Canagliflozin: New drug for management of type 2 diabetes mellitus

The U.S. Food and Drug Administration approved Invokana (canagliflozin) tablets, to be used with diet and exercise, to improve glycemic control in adults with type 2 diabetes on 30^th March, 2013.¹

Canagliflozin is a sodium-glucose co-transporter2 (SGLT2) inhibitor, a new group of oral hypoglycemic drugs.

Invokana works by blocking the reabsorption of glucose by the kidney, increasing glucose excretion, and lowering blood glucose levels in diabetics who have elevated blood glucose levels. Its safety and effectiveness were evaluated in nine clinical trials involving over 10,285 patients with type 2 diabetes. The trials showed improvement in hemoglobin A1c levels and fasting plasma glucose levels.

Invokana has been studied as a stand-alone therapy and in combination with other type 2 diabetes therapies including metformin, sulfonylurea, pioglitazone, and insulin.

Invokana should not be used to treat people with type 1 diabetes; patients having diabetic ketoacidosis; severe renal impairment, end stage renal disease, or in patients on dialysis.

Most common side effects of Invokana are vulvovaginal candidiasis and urinary tract infection. As Invokana is associated with a diuretic effect, it can cause a reduction in intravascular volume leading to orthostatic or postural hypotension. This may result in symptoms such as dizziness or fainting, and is most common in the first three months of therapy.

SGLT2 inhibitors:²

Glucose is reabsorbed from the proximal tubule of kidneys via family of membrane proteins (or transporters) called SGLTs. Approximately 180 g of glucose is filtered daily in a healthy adult and most of this is reabsorbed by SGLTs, with, 1% being excreted in the urine. Although there are several dif­ferent types of SGLTs, the two most studied are SGLT1 and SGLT2. The latter is responsible for reabsorption of over 90% of the glucose filtered while SGLT1, located in the distal segments, absorbs the remainder. SGLT2 inhibitors block the reabsorption of filtered glucose leading to glycosuria and improvement in glycemic control. These are also associated with a potential for weight loss.

A rare genetic condition, familial renal glucosuria, has served as a model for SGLT2 inhibition. In this dis­order, due to a mutation of SLCA2 gene there is impaired functioning of SGLT2, secondary to mutation of the SLCA2 gene, leading to daily urinary excretion of up to 100 g of glucose. Such patients are generally asymptomatic.

Inhibition of glucose uptake by the kidneys appears to be a new, unique, and promising insulin-independent approach to the treatment of type 2 diabetes.

References:

1.     US FDA. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm

2.     Kim Y, Babu AR. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2012;5:313-27.

Association between omega 3 fatty acid supplementation and risk of major CV events

Omega-3 PUFA supplementation is not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association according to a recent systemic review and meta-analysis.
http://www.ncbi.nlm.nih.gov/pubmed/22968891?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/22968891?dopt=Abstract

Tudorza- New dry powder inhaler for chronic obstructive pulmonary disease

FDA approves Tudorza Pressair to treat chronic obstructive pulmonary disease
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm313052.htm

New drug for obesity- Qsymia

FDA approves new drug for management of obesity.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm

Association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture.

Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide.

Although short term use of PPIs is generally well tolerated, concern has grown over potential association between long term use and bone fractures, especially of the hip, which is known to be associated with substantial morbidity and mortality.  PPIs may inhibit calcium absorption, directly interfere with osteoclast function, or induce hypergastrinaemia, resulting in reductions in bone mineral density related to hyperparathyroidism.

·       The association between long term PPI use and risk of hip fracture among postmenopausal women was studied in a large prospective cohort, the Nurses’ Health Study, where detailed information about dietary and lifestyle factors are collected biennially.

Main outcome measure Incident hip fracture

Results

·       During 565,786 person years of follow-up, 893 incident hip fractures were documented.

·       The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users.

·       Compared with non-users, the risk of hip fracture among women who regularly used PPIs for at least two years was 35% higher, with longer use associated with increasing risk (P_trend<0.01).

·       Adjustment for risk factors, including body mass index, physical activity, and intake of calcium did not materially alter this association (hazard ratio 1.36 (1.13 to 1.63)). These associations were also not changed after accounting for reasons for PPI use.

·       The relation between PPI use and fracture differed by smoking history (P_interaction=0.03). Among current and former smokers, PPI use was associated with greater than 50% increase in risk of fracture.

