FDA Expands Indication For Type 2 Diabetes Treatment Synjardy (Empagliflozin/Metformin Hydrochloride) To Include Treatment-Naïve Adults

In continuation of my update on empagliflozin and metformin

The U.S. Food and Drug Administration has approved an expanded indication for Synjardy (empagliflozin and metformin hydrochloride) tablets to include treatment-naïve adults with type 2 diabetes (T2D). Synjardy, from Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY), is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D when treatment with both empagliflozin and metformin is appropriate.

empagliflozin Metformin

Synjardy is a combination of empagliflozin (Jardiance) and metformin — two medicines with complementary mechanisms of action — to help control blood glucose in adults with T2D. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney. Metformin, a commonly prescribed initial treatment for T2D, lowers glucose production by the liver and its absorption in the intestine.

"Type 2 diabetes is a complex condition, which often requires that people take more than one treatment to manage their blood sugar," said Paul Fonteyne, president and CEO, Boehringer Ingelheim Pharmaceuticals, Inc. "The expanded indication for Synjardy further validates the potential of this combination therapy to help adults with type 2 diabetes who are not at goal, including those already being treated and, now, those at the beginning of their treatment journey."

The Synjardy label was updated to include results from a phase III, double-blind, randomized, active-controlled study that evaluated the efficacy and safety of empagliflozin in combination with metformin as initial therapy compared with the individual components. In the study, at 24 weeks, the combination of empagliflozin 10 mg or 25 mg with metformin 1000 mg or 2000 mg resulted in significant reductions in A1C (a measure of average blood glucose over the past two to three months) compared with the corresponding dose of either component alone.

Synjardy can cause serious side effects, including Lactic Acidosis (a buildup of lactic acid in the blood). Metformin, one of the medicines in Synjardy, can cause lactic acidosis, a rare, but serious condition that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. Synjardy is not for the treatment of type 1 diabetes or diabetic ketoacidosis.

Diabetes drug metformin could help reduce toxic acid levels linked to MSUD

In continuation of my update on metformin 

Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the dysfunction of an enzyme which breaks down three essential amino acids: leucine, isoleucine and valine. Left untreated, infants die from a toxic buildup of resulting keto-acids within weeks of birth. Those who are diagnosed early can live a normal life, but are forced to eat a very controlled, formula-based diet. The only proven treatment for the disease, which is characterized by sweet-smelling urine, is a liver transplant. Publishing in Scientific Reports, researchers at the Buck Institute show that the widely-used diabetes drug metformin reduces the toxic acid levels associated with MSUD in both skin cells derived from MSUD patients and in mice. The discovery offers the possibility of a new treatment for a disorder identified 1 in 180,000 births.

Senior author and Buck faculty Arvind Ramanathan, PhD, says metformin reduced the levels of toxic ketoisocaproic acid (KIC) in patient-derived fibroblasts by 20 to 50 percent and significantly reduced KIC levels in the skeletal muscle of mice bred to have the disease by 69 percent. "We think there is a clear path to a clinical trial and we are hoping that physicians who treat MSUD patients will start pushing in that direction," he said. "There is a definite need for novel interventions."

Ramanathan, who specializes in metabolomics, came to the MUSD discovery as he was studying various compounds and the enzymes they impact in the context of aging. The work could provide a mechanistic explanation for metformin's success in controlling diabetes and possibly extending healthspan in both animals and humans. The research also highlights similarities between a rare pediatric disease and normal aging - and shows how studying one can inform the other.

Researchers studied the enzyme BCKDH, which is defective in MSUD and also decreases in activity with normal aging. Ramanathan says decreased BCKDH is implicated in obesity and diabetes; he believes it may be involved in a number of other age-related conditions as well. Ramanathan also studied an enzyme upstream of BCKDH - called BCAT. He says in MSUD, BCAT converts leucine, isoleucine and valine to toxic ketones in the mitochondria of skeletal muscle -resulting in the muscle weakness and atrophy associated with MUSD. "We think the same process may be afoot with age-related sarcopenia and frailty," he said. "Interestingly, metformin interacts with BCAT and in our MSUD mice treatment with metformin significantly reduced toxic acid buildup in the skeletal muscle."

"This is a prime example how aging research can have a significant impact on people at any age and the work also highlights the value of studying drugs already approved by the FDA," said Brian Kennedy, PhD, senior co-author and Buck Institute CEO. "In this case, we hope our discovery will help those living with MUSD. We plan on building on these insights to further our research aimed at extending the healthy years of life for all of us."

