Neuraminidase inhibitors tamiflu and relenza

 Neuraminidase inhibitors (NAIs) are a class of drugs which block the neuraminidase enzyme. They are commonly used as antiviral drugs because they block the function of viral neuraminidases of the influenza virus, by preventing its reproduction by budding from the host cell. Oseltamivir (Tamiflu) a prodrug, Zanamivir (Relenza), Laninamivir (Inavir), and Peramivir belong to this class. Unlike the M2 inhibitors, which work only against the influenza A, neuraminidase inhibitors act against both influenza A and influenza B.^[1][2][3][4] The neuraminidase inhibitors oseltamivir and zanamivir were approved in the US and Europe for treatment and prevention of influenza A and B. Peramivir acts by strongly binding to the neuraminidase of the influenza viruses and inhibits activation of neuraminidase much longer than Oseltamivir or Zanamivir.^[5] However, Laninamivir in the cells is slowly released into the respiratory tract, resulting in long-lasting anti-influenza virus activity. Thus the mechanism of the long-lasting activity of laninamivir is basically different from that of Peramivir.^[6]

The efficacy was highly debated in recent years.^[7][8][9] However, after the pandemic caused by H1N1 in 2009, the effectiveness of early treatment with neuraminidase inhibitors in reducing serious cases and deaths was reported in various countries.^{[10][11][12][13]}

In countries where treatment of influenza like illness are done using neuraminidase inhibitors on a national level, statistical reports show a low fatality record for symptomatic illness because of the universal implementation of early treatment using NAIs.^[14] Although oseltamivir is widely used in these countries there have been no outbreaks caused by oseltamivir-resistant viruses and also no serious illness caused by oseltamivir-resistant viruses has ever been reported.^[14] The United States Centers for Disease Control continues to recommend the use of oseltamavir treatment for people at high risk for complications and the elderly and those at lower risk who present within 48 hours of first symptoms of infection.^[15]

Common side effects include nausea and vomiting. The abnormal behaviors of children after taking oseltamivir that have been reported may be an extension of delirium or hallucinations caused by influenza.^[14] It occurs in the early stages of the illness, such as within 48 hours after onset of the illness. Therefore, children with influenza are advised to be observed by their parents until 48 hours after the onset of the influenza illness, regardless of whether the child is treated with NAIs.^[14]

orexin receptor antagonist

 Dayvigo is an orexin receptor antagonist...it blocks neurotransmitters that promote wakefulness.

It isn’t likely to cause rebound insomnia or withdrawal symptoms when stopped...but don’t expect it to fly off shelves.

Dayvigo doesn’t seem to work better than benzos or “Z-drugs”... and it has additional adverse effects and interactions.

For example, Dayvigo can rarely cause transient leg weakness... or sleep paralysis during sleep-wake transitions.

Plus it can cause “sleep driving” and daytime impairment... similar to benzos and Z-drugs.

And watch for interactions, since it’s metabolized by CYP3A4.

Expect Dayvigo to cost about $1.60/dose.

Orexin (/ɒˈrɛksɪn/), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.^[1] The most common form of narcolepsy, type 1, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.^[2][3]

There are only 10,000–20,000 orexin-producing neurons in the human brain,^[2] located predominantly in the perifornical area and lateral hypothalamus.^[1][4] They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviours.^[1] There are two types of orexin peptide and two types of orexin receptor.^[5][4]

Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the rat brain.^[6][7] One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, another peptide.^[2] Officially, hypocretin (HCRT) is used to refer to the genes and transcripts, while orexin is used to refer to the encoded peptides.^[8] There is a high affinity between the orexin system in the rat brain and that in the human brain.^[5]

The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. In addition, it stimulates wakefulness, regulates energy expenditure, and modulates visceral function.

Wakefulness[edit]

Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep, or awake and active. Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems^[18][19] and appear to play an important role in stabilizing wakefulness and sleep.

The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy^[20] in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy.^[21] Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. Researchers are using this animal model of narcolepsy to study the disease.^[22] Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy.

Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30–36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.^[23][24]

In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.^[25] Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus.^[26] In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.^[27]

Food intake[edit]

Orexin increases the craving for food, and correlates with the function of the substances that promote its production. Orexin is also shown to increase meal size by suppressing inhibitory postingestive feedback.^[28] However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.^[29]

Review findings suggest that hyperglycemia that occurs in mice due to a habitual high-fat diet leads to a reduction in signalling by orexin receptor-2, and that orexin receptors may be a future therapeutic target.^[30] Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake. Orexin-producing cells have recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation.^[31][32] Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis. Sleep deprivation then leads to a lack of energy. In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. Other dietary nutrients, amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.^[33]

Addiction[edit]

Preliminary research has been conducted that shows potential for orexin blockers in the treatment of cocaine, opioid, and alcohol addiction.^[34][35][36] For example, lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.^[37][38]

Studies of orexin involvement in nicotine addiction have had mixed results. For example, blocking the orexin-1 receptor with the selective orexin antagonist SB-334,867 reduced nicotine self-administration in rats and that smokers who suffered damage to the insula, a brain region that regulates cravings and contains orexin-1 receptors, lost the desire to smoke.^[39] However, other studies in rats using the dual orexin receptor antagonist TCS 1102 have not found similar effects.^[40]

Lipid metabolism[edit]

Orexin-A (OXA) has been recently demonstrated to have a direct effect on an aspect of lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes.^[41] The link between OXA and the lipid metabolism is new and currently under more research.

Mood[edit]

High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.^[42] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression.

Do omega-3 fatty acid supplements reduce CV risk?

 Mounting evidence suggests they don’t...despite prior evidence with Rx Vascepa (icosapent ethyl), a form of EPA (eicosapentaenoic acid).

Vascepa 2 g BID is approved to reduce CV risk in some high-risk patients with elevated triglycerides despite statins.

Now evidence suggests that adding Rx Epanova 4 g/day for about
 3 years does NOT improve CV outcomes in high-risk patients on statins.

Epanova is a combo of EPA and DHA (docosahexaenoic acid) for severely high triglycerides over 5.6 mmol/L.  But it’s not approved in Canada...since the company was awaiting results of this CV trial.

Other new data show no CV benefit of a European omega-3 product with 1.8 g/day EPA and DHA after about 2 years in seniors with a recent heart attack.

Plus older studies with omega-3 doses of about 1 g/day are conflicting or suggest only slight benefit in some CV patients.

The contrasting data have researchers scratching their heads.

Some question if DHA negates the CV benefit of EPA.  Or if Vascepa’s results were inflated by the study’s mineral oil placebo, which may have increased CV risk...possibly by reducing statin absorption.

For example, mineral oil raised LDL and high-sensitivity C-reactive protein.   This wasn’t seen with the Epanova study’s corn oil placebo.

Educate that the CV benefits of omega-3s seem questionable... and all omega-3s may NOT have the same effects.  Keep in mind, fish oil supplements have both EPA and DHA.

Consider risks.  Rx omega-3s are linked with increased risk of atrial fib...and omega-3 doses above 3 g/day may increase bleeding.

Plus Vascepa costs about $320/month.

Advise saving Vascepa for patients with severely high triglycerides...to possibly reduce the risk of pancreatitis.

Don’t rely on omega-3s for CV benefits.  If needed, reinforce other measures...an optimized statin, BP control, smoking cessation, etc.

If a patient wants to use a fish oil supplement, encourage them to get one with a Health Canada Natural Product Number (NPN).

But point out that CV benefit isn’t likely, no matter the dose or source (krill oil, etc).

Explore our chart, Omega-3s: Fish Oil and More, for guidance about dietary intake...and a deeper dive into the evidence.

View additional resources.

Key References

• JAMA 2020;324(22):2268-80
• Circulation Published online Nov 15, 2020; doi:10.1161/CIRCULATIONAHA.120.052209
• N Engl J Med 2019;380(1):11-22

Pharmacist’s Letter Canada. January 2021, No. 370105

heart failure with reduced ejection fraction (HFrEF) and Heart failure with preserved ejection fraction (HFpEF)

  HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. -Heart Failure With Reduced Ejection Fraction: A Review - PubMed (nih.gov)

Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%;^[1] this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).^[1]

Risk factors for HFpEF include hypertension, hyperlipidemia, diabetes, smoking, and obstructive sleep apnea.

HFpEF is characterized by abnormal diastolic function: there is an increase in the stiffness of the left ventricle, which causes a decrease in left ventricular relaxation during diastole, with resultant increased pressure and/or impaired filling.^[2] There is an increased risk for atrial fibrillation and pulmonary hypertension.

