or without a second or third oral medication. The type 2 study showed a drop in mean A1c levels of 0.82% in patients using Afrezza, compared to a 0.42% decrease in the comparator group. The type 1 study met its primary endpoint of noninferiority to insulin aspart.

Afrezza combines an inhalation powder with an inhaler called Dreamboat™ designed for use by diabetics at the start of meals. The powder dissolves immediately when inhaled to the deep lung and delivers insulin quickly to the bloodstream. According to MannKind, peak insulin levels occur within 12 to 15 minutes of administration, compared with 45 to 90 minutes for injected rapid acting insulin analogs, and 90–150 minutes for injected regular human insulin.

Joseph Kocinsky, MannKind’s svp, pharmaceutical technology development, told GEN Afrezza’s Technosphere® pulmonary drug delivery platform offers competitive advantages. In addition to ultra-fast delivery, insulin administered via Technosphere formulation avoids the hepatic first-pass metabolism that reduces drug bioavailability.

“The Technosphere technology is applicable to a wide variety of drugs (small molecules, peptides, proteins, monoclonal antibodies) and a wide variety of clinical indications like diabetes, pain, osteoporosis, and respiratory disease,” Kocinsky said.

Perhaps Afrezza’s best advantage is the same one offered by the oral insulin products—it doesn’t require a needle. Injection remains no small hurdle to insulin use among people with diabetes, despite improvements over the past generation such as shorter and sharper disposable needles, notes Robert E. Ratner, M.D., FACP, FACE, chief scientific and medical officer for the American Diabetes Association.

Dr. Ratner’s previously work as an investigator included studying Novo Nordisk’s insulin degludec, a long-acting injectable insulin analog. He said injection has one important advantage: Doses can be titrated and adjusted.

“When you’re giving oral or inhaled insulin, that level of precision in terms of dosing is probably going to be considerably harder,” Dr. Ratner told GEN. “We don’t yet know all of the details about the pharmacokinetics of these [noninjectable] agents—how quickly they’ll get absorbed, what percentage will get absorbed, are we going to be able to change the doses to meet the biologic needs of the individual? Those all remain unknowns. Those are the hurdles the companies need to overcome before we have a viable product.”

Road to Success Paved with Failure

Drug developers have long struggled to develop noninjectable diabetes treatments. In 2007, Pfizer stopped marketing Exubera® after 13 months following disappointing sales, took $2.8 billion in pre-tax charges, and returned product rights to partner Nektar Therapeutics.

One key factor in Exubera’s failure was its delivery system: Its inhaler was about a foot long, more conspicuous and clumsier than even the needle. Afrezza can be inhaled through a smaller inhaler requiring no maintenance because it is discarded and replaced every 15 days. Also unlike Exubera, Afrezza is dosed in traditional insulin units that are linear; two three-unit cartridges equal a six-unit cartridge.

Within months of Exubera’s exit, both Novo Nordisk and Eli Lilly ended programs to develop new inhalable insulin products that had advanced to Phase III trials, insisting they had not acted from safety concerns. Lilly brought insulin to market in 1923, and 60 years later launched the first insulin analogs.

Today, Novo Nordisk and another drug developer, Oramed, are well into clinical studies of oral insulin products, with years to go: “We won’t be looking at oral insulin for the next five to six years at the very least.”

Future Possibilities

Also working on noninjectable insulin is Biocon, which last year landed Bristol-Myers Squibb (BMS) as its partner to partially fund Phase II trials of its IN-105 outside India for two years. After that, BMS has the option to assume full responsibility for IN-105, including all development and commercialization activities outside India—in return for BMS paying Biocon a license fee, milestone payments, and royalties on IN-105 sales outside India.

Oramed in July enrolled its first patient in a Phase IIa trial assessing the safety of ORMD-0801, an orally ingestible insulin capsule on patients with type 2 diabetes. A total 30 patients will be enrolled.

“Results of the trial are anticipated by the end of the calendar year,” Aviva Sherman, an Oramed spokeswoman, told GEN.

ORMD-0801 is also under study in a clinical trial in Israel in August that began recruiting patients with type 1 diabetes, for which -0801 is envisioned as a complement to injections, allowing fewer daily injections.

