Luseogliflozin I Sodium Glucose Co-transporter 2 Inhibitor I Treatment for Diabetes Mellitus

Luseogliflozin [(2S,3R,4R,5S,6R)-2-{5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}- 6-(hydroxymethyl)thiane-3,4,5-triol hydrate] is an oral, 1-thio-D-glucitol derivative Sodium glucose co-transporter 2 (SGLT2) inhibitor that is developed for the treatment of type 2 diabetes mellitus (T2DM).

Luseogliflozin is a potent and selective SGLT2 inhibitor, with a 50% inhibitory concentration (IC₅₀) of 2.26 nM, which is 1765 times lower than its IC₅₀ for SGLT1 (IC₅₀ = 3990 nM). This potency allows the administration of lower doses of Luseogliflozin compared with other SGLT2 inhibitors for the treatment of T2DM.

Luseogliflozin: 2D and 3D Structure

Luseogliflozin an orally active second-generation SGLT2 inhibitor is developed for the treatment of patients with type 2 diabetes mellitus (T2DM). In March 2014, the drug received its first global approval for this indication in Japan, either as monotherapy or in combination with other antihyperglycaemic agents.

Diabetes and SGLT Inhibitors

Good control of blood glucose can be achieved by a controlled diet and physical exercise. Diabetes is associated with an increased risk of both macrovascular (cardiovascular disease) and microvascular (nephropathy, retinopathy, and neuropathy) complications. Diabetes can also be managed by orally active drugs including sulfonylurea, biganide etcs.

Sodium-dependent glucose transporters (SGLTs) present on the chronic membrane of the intestine and kidney play an important role in the absorption and reabsorption of glucose. Inhibition of renal glucose reabsorption is emerging as a novel therapy for patients with type 2 diabetes mellitus (T2DM).

In particular, blocking the sodium-glucose cotransporter 2 (SGLT2)-a low-affinity high-capacity transporter localised to the renal proximal tubules-has been shown to suppress glucose reabsorption, leading to increased urinary excretion with a concomitant reduction in plasma glucose levels. Compounds selective for SGLT2 are desirable as SGLT1 is highly expressed in the gastrointestinal tract but only moderately expressed in the kidneys.

SGLT2 inhibitors have an insulin-independent mechanism of action; these drugs are expected to improve glycemic control with a low risk of major hypoglycemic events. Furthermore, total calorie loss through urinary glucose excretion may not cause weight gain and may even achieve weight loss.

Dosages and Approvals:

Luseogliflozin [Tradename: Lusefi] is a selective SGLT2 inhibitor, which received its first marketing approval in Japan for the treatment of T2DM on the 24^th of March 2014. The drug has received approval as 2.5 and 5 mg oral tablets with a recommended starting dose of 2.5 mg once daily. This may be increased to 5 mg once daily if necessary for optimal clinical effect.

Luseogliflozin is manufactured by Taisho Pharmaceutical, Japan and co-marketed by both Taisho and Novartis in Japan. Novartis licensed the marketing rights for Luseogliflozin in Japan. Under the terms of this agreement, Taisho will receive an upfront payment and milestone payments from Novartis.

Luseogliflozin Synthesis

J Med Chem 2010, 53(8), 3247-3261:

Final Synthesis:

Identifications:

1H NMR (Estimated) for Luseogliflozin

References:

1. Markham, A.; et. al. Luseogliflozin: first global approval. Drugs 2014, 74(8), 945-50. (FMO only)

2. Seino, Y. Luseogliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother 2014, 15(18), 2741-9. (FMO only)

3. Yamamoto, K.; et. al. TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity. Br J Pharmacol 2011, 164(1), 181-91. (Free copy)
4. Kakinuma, H.; et. al. (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment. J Med Chem 2010, 53(8), 3247-3261. (FMO only)

Saroglitazar | Antidiabetic Drug | Dual PPAR Inhibitor | Treatment of Diabetic Dyslipidemia | Glitazar

Saroglitazar [(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid] is a novel class of anti-diabetic drug, which target both α and γ Peroxisome Proliferator Activated Receptors (PPAR) isoforms. This new class of dual PPAR agonists, termed as glitazar, which bind to both α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome [1].