For example, explain that patients with HFrEF feel better and live longer with “triple therapy”

 1)...an ACEI, ARB, or Entresto (sacubitril/valsartan) 

2)PLUS an evidence-based beta-blocker (carvedilol, etc) 

3) AND aldosterone antagonist (spironolactone, etc).

• Eur J Heart Fail Published online Sep 18, 2020; doi:10.1002/ejhf.2008
• J Am Coll Cardiol 2018;71(2):201-30
• Circulation 2016;134(6):e32-e69
• J Card Fail 2011;17(8):664-9

Lancet. 2012 Jul 21;380(9838):219-29. doi: 10.1016/S0140-6736(12)61031-9.

Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy.

Lee IM1, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT; Lancet Physical Activity Series Working Group.

Collaborators (33)

Author information

Abstract

BACKGROUND:

Strong evidence shows that physical inactivity increases the risk of many adverse health conditions, including major non-communicable diseases such as coronary heart disease, type 2 diabetes, and breast and colon cancers, and shortens life expectancy. Because much of the world's population is inactive, this link presents a major public health issue. We aimed to quantify the eff ect of physical inactivity on these major non-communicable diseases by estimating how much disease could be averted if inactive people were to become active and to estimate gain in life expectancy at the population level.

METHODS:

For our analysis of burden of disease, we calculated population attributable fractions (PAFs) associated with physical inactivity using conservative assumptions for each of the major non-communicable diseases, by country, to estimate how much disease could be averted if physical inactivity were eliminated. We used life-table analysis to estimate gains in life expectancy of the population.

FINDINGS:

Worldwide, we estimate that physical inactivity causes 6% (ranging from 3·2% in southeast Asia to 7·8% in the eastern Mediterranean region) of the burden of disease from coronary heart disease, 7% (3·9-9·6) of type 2 diabetes, 10% (5·6-14·1) of breast cancer, and 10% (5·7-13·8) of colon cancer. Inactivity causes 9% (range 5·1-12·5) of premature mortality, or more than 5·3 million of the 57 million deaths that occurred worldwide in 2008. If inactivity were not eliminated, but decreased instead by 10% or 25%, more than 533 000 and more than 1·3 million deaths, respectively, could be averted every year. We estimated that elimination of physical inactivity would increase the life expectancy of the world's population by 0·68 (range 0·41-0·95) years.

INTERPRETATION:

Physical inactivity has a major health eff ect worldwide. Decrease in or removal of this unhealthy behaviour could improve health substantially.

FUNDING:

None.

Benzodiazepines Tied to Dementia in Elders

Benzodiazepine drugs are associated with increased risk for dementia, according to a BMJstudy.

The study included nearly 1100 community-dwelling, older adults in France who were free of dementia; 9% were considered new users of benzodiazepines — that is, they began using the drugs after the third year of follow-up.

During the next 15 years, dementia was diagnosed significantly more often in new benzodiazepine users than in nonusers (32% vs. 23%). After adjustment for confounders such as age, diabetes, and depression, new users had a 60% increased risk for dementia. A complementary, nested case-control analysis found a similar increase in risk.

The researchers argue against the idea that benzodiazepine use is simply a marker for other conditions (e.g., anxiety) that are linked to dementia — for example, the association between the drugs and dementia increased after 7 years of use. However, they acknowledge that such a theory cannot be "entirely ruled out."

Newer Oral Anticoagulants Associated with 'Dramatic Increase' in Bleeding After ACS

When used to prevent thrombotic events after an acute coronary syndrome, the newer oral anticoagulants (for example, apixaban, dabigatran, and rivaroxaban) are associated with increased rates of major bleeding that offset their antithrombotic benefit, according to anArchives of Internal Medicine meta-analysis.

Researchers examined seven randomized controlled trials comprising over 30,000 patients who were hospitalized with ACS and received antiplatelet therapy. Compared with placebo recipients, those on new-generation oral anticoagulants had "a dramatic increase in major bleeding events." Significant (but moderate) reductions in the risks for stent thrombosis and other ischemic events were seen, but there was no significant effect on overall mortality.

An editorialist concludes that routine use of these drugs in patients with ACS "is unwarranted."

Acute coronary syndrome is a term used for any condition brought on by sudden, reduced blood flow to the heart.