In September, Oramed submitted a pre-IND package to FDA for its ORMD-0901 (oral exenatide), a GLP-1 analog for type 2 diabetes. “By acting on multiple fronts, i.e., stimulation of insulin release and suppression of glucagon release, as well as other actions, GLP-1 addresses diabetes-related glycemia issues on a broader level than does exogenously administered insulin,” Sherman said.

Oramed said its oral insulin mimics insulin’s natural location and gradients in the body by traveling through the gastrointestinal tract encapsulated, then releasing the insulin in the small intestine, from which it is ferried to the liver via the portal vein. The first-pass metabolism significantly reduces the risk of hypoglycemia, the most common side effect of injected insulins.

Novo Nordisk’s candidate OI362GT or NN1954, an oral basal insulin analog intended as a tablet treatment, generated successful results from a single-dose Phase I trial earlier this year. Peter Kurtzhals, svp in diabetes research at Novo Nordisk, told GEN NN1954 is delivered through enteric coated tablets targeting the duodenum, facilitated by the rise in pH that occurs when a substance passes from the acidic milieu in the stomach into the intestine.

“The delivery in duodenum is not more porous, but contents of the gall fluid secreted here may play a role in facilitating absorption of some substances from this part of the gut,” Kurtzhals said.

NN1954 absorption is enabled via partner Merrion Pharmaceuticals’ GIPET® technology. GIPET uses specifically designed oral formulations of patented absorption enhancers designed to activate micelle formation, facilitating transport of drug and increasing absorption.

The drug and enhancer are not bound to each other chemically, but are both ingredients of the tablet, with no interaction between active pharmaceutical ingredient and absorption enhancer. Co-release of the drug and absorption enhancer occurs following dissolution of the coating and a general disintegration of the tablet.

“The oral insulin project is currently in Phase I clinical development. Contingent on successful outcome of these trials, Phase II will be initiated within 1–2 years,” Kurtzhals said.

By the time Novo Nordisk and Oramed complete their required additional trials, followed by formal regulatory reviews, MannKind may have already delivered the first noninjectable insulin to grateful diabetics. Or not. FDA can be expected to show particular caution with noninjectable insulin candidates, given the problems inhalables have had in recent years. To win approvals, companies will have to show not only the usual safety and efficacy, but that their products are better than past noninjectable candidates—drugs young Leonard Thompson could only dream about when he took insulin by needle and made history nearly a century ago.

Diabetes prevalence continues to climb in China.


Data from a survey of over 98,000 Chinese adults indicate that the prevalence of diabetes affects approximately 50% of the Chinese population, and only 25.8% of diagnosed patients are being treated.

“These data suggest that diabetes may have reached an alert level in the Chinese general population with the potential for a major epidemic of diabetes-related complications, including cardiovascular disease, stroke and chronic kidney disease in China in the near future without an effective national intervention,” the researchers wrote.

Researchers from the 2010 China Noncommunicable Disease Surveillance Group collected data from 162 study sites in the Chinese Center for Disease Control and Prevention’s (CDC’s) National Disease Surveillance Point System. According to researchers, measurements of HbA1c, fasting plasma glucose and 2-hour plasma glucose were collected from a nationally representative sample of 98,658 adults aged 18 years or older in 2010.

They found that the overall prevalence of diabetes was about 11.6% (95% CI, 11.3% to 11.8%) among the adult Chinese population (12.1% in men vs. 11% in women).

Further data indicate the prevalence of previously diagnosed diabetes was estimated to be 3.5% (95% CI, 3.4% to 3.6%) in the Chinese population (3.6% in men vs. 3.4% in women). Undiagnosed diabetes was estimated at 8.1% (95% CI, 7.9% to 8.3%) in the overall population (8.5% in men vs. 7.7% in women), according to data.

Moreover, the prevalence of prediabetes was estimated to be 50.1% (95% CI, 49.7% to 50.6%) in Chinese adults (52.1% in men vs. 48.1% in women).

The prevalence for prediabetes was greater among patients in older age groups (P<.001), urban residents, patients living in economically-developed regions and those who were overweight or obese, researchers wrote.

Data also demonstrate only 25.8% of patients with diabetes received treatment. Of those treated, only 39.7% had HbA1c levels less than 7% (40.7% in men vs. 38.6% in women), researchers wrote.