·        In contrast, among women who never smoked there was no association.

·       In a meta-analysis of these results with 10 prior studies, the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.25 to 1.36).

Among postmenopausal women, regular use of proton pump inhibitors was associated with a 35% increased risk of hip fracture. The risk seemed to be confined to women with a history of smoking

Smoking cessation

http://www.dovepress.com/articles.php?article_id=9502

Bevacizumab- change in label

On 30^th September, 2011, US FDA informed that changes in bevacizumab (Avastin, Genentech, Inc.) package insert regarding: risk of ovarian failure, osteonecrosis of the jaw, risk of venous thromboembolic event (VTE) and bleeding in patients receiving anticoagulation therapy after first VTE event have been made.

These changes include the following:

• Warning subsection added- increased risk of ovarian failure in premenopausal patients receiving bevacizumab and chemotherapy. It also states a recommendation that females of reproductive potential be informed of the increased risk of ovarian failure prior to starting treatment with bevacizumab,
• Osteonecrosis of the jaw is an adverse reaction of bevacizumab,
• new information regarding the risks of venous thromboembolic events and bleeding in patients receiving anti-coagulation therapy after first VTE event while receiving bevacizumab.

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm274394.htm

High olive oil consumption has a protective role

A protective role for high olive oil consumption on the risk of stroke in older subjects has been suggested by a study published online on 15^th June, 2011 in Neurology 2011;77:1–1

Sameiri C from From the Research Center INSERM, U897, Department of Nutritional Epidemiology, France determined whether high olive oil consumption, and high plasma oleic acid (as an indirect biological marker of olive oil intake), are associated with lower incidence of stroke in older subjects. They enrolled participants from the Three-City Study with no history of stroke at baseline.

They found that in the main sample, 148 incident strokes occurred. After adjustment for sociodemographic and dietary variables, physical activity, body mass index, and risk factors for stroke, a lower incidence for stroke with higher olive oil use was observed (p for trend = 0.02). Compared to those who never used olive oil, those with intensive use had a 41% lower risk of stroke. It was also seen that higher plasma oleic acid was associated with lower stroke incidence. Compared to those in the first tertile, participants in the third tertile of plasma oleic acid had a 73% reduction of stroke risk.

The authors concluded that in the present population-based study, intensive olive oil use was prospectively associated with a lower stroke risk after controlling for numerous confounding factors, including lifestyle and nutritional factors, main stroke risk factors, and blood lipids.

Statin therapy associated with excess risk of developing diabetes mellitus

Priess D and colleagues from BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom conducted a meta-analysis to investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. They included all randomized controlled end-point trials (January 1, 1996, through March 31, 2011) that compared intensive-dose statin therapy with moderate-dose statin therapy and had more than 1000 participants with > 1 year follow-up.

They found that in 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 for new-onset diabetes and 0.84 for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy.

The authors concluded that in a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

http://www.ncbi.nlm.nih.gov/pubmed/21693744

PPI use associated with antifracture activity of Alendronate

The use of PPIs to control upper GIT complaints in patients treated with oral bisphosphonates should be discouraged according to a study published on 13^th June, 2011 online in Archives of Internal Medicine.

Bo Abrahamsen, MD, PhD from Institute of Clinical Research, Denmark and colleagues conducted a population-based, national register–based, open cohort observational study of 38 088 new alendronate sodium users with a mean duration of follow-up of 3.5 years.  They related risk of hip fracture to recent pharmacy records of refill of prescriptions for alendronate.

They found that for hip fractures, there was a statistically significant interaction with alendronate for PPI use (P < .05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (P < .001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (P = .06). It was found that decrease of the risk reduction was dependent on dose and age. In contrast, there was no significant impact of concurrent use of histamine H₂ receptor blockers.

The authors concluded that the concomitant use of PPI and alendronate was associated with a dose-dependent loss of protection against hip fracture with alendronate in elderly patients.

http://archinte.ama-assn.org/cgi/content/abstract/171/11/998?etoc.

Consumption of coffee independent predictor of improved virologic response to therapy in hepatitis C patients

High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C, according to a study published online on 10^th June, 2011  in the Gastroenterology journal.