Saroglitazar: Dual PPAR Inhibitor for T2DM Patients

In February 2013, Saroglitazar became the first glitazar that has been approved by any FDA for clinical use. Saroglitazar is marketed under the trade name Lipaglyn and developed by Zydus Cadila. Saroglitazar (2 and 4 mg q.d.) is currently approved in India by Drug Controller General of India (DCGI ) for the management of diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy. Lipaglyn provides the option of a once-daily oral therapy for the patients suffering from diabetic dyslipidemia.

Saroglitazar has another first attached to it. It is the first indigenously developed NCE by any Indian company; in this case Zydus Cadila.

Lipaglyn is indicated 4 mg (or 2 mg where such a need arise) oral dose once daily. 

Saroglitazar Synthesis

WO2003009841A1: Industrial Process

Identification:

1H NMR (Estimated) for Saroglitazar

Experimental: ¹H NMR: 1.14 (3H, t, J = 6.9Hz); 2.37 (3H, s); 2.48 (3H, s); 2.92-3.06 (2H, m); 3.32-3.42 (1H, m); 3.57-3.64 (1H, m); 3.9 (2H, t, J=6.36 Hz); 4.0 (1H, dd); 4.28(2H, t, J = 6.2 Hz); 5.9 (1H, d, J = 3.3 Hz); 6.08 (1H, d, J = 3.38 Hz); 6.6 (2H, d, J = 8.5Hz); 7.1(2H, d, J = 8.5Hz); 7.26 (2H, d, J = 8.4Hz); 7.3 (2H, d, J = 8.34Hz)

Sideeffects:

The results from various clinical trials do not cite any serious adverse events for Saroglitazar. A small number of incidence reported are dyspepsia, gastritis, pyrexia, pain and chest pain. Their occurrence is nearly as those reported for placebo in the study.

None of the study reports any of the sideeffects commonly associated with PPAR inhibitors such as edema, weight gain, myopathies or derangement of liver and/or kidney functions.

Saroglitazar controversy:

Zydus Cadila says that's its antidiabetic pill is free from side-effects. One expects Saroglitazar to exhibits few (if not all) of the side-effects that occur with other members of glitazar family. I agree that in Saroglitazar case these side-effects may not be life threatening as in other marketed antidiabetic drugs such as pioglitazone, etc; but a pill with no side-effect is "hard to swallow" pill.

Lancet in one of its publication has cited three antidiabetic launched in India that have a used a very "un-scientific" technique to do so. Saroglitazar is the only NCE here, the other two being Hydroxychloroquine (already used as for rheumatoid arthritis treatment) and Berberine (a herbal preparation). Lancet cites that these drugs or preparations have been launched without any extensive clinical trials. The clinical trials done are with small sample size; and/or of very short time frame. In simple words, Lancet feels that these drugs have been "pushed" down the Indian throats. Though the originator companies have strongly refuted this publication; but the question still stay ..... how can be there no AEs? Any foreign particle (including drug molecules) trigger a wide range of receptors, some have an instantaneous reaction (or visualization); other are like slow poison, waiting for a time period to strike. Lack of time-based knowledge of effects is pretty dangerous and west knows it best; as they have launched pain-killers that killed people via heart-attacks [3].

References:

1. Agrawal, R. The first approved agent in the Glitazar's Class: Saroglitazar. Curr Drug Targets 2014, 15(2), 151-155.
2. Lohray, B. B.; et. al. Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine. WO2003009841A1
3. Luthra, A.; et. al. The marketing of unproven drugs for diabetes and dyslipidaemia in India. The Lancet Diabetes and Endocrinology 2015, 3(10), 758-760.

Drugs in Clinical Pipeline: GSK-1614235

GSK-1614235 [3-{[3-(4-{[3-(ß-D-Glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-yl]methyl}-3-methylphenoxy)propyl]amino}-2,2-dimethylpropanamide] is a potent and selective inhibitor of SGLT1. It has inhibition constant (K_i) values of 27 and 8170 nM for human (h) SGLT1 and hSGLT2, respectively. GSK-1614235 is an analog of KGA-2727 and has nearly 2 fold more specificity for SGLT1 than KGA-2727. Also, this specific behaviour towards SGLT1 makes GSK-1614235 an unique inhibitor compared with other molecules that primarily inhibit renal glucose reabsorption via SGLT2 or have dual effects on SGLT1 and SGLT2 [1].