OTC Topical Pain Relievers Pose Burn Risk

Over-the-counter topical muscle and joint pain relievers containing capsaicin, methyl salicylate, or menthol (e.g., Bengay, Icy Hot) may cause serious chemical burns, according to the FDA.

A review of two adverse drug event databases, as well as the medical literature, found 43 reports of burns linked to these products. Those containing menthol were the most likely to cause second- and third-degree burns.

The FDA advises clinicians to warn patients about the burn risk and to provide guidance on using the products appropriately. In particular, the pain relievers should not be applied to broken or damaged skin; the area should not be bandaged tightly; and heating pads should not be used.

Adverse events linked to these pain relievers should be reported to the FDA's MedWatch program, the agency says.

Metformin in Diabetes: Evidence Overwhelming, or Unclear? Becky McCall September 26, 2014

VIENNA — The extent of evidence supporting the most widely used, first-line drug for type 2 diabetes, metformin, was the topic under discussion during the Michael Berger debate on the closing day of this year's European Association for the Study of Diabetes (EASD) 2014 Meeting.

Synthesized in 1922, with its first trial in 1957, metformin has been available in Europe since 1960 but made its debut in the United States only in 1995. Arguing for the motion, Metformin: Where is the evidence? Rury Holman, MD, director of the University of Oxford Diabetes Trials Unit, United Kingdom, said it isn't clear that there is sufficient proof to support metformin use: "If it were clear, we wouldn't be having this debate."

Against the motion, claiming that the existing evidence supports first-line use of metformin, was Harold Lebovitz, MD, professor of medicine at the division of endocrinology and metabolism/diabetes at the State University of New York Health Center, Brooklyn, NY.

The Evidence for...

Dr. Lebovitz took the audience through an extensive tour of trials supporting the use of metformin, beginning with a 1995 study that showed, "It's very effective at improving HbA1c" (N Engl J Med 1995;333:541-549).

Dr. Lebovitz then referred to another paper showing that metformin is second only to thiazolidinediones in its durability of action and a lot better than sulfonylureas in this regard (N Engl J Med 2006;355:2427-2443).

Regarding the evidence for metformin's use as first-line therapy, Dr. Lebovitz cited a paper by the UK Prospective Diabetes Study (UKPDS) group that concluded: "Since intensive glucose control with metformin appears to decrease the risk of diabetes-related end points in overweight diabetic patients and is associated with less weight gain and fewer hypoglycemic attacks than insulin and sulfonylureas, it may be the first-line pharmacological therapy of choice in these patients" (Lancet. 1998;352:854-865).

This conclusion was based on a study that compared intensive therapy with metformin with that using insulin and sulfonylureas. "It was found to be no more effective at lowering HbA1c than the other agents, but in reducing diabetes-related deaths, metformin was statistically significant," he noted.

Dr. Lebovitz added that this same UKPDS study showed that cardiovascular disease accounted for 62% of the mortality in overweight patients assigned to conventional treatment, which was primarily diet alone.

And patients assigned to metformin had a significant 42% reduction in cardiovascular mortality and a 39% lower risk of myocardial infarction (MI) compared with patients assigned to diet alone. "Metformin is also weight neutral or may even cause small weight loss. It works by mechanisms that may be independent of lowering of HbA1c."

Lack of Good RCTs, Inconclusive Observational and Meta-analyses

Despite the evidence from the UKPDS, Dr. Lebovitz conceded that since this study there had not been any well-designed randomized controlled trials (RCTs) that measured outcomes with metformin.

"One study, called HOME, investigated all vascular outcomes, and no difference was found between metformin and placebo. But when incidence of macrovascular events, a secondary end point, was considered, metformin caused a highly statistically significant decrease. This confirms the UKPDS."

All other studies Dr. Lebovitz could locate were observational. "These generate hypotheses, and you really need to do randomized controlled trials to determine" whether the findings are true, he said.

Acknowledging this caveat, he shared some of the findings from observational studies, which include:

•  The hazard ratio for all-cause mortality is around 0.6 in metformin patients compared with sulfonylureas. Sulfonylureas caused a 50% to 60% increase in deaths.

•  The Reduction of Atherothrombosis for Continued Health (REACH) registry, which looked at metformin use among patients with diabetes and atherothrombosis, showed all-cause mortality at 6.3% with metformin and 9.3% without metformin.