Neel D Freedman PhD MPH, from National Cancer Institute, Maryland, USA and colleagues  assessed patients for early virologic response (2 log₁₀ reduction in level of hepatitis C virus RNA at week 12; n = 466), and undetectable hepatitis C virus RNA at weeks 20, 48 , and 72. They enrolled 885 patients from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000–1200 mg/day).  

Median log₁₀ drop from baseline to week 20 was 2.0 among nondrinkers and 4.0 among patients that drank 3 or more cups/day of coffee (P trend <.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (P trend = .004) for early virologic response, 2.1 (P trend = .005) for week 20 virologic response, 2.4 (P trend = .001) for end of treatment, and 1.8 (P trend = .034) for sustained virologic response.

The authors highlighted that in patients with advanced HCV-related chronic liver disease in the HALT-C trial receiving peginterferon plus ribavirin treatment, 3 or more cups per day coffee drinkers were 3 times more likely to have a virologic response than nondrinkers. In contrast to results for coffee, no effect was observed for tea drinking.

http://www.gastrojournal.org/article/S0016-5085(11)00273-3/fulltext

Finasteride and Dutasteride- Recommendations for label change

FDA has recommended that prior to initiating therapy with 5-alpha reductase inhibitors (ARIs) like finasteride or Dutasteride, the healthcare professionals should  perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).
The Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).
The decision has been taken in view of the results of two large randomised controlled trials (RCTs) conducted in 2010-the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.
Finasteride and Dutasteride are available as Proscar, Avodart, and Jalyn.
These are approved to improve symptoms of benign prostatic hyperplasia (BPH).
Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate.
Propecia is approved to treat male pattern hair loss.
Ironically, 5-ARIs were used for chemoprevention of prostate cancer without the FDA approval.
Also, the guidelines released jointly in 2009 by the American Society of Clinical Oncologists and the American Urological Association recommended that, "Asymptomatic men with a prostate-specific antigen (PSA) ≤3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer)." ⁽¹⁾
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm
(1) http://caonline.amcancersoc.org/cgi/content/full/61/1/1

Simvastatin (ZOCOR)- New recommendations by FDA

US FDA has recommended that Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. 
Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy).
Simvastatin is a lipid lowering drug used by patients who have had a Coronary Artery Disease (CAD) or they are at a high risk of having  CAD.
Simvastatin belongs to the group of HMG-CoA reductase inhibitors (or statins). The known adverse effects of statins are the hepatic damage and myopathy.
FDA has mentionedd that patients taking simvastatin 80 mg daily have an increased risk of myopathy compared to patients taking lower doses of this drug or other drugs in the same class. This risk appears to be higher during the first year of treatment, is often the result of interactions with certain medicines, and is frequently associated with a genetic predisposition toward simvastatin-related myopathy. The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure which can be fatal. FDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.
The new changes to the drug labels for simvastatin-containing medicines are based on FDA's review of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and other data described in the Agency's March 2010 Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258384.htm

Systolic BP treatment goal of 130 to 135 mm Hg acceptable in Type 2 diabetes

In patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable, according to the results of a meta-analysis published online in June 1, 2011 issue of Circulation.

Sripal Bangalore, MD, MHA, Assistant Professor of Medicine,  from, New York University School of Medicine, USA and colleagues performed a meta-analysis of randomized clinical trials from 1965 to October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of 135 mm Hg in the intensive BP control group and 140 mm Hg in the standard BP control group, had a follow-up of at least 1 year, and evaluated macrovascular or microvascular events.

They found that intensive BP control was associated with a 10% reduction in all-cause mortality, a 17% reduction in stroke, and a 20% increase in serious adverse effects, but with similar outcomes for other macrovascular and microvascular (cardiac, renal, and retinal) events compared with standard BP control. More intensive BP control ( 130 mm Hg) was associated with a greater reduction in stroke, but did not reduce other events. Meta–regression analysis showed continued risk reduction for stroke to a systolic BP of <120 mm Hg.

The authors also reported that with more aggressive goals (<130 mm Hg), they observed target organ heterogeneity in that the risk of stroke continued to fall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal and retinal) events, and the risk of serious adverse events even increased.

New drugs approved in India in April 2011

Tioconazole Vaginal Gel 65mg per gm	For the local treatment of vulvovaginal candidiasis in adult patients.
Ilaprazole Tablets 5mg/10mg	For the treatment of duodenal ulcer in adults only.
Tapentadol Hydrochloride tablets 50mg/75mg/100mg	For relief of moderate to severe acute pain in adults 18 years of age or older.
S-Bupivacaine Hydrochloride Injection 2.5mg/5mg/7.5mg per ml	For surgical anaesthesia in adults for epidural (including caesarean section), intrathecal, peripheral nerve block.