References:
1. Dobbins, R. L.; et. al. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am J Physiol Gastrointest Liver Physiol 2015, 308(11), G946-G954.
2. Fushimi, N.; et. al. Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof. US20090203633A1 (synthesis and activity)

Drugs in Clinical Pipeline: KGA-2727

KGA-2727 [3-(3-{4-[3-(beta-D-glucopyranosyloxy)-5-isopropyl-1Hpyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide], is the first reported selective SGLT1 inhibitor which has a pyrazole-O-glucoside structure. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. It has inhibition constant (K_i) values of 97 and 13,600 nM for human (h) SGLT1 and hSGLT2, respectively.

In March 2005, Kissei Pharmaceutical Co., Ltd. and Dainippon Pharmaceutical Co., Ltd. announced that they have entered into a license agreement on "KGA-2727", a novel agent for the treatment of diabetes, which was discovered by Kissei. It was reported than in future, Kissei will continue to conduct non-clinical studies while Dainippon will conduct clinical development and marketing in Japan. Kissei reserves the right to participate in the clinical development to be conducted by Dainippon as well as the right to co-market the agent. Kissei continues to own the right for this agent outside Japan, including the right for development, manufacturing and marketing.

Drugs in Clinical Pipeline: SHR3824

SHR3824 [(1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] octane-2,3,4-triol] is a novel, oral and selective SGLT2 inhibitor, which is structurally different from other SGLT2 inhibitors (flozins) that are currently available or in the late stages of clinical development.

In vitro, SHR3824 potently inhibits human SGLT2, but exerts much weak inhibition on human SGLT1 (IC₅₀ hSGLT2, hSGLT1 = 2.38 and 4324 nM, respectively) showing a selectivity of 1817 for SGLT2. Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg.d) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice [1].

SHR3824 is discovered by Shanghai Hengrui Pharmaceuticals Co, Ltd, (Shanghai) and is currently in Phase I clinical studies in China  for treatment of type 2 diabetes (T2DM).

References:
1. Yan, P. K.; et. al. SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models. Acta Pharmacol Sin 2014, 35(5), 613-624.

Drugs in Clinical Pipeline: LIK066

LIK066 [(2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, (S)-Pyrrolidine-2-carboxylic acid (2:1)] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 22.0 nM against human SGLT1 and 0.5 nM against human SGLT2 [1, 2].

References:

1. Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan and a deferral and a waiver. 2014, EMEA-001527-PIP01-13 (here) [ Novartis revealed the IUPAC name here].

2. Bebernitz, G. R. Glycoside derivatives and their uses for the treatment of diabetes. WO2012140597A1 (synthesis and activity)

Drugs in Clinical Pipeline: Sotagliflozin

Sotagliflozin [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 36 nM against human SGLT1 and 1.8 nM against human SGLT2.

Drugs in Clinical Pipeline: ARRY-403

ARRY-403 [(1S)-1-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]ethane-1,2-diol] is an orally available allosteric glucokinase (GK) activator developed for the treatment of type 2 diabetes mellitus (T2DM). ARRY-403 has many favorable physicochemical characteristics (log P less than 5, molecular weight less than 500, fewer than five hydrogen bond donors, fewer than 10 hydrogen bond acceptors, high permeability) and ADME properties (low potential to cause drug–drug interactions (DDIs), a weak substrate of P-glycoprotein (P-gp), clearance by direct glucuronidation and CYP3A-mediated oxidative metabolism, data on file), but exhibits pH-dependent solubility and concentration-dependent plasma protein binding in vitro. Less than dose-proportional exposure of ARRY-403 was observed during single ascending dose studies in humans [1]. ARRY-403 holds promise for superior efficacy to other oral anti-hyperglycemic agents based on its ability to control postprandial and non-fasted blood glucose, as well as fasting blood glucose. Once a day oral therapy is predicted to provide 24-hour glycemic control in patients with mild to severe diabetes [1].