•  A 2014 paper, a retrospective analysis of the UK Clinical Practice Research Datalink 2000–2012, looked at first-line monotherapy with a sulfonylurea vs metformin and risk of all-cause mortality and found that sulfonylureas were associated with a hazard ratio of 1.58 for mortality compared with metformin (Diabetes Obes Metab. 2014;16:957–962).

Dr. Lebovitz went on to critique meta-analyses, saying he was skeptical of the findings of a number of these that did not find in favor of metformin: "You can't compare apples to oranges to pears," he observed.

He then moved on to present evidence supporting metformin use with regard to delaying development of type 2 diabetes. The US Diabetes Prevention Program (DPP) study showed that metformin was not as good as lifestyle modification for this outcome, but half as good — particularly in young or middle-aged obese patients (Lancet. 2009;374:1677–1686). "Most data from the DPP show that it is weight loss with metformin that is the factor that delays development of diabetes," he noted.

Metformin Compared With Other Agents

Next he compared metformin with other agents for type 2 diabetes.

Thiazolidinediones have a durable effect, preserve beta-cells well, and do not cause hypoglycemia but can cause weight gain and are associated with edema, congestive heart failure, and bone fracture, he noted.

Sulfonylureas cause hypoglycemia; alpha-glucosidase inhibitors cause gastrointestinal side effects and are associated with poor compliance; dipeptidyl peptidase-4 (DPP-4) inhibitors appear to be associated with increased hospitalization due to congestive heart failure; glucagonlike peptide-1 (GLP-1) receptor agonists can cause nausea and vomiting and may be associated with acute pancreatitis; and the sodium-glucose cotransporter 2 (SGLT-2) inhibitors can cause fungal infections and have insufficient long-term data.

"I conclude the other agents do not have data to suggest they replace metformin as a first-line therapy."

Speaking particularly to the issue of hypoglycemia, Dr. Lebovitz noted that if a patient has 1 or more episodes of severe hypoglycemia they are more likely to develop a cardiovascular complication and die in the next 5 years. "I use agents that cause hypoglycemia only if absolutely necessary."

To illustrate his point, he focused on the ORIGIN/ORIGINALE trial: "This is a magnificent trial with patients treated with insulin or sulfonylurea for around 6 years, and if a patient had an episode of severe hypoglycemia, they were found to have an increased mortality in either group."

Dr. Lebovitz also mentioned a series of studies that suggest metformin might have a favorable effect on cancers.

Finally and "most important, every patient can afford metformin; it's not an expensive drug," he concluded.

The Evidence is Unclear...

Taking the podium to outline his stance, Dr. Holman first spoke to the positives, acknowledging that metformin reduces HbA1c to a similar extent as sulfonylureas and even outperforms some of the newer drugs. "There's a low risk of hypoglycemia, no weight gain, and it can reduce LDL cholesterol and has few adverse effects," he observed.

He also conceded that it is "pretty much a done deal" that metformin prevents onset of type 2 diabetes, with a study by the DPP "showing a 31% reduction in new-onset diabetes over 2.8 years" (N Engl J Med. 2002;346:393-403).

"There's a lot to like about metformin, and it's inexpensive," he commented.

However, there remain many unanswered questions, he said.

One sore point is the issue of metformin-associated lactic acidosis (MALA).

"Lactic acidosis is extremely rare (0.02 to 0.09 per 1000 patient-years), but it is fatal in 30% to 50% of cases, so use of metformin is restricted in patients with impaired renal function. It…does frighten people," he observed.

And he noted that guidance on this differs around the world.

The Food and Drug Administration (FDA) has a boxed warning on the label to signify that metformin can cause serious or life-threatening side effects. "This was driven by the increased risk of lactic acidosis as shown with phenformin, another biguanide, in the [University Group Diabetes Program] UGDP study. Because lactate is eliminated through the kidneys, it is wise to limit exposure in renal impairment, where risk of undue accumulation is high," he observed.

The FDA advises stopping metformin if the estimated glomerular filtration rate (eGFR) is less than 60 mL/min/1.73m2, but the UK National Institute for Health and Care Excellence (NICE) guidance is more liberal, indicating the dose of metformin should be reviewed if eGFR is less than 45 mL/min/1.73m2 and stopped if eGFR is less than 30 mL/minute/1.73m2.