Gatifloxacin and Tegaserod banned

DCGI banned the manufacture, sale and distribution of Gatifloxacin for human use by oral or injectable route.
http://cdsco.nic.in/PRohibited_gatifloxacin_tegaserod.pdf

DCGI also banned the manufacture, sale and distribution of Tegaserod for human use.
http://cdsco.nic.in/PRohibited_gatifloxacin_tegaserod.pdf

Drugs banned in India

Link to DCGI website which mentions the drugs banned in India.
http://cdsco.nic.in/html/Drugsbanned.html

Azilsartan/chlorthalidone combo bests olmesartan/HCTZ in stage 2 systolic hypertension

Heartwire reported on 24^th May, 2011 that the use of the combination therapy azilsartan medoxomil (Edarbi, Takeda Pharmaceuticals) and chlorthalidone resulted in a more effective reduction in systolic blood pressure (SBP), including ambulatory measures of blood pressure, when compared with combination therapy of olmesartan (Benicar, Daiichi Sankyo) and hydrochlorothiazide (HCTZ) in patients with hypertension, according to the results of a new study.

Presenting the data this week during the late-breaking clinical trials session at the American Society of Hypertension (ASH) 2011 Scientific Meeting, lead investigator Dr William Cushman (Veterans Affairs Medical Center, Memphis, TN) noted that azilsartan, a new angiotensin-receptor blocker (ARB) approved by FDA in February this year, is a highly effective, long-acting agent that is currently in development as a fixed-dose combination with chlorthalidone, a thiazidelike diuretic.

Speaking with the media during a press conference announcing the results, Cushman said chlorthalidone was selected as the second agent with azilsartan and partnered in development because there is growing evidence the drug is more effective than HCTZ. The purpose of the study was to compare the effectiveness of the azilsartan/chlorthalidone combination with the maximum approved dose of olmesartan/HCTZ, that being 40/25 mg.

http://www.theheart.org/article/1230773.do

Celecoxib should not be used in FAP

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has finalised that existing evidence of safety and efficacy does not support the use of celecoxib in the reduction of the number of adenomatous intestinal polyps in familial adenomatous polyposis (FAP).

This review follows Pfizer’s voluntary withdrawal of the marketing authorisation of its celecoxib-containing orphan medicine, Onsenal, which had been authorised for use in FAP patients. The reason for the withdrawal was that Pfizer was unable to provide confirmatory data regarding clinical benefit due to slow enrolment in a clinical trial. These data had been requested by the CHMP at the time of granting of the marketing authorisation for Onsenal.

Celecoxib-containing products are currently authorised in the European Union for the treatment of the symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. This review was initiated because of concerns that celecoxib may be used off-label in the FAP indication following the withdrawal of Onsenal.

The CHMP concluded that the benefit of celecoxib in FAP patients had not been sufficiently demonstrated and did not outweigh the increased risk of cardiovascular and gastrointestinal side effects, which would result from high dose and long-term treatment used in FAP patients.

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/05/WC500106524.pdf



FDA approves injectable gel to treat fecal incontinence

The U.S. Food and Drug Administration today approved a sterile, injectable gel to treat fecal incontinence in patients for whom other therapies such as diet change, fiber therapy or anti-motility medications failed.
Fecal incontinence is the involuntary loss of bowel control. It can have different causes including nerve damage, weakened anal sphincter associated with aging, or rectum muscle damage.

The Solesta gel is injected into a layer of tissue beneath the anus lining and may help build tissue in that area. By growing the surrounding tissue, the opening of the anus narrows and the patient may be able to better control those muscles.
Solesta is approved for use in patients ages 18 and up.

It should not be used in patients who have active inflammatory bowel disease, immunodeficiency disorders, previous radiation treatment to the pelvic area, significant rectal prolapse, active infections, bleeding, tumors or malformations in the anorectal area, rectal distended veins, an existing implant in the anorectal region, or allergy to hyaluronic acid based products.

Most common side effects are injection area pain and bleeding.
Infection and inflammation of anal tissue are more serious risks, but are less common.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257112.htm