ARRY-403 potently activates human glucokinase (GK) in vitro (EC₅₀ = 79 nM at 5 mM glucose), with an S_0.5 = 0.93 mM glucose (ARRY-403 at 5 mM) and V_max = 134% compared to the no activator control. It possesses good in vitro drug-like properties (aqueous solubility, cell permeability, low potential for drug-drug interactions, low predicted hepatic clearance), and selectivity against broad panels of receptors and enzymes. 

Binding studies reveal that when ARRY-403 binds to GK, a conformational change causes both its affinity for glucose and maximal velocity to increase. Moreover, preclinical studies predicts it to be effective in “hard-to-treat” T2DM population, without contraindication or dose adjustment in patients with kidney disease or risk factors for congestive heart failure [2]. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The candidate demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety.

The activity of ARRY-403 is as follows:

EC₅₀ (GK activation assay @ 5 mM glucose) = 79 nM

Common Name: ARRY-403

Synonyms: ARRY-403; ARRY 403; ARRY 403; AMG-151; AMG 151; AMG151

IUPAC Name: (1S)-1-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]ethane-1,2-diol

CAS Number: 

Mechanism of Action: Kinase Activator; Glucokinase Activator

Indication: Treatment of Type 2 Diabetes Mellitus; Treatment of T2DM

Development Stage: Phase II

Company: Array BioPharma/Amgen

Glucokinase (GK) is an enzyme that, among other things, facilitates phosphorylation of glucose to glucose-6-phosphate. In vertebrates, GK-mediated phosphorylation generally occurs in cells in the liver, pancreas, gut, and brain. In each of these organs, GK can play a role in regulating carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising and/or falling levels of blood-glucose. Small-molecule GK activators are useful in treating type 2 diabetes because they can enhance the rate of glucose phosphorylation, and thereby reduce the amount of glucose in the blood. Therefore, GK activators lower the body's demand for insulin, especially following intake of food. In this way, GK activators provide an alternate treatment option for type 2 diabetics who otherwise may have difficulty achieving effective glycemic control. Various GK activators are known.

Glucokinase activators (GKAs) represent a promising new class of drugs for the treatment of type 2 diabetes that act directly on both the pancreas and the liver. Glucokinase (GK) is a key enzyme in glucose-sensing tissues that regulates glucose homeostatasis. GKAs lower glucose levels by enhancing the ability of pancreatic beta cells to “sense glucose” and increase insulin secretion in a glucose-dependent manner. Simultaneously, GKAs increase the uptake and disposal of glucose in the liver, while simultaneously reducing the amount it produces.

In multiple well-established in vivo models of type 2 diabetes, ARRY-403 was highly efficacious in controlling both fasting and postprandial blood glucose, with rapid onset of effect and maximal efficacy within five to eight days of once-daily dosing. Of note, ARRY-403 did not induce hypoglycemia in these diabetic animal studies. ARRY-403 was combined with existing standard-of-care drugs such as metformin, sitagliptin (a DPP-4 inhibitor), or pioglitazone (a PPARγ agonist) for additional glucose control. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The drug demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety [3].

References:

1. Chung, J.; et. al. Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a compound with pH-dependent solubility. J Pharm Sci 2015, 104(4), 1522-1532.

2. Boyd, S. A.; et. al. ARRY-403, A Novel Glucokinase Activator with Potent Glucose-Dependent AntiHyperglycemic Activity in Animal Models of Type 2 Diabetes Mellitus. Poster 126-Keystone Symposium: Type 2 Diabetes and Insulin Resistance (J3), Jan 20-25, 2009, Banff, AB.
3. Boyd, S. A.; et. al. Drug Pipeline. Drug Discovery and Development Oct 2009.

Risk of Type 2 Diabetes from Antibiotics

Results from a population-based case-control study could support the possibility that antibiotics exposure increases type 2 diabetes risk. There are two types of theories which link antibiotic with type 2 diabetes:

a: patients with type 2 diabetes are more prone to develop infections many years before they become diagnosed with type 2 diabetes and therefore have increased demand for antibiotics

b: antibiotics increase the risk of type 2 diabetes

There are suitable examples in literature that support both the theories, individually.