There have been two Citizen Petitions in the United States asking the FDA to reconsider its recommendations, but the agency responded by effectively saying the issues were "unclear and 'complex,' " Dr. Holman said.

He conceded that it is unclear from existing evidence whether metformin "is causative, a passive bystander, or in some way augmenting a metabolic problem" with regard to lactic acidosis. But "nearly all cases are due to inappropriate coprescribing in patients with impaired renal function or other comorbidities."

Cardiovascular and Cancer Risk: New Trial to Start in Oxford

Dr. Holman then went on to address whether metformin reduces cardiovascular risk. There appears to be a 33% to 39% reduction in MI and a 27% to 36% reduction in deaths from UKPDS, but this study was small, involving only 753 patients, he said.

"To date, there have been numerous observational analyses, but no further randomized controlled trials. I was taught you need 2 pivotal RCTs ideally on 2 continents to change practice. UKPDS has stood the test of time, but we need another trial."

He then moved to the increased risk for cancer in type 2 diabetes, pointing out that there is an approximate doubling of the risk for pancreatic, liver, and endometrial cancer.

"Epidemiological analyses have suggested that metformin therapy can reduce this risk, but a meta-analysis of currently available short-term metformin RCTs showed no difference in cancer rates.

"What is clear is that we need more robust evidence [for metformin] — in particular with respect to reducing cardiovascular and cancer outcomes. Where there is genuine equipoise, then randomized controlled trials are needed."

Indeed, he announced, 1 such study is beginning in Oxford: a new UK multicenter cardiovascular-outcomes RCT called Glucose Lowering in Nondiabetic Hyperglycaemia Trial (GLINT).

This will enroll around 13,000 patients with elevated but not diabetic HbA1c levels who also have an estimated 10-year cardiovascular disease risk of 20% or greater; they will be randomized to receive metformin or placebo.

The primary end point is time to cardiovascular death, nonfatal MI, or nonfatal stroke, with prespecified secondary end points that include incident cancer and new-onset diabetes.

No Money to Be Made

At this point further discussion was invited from the audience and both speakers.

Dr. Lebovitz said: "We've had metformin for so long, but we haven't had another trial. The reason is because nobody can make money marketing it. A major problem in clinical diabetes is that critical studies that have no profit linked to them are unlikely to be done. We need to encourage industry and government to collaborate and answer important questions that might not make someone rich.

"I also see a problem with long-term clinical trials. If a study comes out next year to say metformin decreases cancer risk and mortality, it is unethical to continue a study to reach the end point," he continued. "This is a real problem in a 10-year study. We're going to need to take the best clinical and basic-science data and put them together to make a judgment."

One audience member from Argentina asked about the use of metformin in pregnancy.

"Data from South Africa, where metformin has been used in pregnant women for a very long time, show no evidence of abnormalities," replied Dr. Lebovitz. "The doctors who treat infertility with metformin find that you can reestablish ovulation and pregnancy, but if you stop the metformin you have a high incidence of abortion. So I would say metformin is widely used in pregnancy," he added.

Another attendee, from Denmark, noted that neither speaker had mentioned a second UKPDS metformin trial that showed an increase in all-cause and cardiovascular mortality vs standard care.

In response, Dr. Holman said: "There was no second trial, but [there was] a post hoc subgroup analysis of a group of patients in whom metformin was added to those previously randomized to sulfonylurea. At the time, it showed a statistical doubling of risk of cardiovascular death and myocardial infarction that was unexplained. The 10-year follow-up data showed this separation in the curves had in fact disappeared. This will be published shortly.

"The fact that metformin is added to nearly every [diabetes] drug licensed to improve efficacy inexpensively means that people have not accepted this [the CV findings above]," Dr. Holman added.

"I think people have assessed these data and decided this is not a real risk. But it would be good to do a study," he concluded.

Dr. Lebovitz declares he has shares in Merck, Abbott, Abbvie, and Mannkind; is on the scientific advisory boards of Biocon, Intarcia, MetaCure, and Poxel Pharma; performs occasional consultancy to AstraZeneca, Janssen, and Sanofi; he does not participate in any speaker's bureaus. Dr. Holman has declared that he receives research funding from Bayer, Bristol-Myers Squibb, and MSD and honoraria from Amgen, Bayer, Elcelyx, Janssen, MSD, Novartis, and Novo Nordisk.

European Association for the Study of Diabetes. September 19, 2014; Vienna, Austria.