In an accompanying editorial, Juliana C. N. Chan, MD, FRCP, from the department of medicine and therapeutics at the Hong Kong Institute of Diabetes and Obesity, the Chinese University of Hong Kong Prince of Wales Hospital International Diabetes Federation Centre of Education, Shatin, Hong Kong, SAR, China, wrote that diabetes is a societal and health care challenge.

“To this end, government leaderships, partnerships, and community empowerment will be needed to create a health-promoting environment, encourage self-management, and strengthen the health care system to make health a reality,” Chan wrote.

Source: Endocrine Today.

 

 

Association of seasonal variation in the prevalence of metabolic syndrome with insulin resistance.


The aim of this study was to examine the hypothesis that seasonal variation in the prevalence of metabolic syndrome (MetS) is associated with increased insulin resistance. Among 840 Japanese male workers who were evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR) in June (summer) 2010, we prospectively studied a total of 758 subjects (40–65 years of age) who underwent an assessment in December (winter) 2010. MetS was defined according to the criteria proposed by the International Diabetes Federation (IDF) and the Japanese Society of Internal Medicine (JSIM). The median level of HOMA-IR in the study subjects was 0.84 (interquartile range: 0.60–1.19). The prevalence rates of IDF- and JSIM-MetS significantly increased from 12.4 and 9.6% in the summer to 16.6 and 13.3% in the winter, respectively (each P<0.05). Our data suggest that these increases are mainly due to increases in blood pressure (BP) and glucose during the winter assessment. The prevalence rates of IDF-MetS in the first, second, third and fourth quartiles of HOMA-IR were 1.1, 5.8, 14.3 and 29.1% in the summer and 3.1, 10.6, 21.9, and 31.3%in the winter, respectively. Similar results were obtained when using the JSIM criteria. In the third quartile, the frequency of elevated BP increased from 42.4% in the summer to 61.2% in the winter (P<0.05), and these values were mainly correlated with significant variations in IDF- and JSIM-MetS prevalence rates. This study demonstrates that seasonal variation in MetS prevalence is associated with mildly to moderately increased insulin resistance in middle-aged Japanese men.

 

Source: Nature

Rice gene holds clue to diabetes risk.


Contrary to popular belief, a new study suggests that eating rice does not substantially raise blood sugar levels – thus increasing the risk of type 2 diabetes – although researchers warn that some varieties of rice may need to be avoided.

The study was published this month in the journal Rice by the International Rice Research Institute (IRRI) in the Philippines, and Australia’s Commonwealth Scientific and Industrial Research Organization (CSIRO).

It found that as many as three quarters of 235 rice varieties analysed had a low to medium glycaemic index (GI), and were therefore less likely to lead to diabetes.

GI measures the effect of carbohydrates on blood sugar levels. Low GI foods are more slowly absorbed, causing a gradual release of sugar in the body and a lower risk of diabetes. Doctors often advise diabetics to avoid rice, believing it is a high-GI food.

The findings could have important implications for Asia where rice is the staple food for 3.5 billion people, and diabetes is a growing public health concern, said Melissa Fitzgerald, who led the IRRI team.

“With or without diabetes, it will be difficult for them to give up rice,” Fitzgerald told SciDev.Net.

The International Diabetes Federation estimates that by 2030, seven of the ten countries with the highest number of diabetics will be in Asia, straining public health budgets.

The researchers found that the so-called “waxy gene”, and the related amylose content, are the key determinants of the GI of rice. Rice varieties with high amylose have lower GI.

Amylose is also the chemical component which makes rice either firm or sticky after cooking, influencing consumer preferences. The waxy or sticky rice types have the highest GI, but some sticky rice varieties have little or no amylose.

Rice varieties with a low to medium GI include Basmati, India’s widely grown Swarna variety, and Doongara from Australia.

The researchers say that the findings will help rice breeders to develop lower GI rice by identifying varieties with better traits.

Tony Bird, a CSIRO Food Futures Flagship researcher said “this is good news for diabetics and people at risk of diabetes who are trying to control their condition through diet, as it means they can select the right rice to help maintain a healthy, low-GI diet.”

But Claire Kerslake, a health counsellor and certified diabetes educator in Australia, warned that although it was true that some varieties of rice are lower in GI, “the GI is only part of the picture. You also need to take into account the total carbohydrate load”.

She advised diabetics to limit carbohydrates such as rice “to half a cup per meal.”

Source: ScivX