Concept: The human gut is populated by a dense community of microbes, aptly called, the gut microbiota. As the name suggest, it provides the host body “guts” to hold a battle against many auto-immune diseases like diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, fibromyalgia, and perhaps some cancers. The human body contains over 10 times more microbial cells than human cells, although the entire microbiome only accounts for about for 1-3% total body mass, with some weight-estimates ranging as high as 1.5 – 2.0 Kgs. Obesity too is believed to be caused by inefficiency of gut microbes. Gut microbiota is unique to each individual, is generally non-pathogenic and they exist in harmony and symbiotically with their hosts. In rare cases even their abnormal growth can cause some alarming situations. In addition, gut bacteria are known to aid the production of certain vitamins - such as vitamins B and K.

The very fact that an infant gut is sterile, and that gut microbiota is unique to each individual makes them good study material to understand the immunity and disease pattern of a person. Antibiotics cause marked alterations in the human gut microbiota with stereotypic declines and expansions in the abundance of certain taxa and incomplete recovery to the initial composition in some individuals. In simple words, antibiotics are able to change the composition and concentration of gut microbes, weakening bodies response against certain disease set. No wonder antibiotic abuse has alarming results.

To understand the consequences of such an absue, Danish researchers conducted a nationwide case-control study to investigate whether use of antibiotics influences the risk of developing type 2 diabetes and, if so, if the effect can be attributed to individual types of antibiotics, individual groups of antibiotics, or the number of antibiotics courses.

Methods: Researchers conducted a population-based case-control study of incident type 2 diabetes cases in Denmark (population 5.6 million) between January 1, 2000, and December 31, 2012. Researchers obtained information on use of all systemic antibiotics for the cohort between January 1, 1995, and July 1, 2012. Antibiotics were classified into narrow-spectrum or broad-spectrum and bactericidal or bacteriostatic. Exposure was quantified according to number of antibiotic courses before the index date, three different categories were defined; 0-1 antibiotic courses (reference), 2-4 antibiotic courses or greater than/equal to 5 antibiotic courses. Filling a prescription on the same antibiotic within 20 days of the first use was considered as belonging to the same course. Moreover, some certain type of diabetic patients was excluded from the study such as cases with chronic pancreatitis, pancreatic cancer, or polycystic ovary syndrome etc. The analysis conformed to a conventional matched case-control study. The crude and adjusted odd ratios (ORs) for developing type 2 diabetes associated with antibiotic exposure were estimated using conditional logistic regression, controlling for potential confounders.

Results:

1. The OR for type 2 diabetes increased almost linearly with the exposure to antibiotics.

2. Patients with type 2 diabetes redeemed on average 0.8 prescriptions on antibiotics per year compared to 0.5 prescriptions per year among controls.

3. Slightly higher ORs were found for narrow-spectrum and bactericidal antibiotics compared with broad-spectrum and bacteriostatic antibiotics, respectively.

4. Researchers found increased ORs for all groups of antibiotics except for clindamycin.

4. Researchers found a steep increase in OR for type 2 diabetes with increasing exposure to narrow spectrum antibiotics when the exposure to broad-spectrum antibiotics was held fixed. In contrast, there was a relatively unchanged OR for type 2 diabetes with increasing exposure to broad-spectrum antibiotics when exposure to narrow-spectrum antibiotics was fixed.

5. The increased exposure to antibiotics was observed both 5 years before and 5 years after the type 2 diabetes index date for cases.

The authors conclude as “Patients with type 2 diabetes, compared to control subjects free of type 2 diabetes, are overexposed to antibiotics before their diagnosis with type 2 diabetes as defined by the first redemption of a prescription on an oral glucose-lowering agent. However, the possibility that antibiotics exposure increases diabetes risk cannot be excluded and deserves further investigation in interventional studies. In particular, we suggest investigation of commonly used narrow-spectrum penicillins because these drugs are frequently prescribed and showed the highest OR for type 2 diabetes risk.”