Experimental lipid-lowering drug improves glucose control in diabetic patients

High triglycerides -- a type of fat, or lipid, in the blood -- increase the risk of heart disease and perhaps type 2 diabetes. For the first time, it has been shown that profoundly lowering triglycerides in diabetics improves their insulin sensitivity over time, which helps them maintain healthy glucose - blood sugar -- levels. Volanesorsen, an experimental lipid-lowering medication, improved insulin sensitivity and glucose control by significantly decreasing patients' overall hemoglobin A1c -- the standard clinical measurement of blood glucose levels for diabetics -- in a new study reported by researchers from the Perelman School of Medicine at the University of Pennsylvania. The results are published online this month in Diabetes Care.

Researchers enrolled 15 adult patients with type 2 diabetes and hypertriglyceridemia who had been taking metformin - an oral medication that helps control blood sugar levels - for their diabetes. Patients were randomly assigned to two groups: one to receive volanesorsen and the other a placebo. After taking the medication for 12 weeks, researchers found that patients on volanesorsen experienced a 69 percent reduction in triglycerides, and a 57 percent improvement in whole-body insulin sensitivity. Several tests of glucose control, including hemoglobin A1c, were also significantly improved. Researchers concluded that the drop in triglycerides was strongly related to improved insulin sensitivity and improved hemoglobin A1c.

"These results prove volanesorsen to be an effective treatment method for improving insulin sensitivity, but what's most interesting, and perhaps most encouraging, is that this drug also significantly improved patients' hemoglobin A1c levels," said the study's lead co-author, Richard Dunbar, MD, an assistant professor of Cardiovascular Medicine at Penn. "In most cases, it takes many months of therapy to improve the hemoglobin A1c, so to move the needle so significantly in a fairly short time is very promising. Scientifically, these results provide important proof that profoundly lowering triglycerides improves insulin sensitivity. And clinically, the results go a step further and show that doing so improves the underlying metabolic problems enough to actually improve diabetes."

To quantify the effects of the drug, researchers used a very sophisticated test of insulin sensitivity, the hyperinsulinemic-euglycemic clamp or "the clamp," which is largely regarded as the gold standard in insulin sensitivity measurement. This technique infuses insulin at fixed rates, and infuses glucose at a varying rate to keep blood glucose constant, in order to determine how well a patient responds to insulin.

For many years, researchers had suspected that high triglycerides worsened diabetes, but there had not been powerful tool to prove this concept.

"While we were able to determine the effectiveness of this medication in a very specific group of diabetic patients, it will be important to evaluate this drug in a broader diabetic population," Dunbar said. "The next phase will be to determine clinical success in patients with type 2 diabetes on the whole range of diabetic medications or perhaps with less severe lipid problems. It will also be important to conduct longer studies, as glucose control may improve even further with longer exposures to the drug."

Several other classes of medications that profoundly lower triglycerides are also in development. If improved insulin sensitivity and improved glucose control are truly the result of lowering triglycerides, researchers suggest these other novel drugs should show the same effect.

Dunbar added, "after a long dry spell, there is a lot of activity right now for triglyceride-lowering therapies. Penn Medicine has been conducting several clinical trials evaluating this and other novel triglyceride-lowering drugs. Not only do we have a variety of very potent options emerging, we may be able to help improve glucose at the same time. Both of these developments would be great news for our patients with high triglycerides, including diabetics."

This Diabetes Drug Saves Lives. You Can Thank The FDA

Researchers are announcing that Victoza, a diabetes drug sold by Danish drug giant Novo Nordisk , prevents heart attacks, strokes and cardiovascular deaths.

 liraglutide-Victoza

It is only the second diabetes drug ever to do so. The first, Jardiance, a pill sold by Eli Lilly LLY -0.91% and Boehringer Ingelheim , presented its positive results just last year. Researchers say that the new results could change the way that doctors treat diabetes, shifting the treatments doctors reach for after metformin, the tried-and-true first-line drug, which is generic. “There’s a building momentum that maybe we do need to rethink the way diabetes is cared for in America,” says John Buse, the University of North Carolina, Chapel Hill researcher who led the study, which was funded by Novo Nordisk.

And doctors and Novo Nordisk itself give credit to the new diabetes data to a surprising source: Tougher regulations for diabetes drugs from the Food and Drug Administration, which many in industry had previously decried, saying it was keeping new drugs from the market and hurting patients. “I can almost guarantee you that these trials would not have been done if it had not been for the FDA regulations,” says Buse, who has been a consultant to many companies for years. “Before the guidance I was constantly pushing on companies to do these trials.”

That fact–that companies and patients are likely to benefit from the FDA’s toughness–goes against one of the common narratives in the drug industry and among the FDA’s critics: that high regulations slow patients’ access. In some cases, it’s clear, they also create a bar for industry to leap over, and deliver billions of dollars in spoils to companies that actually manage to help patients, not just blood test results.

The Victoza result is exactly the kind of marketing claim that makes a drug company salivate: Novo Nordisk can now tell patients and their insurers that the alternative to its drug is an earlier death.