Article Citation: Mikkelsen, K. H.; et. al. Use of Antibiotics and Risk of Type 2 Diabetes: A Population-Based Case-Control Study.  J Clin Endocrinol Metab 2015. DOI: 10.1210/jc.2015-2696

To Be, or Not to Be, Well ...... Do You Have Guts to Answer ?

Egg Consumption And Risk Of Type-2 Diabetes: For Good Results Eat 4 Eggs/week

Egg Consumption And Risk Of Type-2 Diabetes: For Good Results Eat 4 Eggs/week

Eggs are delicious but also a major source of cholesterol. High cholesterol in human has been associated with elevated blood glucose and an increased risk of Type-2 Diabetes Mellitus (T2DM). Hence, high consumption of eggs was always felt against the good health of a person.

Contrary to the above belief, the researchers from the University of Eastern Finland has given all of us a pleasant surprise with their finding showed that eggs could reduce the risk developing Type 2 diabetes by 40 %. Though they are also amazed to see the result of the study but they think the constituents of an egg improves the metabolism in the body to make use of sugar and reduce reasons that can cause diabetes.

The study involved 2332 men aged 42-60 years in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischemic Heart Disease Risk Factor Study in Eastern Finland. Dietary intakes were assessed with 4 day food records at baseline. Incident T2DM was assessed by self-administered questionnaires; by fasting and 2-hour oral-glucose-tolerance-test blood glucose measurement at re-examination rounds 4, 11, and 20 year after baseline; and by record linkage to a hospital discharge registry and reimbursement register of diabetes medication expenses. Cox proportional hazards regression analyses were used to estimate associations with the risk of incident T2DM.

The results are:

1. Eggs, if taken in right amount could reduce the risk developing Type 2 diabetes by 40% per cent.

2. Men those who regularly took 4 eggs a week were 38% less likely to fall ill than those who never ate eggs or rarely consumed them.

3. 38% of men also showed lower blood sugar levels with no increase in their cholesterol levels.

4. The study did not consider the way the egg was cooked for the study. Hence, proving that the cholesterol effect was not much among those who ate it four times in a week.

5. The associations between cholesterol intake and risk of T2DM, plasma glucose, serum insulin, and C-reactive protein were mainly nonsignificant, especially after accounting for egg consumption.

6. The results suggest an inverse association with fasting plasma glucose and serum C-reactive protein but not with serum insulin.

Article Citation: Virtanen, J. K.; et. al. Egg consumption and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2015 DOI: 10.3945/ajcn.114.104109

Strong Link Between Statin Drugs and Diabetes

Strong Link Between Statin Drugs and Diabetes

In a study of nearly 26,000 beneficiaries of Tricare, the military health system, cholesterol-lowering drugs statins have been found to increase the risk of developing diabetes. The study, published in the Journal of General Internal Medicine, confirms past findings on the link between the widely prescribed drugs and diabetes risk. The study included only people who at baseline were free of heart disease, diabetes and other severe chronic disease, is among the first to show the connection in a relatively healthy group of people.

The researchers examined patient records for the period between October 2003 and March 2012.

Statin drugs are the all-time leading prescription drugs sold around the world, prescribed by doctors to lower people’s cholesterol levels. While the side effects are a serious concern, there are also concerns that statin drugs have no therapeutic value either. Studies have never conclusively proven that lowering one’s cholesterol levels by medication increases one’s life span. In fact, there is evidence to the contrary, that higher cholesterol levels are associated with longer life spans.

Some eye-opening findings are:

1. Among 3,351 pairs of similar patients-part of the overall study group-those patients on statins were 250 percent more likely than their non-statin-using counterparts to develop diabetes with complications.

2. Statin users were also 14 percent more likely to become overweight or obese after being on the drugs.

3. Higher the dose of any of the statins, the greater the risk of diabetes, diabetes complications, and obesity.

4. About three-quarters of the statin prescriptions in Mansi's data were for simvastatin, sold as Zocor.

Using two different techniques for data analayis, namely a) propensity score matching where out of the total study population, the researchers chose 3,351 statin users and paired them with non-users who were very similar, at baseline, based on array of 42 health and demographic factors. The only substantial difference, from a research standpoint, was the use of statins. This helped the researchers isolate the effects of the drugs, b) looking at the overall comparison between the study's roughly 22,000 nonusers and 4,000 users, and statistically adjusting for certain factors. The researchers found a similar outcome: Users of statins were more than twice as likely to develop diabetes.

The authors conclude as “Diabetes, diabetic complications, and overweight/obesity were more commonly diagnosed among statin-users than similar nonusers in a healthy cohort of adults. This study demonstrates that short-term clinical trials might not fully describe the risk/benefit of long-term statin use for primary prevention.”

Article citation: Mansi, I.; et. al. Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults. Journal of General Internal Medicine, 2015; DOI: 10.1007/s11606-015-3335-1

Type-2 Diabetes Promotes Alzheimer’s Disease

Type-2 Diabetes Promotes Alzheimer’s Disease

Introduction

Epidemiological studies show that patients with type-2-diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia (2-4 times more), specifically dementia due to Alzheimer’s disease (AD). Although both Aβ and tau are central to AD pathogenesis, it is unclear whether glucose dysregulation is an initiator of AD pathology, a secondary consequence of neuronal dysfunction due to Aβ and tau deposition, or both. Those with elevated blood glucose levels have a more rapid conversion from mild cognitive impairment (MCI) to AD, suggesting that disrupted glucose homeostasis could play a more causal role in AD pathogenesis. These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading researchers to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models.

Methodology

Researchers combined two techniques - glucose clamps and in vivo microdialysis- as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF).

Results

The experimental data demonstrate that elevated blood glucose levels affect hippocampal metabolism, neuronal activity, and ISF Aβ concentrations in young mice, lacking any appreciable Aβ plaque load. However, in aged mice with marked Aβ deposition, the effect of hyperglycemia on ISF Aβ is exacerbated (~40% higher), suggesting that age- or pathology-dependent changes result in an alteration of the brain’s response to a metabolic insult. Since extracellular Aβ, and subsequently tau, aggregate in a concentration-dependent manner during the preclinical period of AD while individuals are cognitively normal, these findings suggest that repeated episodes of transient hyperglycemia, such as those found in T2DM, could both initiate and accelerate plaque accumulation. Thus, the correlation between hyperglycemia and increased ISF Aβ provides one potential explanation for the increased risk of AD and dementia in T2DM patients or individuals with elevated blood glucose levels.

Since cerebral glucose metabolism is tightly linked to neuronal activity and elevated neuronal activity increases Aβ production, researchers explored the role of inward rectifying, ATP-sensitive potassium (K_ATP) channels as one mechanism linking glucose metabolism, neuronal excitability, and ISF Aβ. The findings suggests that K_ATP channels can mediate the response of hippocampal neurons to elevated blood glucose levels by coupling changes in metabolism with neuronal activity and ISF Aβ. In other words, this work suggests that K_ATP channels within the hippocampus act as metabolic sensors and couple alterations in glucose concentrations with changes in electrical activity and extracellular Aβ levels. Not only does this offer one mechanistic explanation for the epidemiological link between T2DM and AD, but it also provides a potential therapeutic target for AD.

The authors conclude as “Given that FDA-approved drugs already exist for the modulation of K_ATP channels and previous work demonstrates the benefits of sulfonylureas for treating animal models of AD, the identification of these channels as a link between hyperglycemia and AD pathology creates an avenue for translational research in AD”.

Article citation: Macauley, S. L.; et. al. Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest 2015 doi:10.1172/JCI79742.

Leave Cola's, Cut Diabetes

Leave Cola's, Cut Diabetes

Researchers determined for each 5% increase in consumption of cola drinks (also known as soft drinks) or other sugary drinks, the risk of developing Type 2 diabetes spiked 18%.

The researchers gathered data from a cohort study of more than 25,000 men and women, aged 40-79, from Norfolk (UK). They logged everything they ate and drank for a week straight and in a followup 11 years later, 847 of them were newly diagnosed with Type 2 diabetes.

Moreover, replacing just one cola filled glass a day with water, black tea or coffee can cut the risk of getting Type 2 diabetes by 14% and by replacing a serving of sweetened milk beverage with water or unsweetened tea or coffee, that reduction could have been 20-25 %.

Researchers found that there was an approximately 22 % increased risk of developing type 2 diabetes per extra serving per day habitually of each of cola drinks, sweetened milk beverages and artificially sweetened beverages (ASB) consumed, but that consumption of fruit juice and sweetened tea or coffee was not related to diabetes. 

After further accounting for body mass index and waist girth as markers of obesity, there remained a higher risk of diabetes associated with consumption of both soft drinks and sweetened milk drinks, but the link with ASB consumption no longer remained, likely explained by the greater consumption of ASB by those who were already overweight or obese.

Consuming ASB instead of any sugar-sweetened drink was not associated with a statistically significant reduction in type 2 diabetes, when accounting for baseline obesity and total energy intake. Finally, they found that each 5 % of higher intake of energy (as a proportion of total daily energy intake) from total sweet beverages (soft drinks, sweetened tea or coffee, sweetened milk beverages, fruit juice) was associated with a 18 % higher risk of diabetes.

Article Citation: Romaguera, D.; et. al. The InterAct consortium Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabetologia 2013, 56(7), 1520-1530.

Drugs in Clinical Pipeline: PF-04937319

PF-04937319 [N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl) benzofuran-4-yl)oxy) pyrimidine-2-carboxamide] is an orally available activator of glucokinase (GCK) which is under trials in patients with Type 2 Diabetes Mellitus (T2DM).

Glucokinase is unique among the members of the hexokinase family given its low substrate affinity (K_m nearly 8 mM), positive substrate cooperativity and lack of product inhibition. As a monomeric enzyme, glucokinase achieves this cooperativity through equilibration between multiple protein conformations. In their pioneering work, Grimsby and coworkers^a demonstrated that small molecule activators were capable of binding to glucokinase at an allosteric site 20 Å remote from the active site and influencing the enzyme’s kinetic profile by modulating both K_m for glucose (also known as S_0.5) and V_max. PF-04937319 was initially evaluated in the biochemical activation assay measuring potency (EC₅₀ = 188 ± 74 uM) as well as effects on K_m (0.10 ± 0.02) and V_max (0.87 ± 0.03). Additionally, human liver microsome (HLM) stability, passive permeability, kinetic solubility (463 uM) and dofetilide binding (0% @ 10 uM), as a surrogate for hERG inhibitory activity, were evaluated [2].

The activity of PF-04937319 is as follows:

EC₅₀ (Biochemical activation assay) = 188 ± 74 uM

Common Name: PF-04937319

Synonyms:  PF-04937319; PF04937319; PF 04937319

IUPAC Name: N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide

CAS Number: -

Mechanism of Action: Kinase Activator; Glucokinase Activator; GCK activator

Indication: Diabetes; Type II Diabetes; T2DM

Development Stage: Phase I/II

Company: Pfizer

Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia [1].

Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC₅₀ = 0.17 µM; M1: EC₅₀ = 4.69 µM). Furthermore, M1 did not inhibit major human P450 enzymes (IC₅₀ greater than 30 µM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling [3].

References:

1. Nakamura, A.; et. al. Present status of clinical deployment of glucokinase activators. J Diabetes Investig 2015, 6(2), 124-132.
2. Pfefferkorn, J. A.; et. al. Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl) benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus. Med Chem Commun 2011, 2, 828-839. (gives synthesis and pre-clinical activity)
3. Sharma, R.; et. al. Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator. Drug Metab Dispos 2014, 42(11), 1926-1939.
4. ClinicalTrials.gov A Trial To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Single Doses Of PF-04937319 In Subjects With Type 2 Diabetes Mellitus. NCT01044537 (retrieved 01-05-2015)

5. ClinicalTrials.gov Study To Understand Efficacy And Safety Of Investigational Agent (PF-04937319) Compared To Approved Agent (Glimepiride) In Patients With Diabetes On Metformin. NCT01517373 (retrieved 01-05-2015)

6. ClinicalTrials.gov Phase 2 Study To Evaluate Safety And Efficacy Of Investigational Drug - PF04937319 In Patients With Type 2 Diabetes. NCT01475461 (retrieved 01-05-2015)

a: For Grimsby, J.; et. al. see Science, 2003, 301, 370.