In the study, presented this evening at the annual meeting of the American Diabetes Association and published in the New England Journal of Medicine, 9,340 patients were randomly assigned to receive either Victoza or placebo for a median of 3.8 years. For those on Victoza, 13% had a heart attack, stroke or death, compared to 14.9% on placebo, a 13% decrease in risk. Reductions in cardiovascular death (22%) and death from any cause (15%) were also statistically significant. A supposed side effect of the drug, pancreatitis, did not show up at all, and patients on Victoza lost 2.3 kilograms (about 5 pounds) more than those on placebo.

Is Okra Good for Diabetes?

According to a handful of recent studies, okra may reduce symptoms of diabetes - a group of diseases that includes type 1 diabetes, type 2 diabetes, and gestational diabetes.

 

Diabetes claimed the lives of 75,578 Americans in 2013, according to the United States Centers for Disease Control and Prevention (CDC). In 2014,8.5 percent of adults worldwide had the condition, the World Health Organization (WHO) report. By 2030, diabetes may be the seventh leading cause of death.

A number of factors increase a person's risk of developing diabetes, including a family history of the disease. Lifestyle factors also play a role, so doctors routinely recommend diet changes and increased exercise to reduce blood sugar levels.

Okra may help reduce blood sugar levels in some people with diabetes. Research into the effects of this seedy vegetable is still in the early stages, but the results are promising.

Okra thrives in temperate climates, producing large hibiscus-like flowers that eventually give rise to green seed pods. It is a member of the mallow family, which includes a number of other popular plants, including hibiscus, cocoa, and cotton.

Scientifically known as Abelmoschus esculentus, okra may have been grown as long ago as 2000 BCE in Egypt.

Okra's flavor is mild, and the entire seed pod can be eaten. This vegetable-like fruit also has a long history in traditional medicine.

Kew Royal Botanic Gardens report that in Eastern traditional medicine, okra leaves and fruit were used as pain relievers, moisturizers, and to treat urinary disorders. In Congolese medicine, okra is used to encourage a safe delivery during childbirth.

Can okra help with symptoms of diabetes?

Diabetes can often be well-managed with increasing a hormone called insulin and other medical therapies. However, some people with diabetes wish to avoid regular insulin injections. Others experience blood sugar dips and other unpleasant side effects, and diabetes medications do not work for everyone.

The possibility that a readily available seed pod could help control diabetes is an exciting one. But there is no evidence yet that okra can cure diabetes. So far, the research on okra has only looked at its effects on animals. Human bodies are similar to animals, but not all research on animals has worked out in humans.

Increased absorption of sugar by muscles

A 2005 study published in Planta Medica investigated the effects of okra on rats with diabetes. A substance called myricetin is present in okra and some other foods, including red wine and tea.

Researchers isolated myricetin from okra, then administered it to the rat. The treatment increased absorption of sugar in the rats' muscles, lowering their blood sugar.

A 2012 Food Science and Human Wellness review points to a number of other laboratory and animal studies that have linked myricetin to lower blood sugar. The study argues that myricetin may also reduce other risk factors for diabetes.

Reduction in blood sugar spikes after eating

A 2011 study published in ISRN Pharmaceutics found a link between okra and decreased blood sugar spikes after eating.

Researchers fed rats liquid sugar as well as purified okra through a feeding tube. Rats who consumed the okra experienced a reduction in blood sugar spikes after feeding. The study's authors think this is because the okra blocked the absorption of sugar in the intestines.

The study also explored possible interactions between okra and metformin, a drug that can reduce blood sugar in type 2 diabetes. Okra appeared to also block absorption of metformin. This suggests that okra could reduce the effectiveness of metformin, and should therefore not be eaten at the same time as the drug.

Lower blood sugar levels

A 2011 study published in the Journal of Pharmacy and Bioallied Sciences points to a link between eating okra and lower blood sugar. The researchers allowed the blood sugar of rats with diabetes to stay level for 14 days. They then gave the rats powdered okra peel extracts and seeds dosages of up to 2,000 milligrams per kilogram of body weight.

There were no poisonous effects linked with these relatively high doses of okra. The rats that ate okra had reduced blood sugar levels after up to 28 days of eating okra. The study ended on day 28, so it is unclear if the effects on blood sugar levels would have lasted longer.

Considerations for using okra

Few studies have linked okra to negative side effects, but some negative side effects are possible:

• Okra may make the drug metformin less effective.
• Okra is high in substances known as oxalates. Oxalates may increase the risk of kidney stones in people vulnerable to kidney stones.
• Okra can contain bacteria, pesticides, and other dangerous substances if it is not thoroughly washed. People should never consume rotten okra, frozen okra that is past its expiration date, or okra that has not been thoroughly washed.
• People with an okra allergy should not consume okra. Those with an allergy to other plants in the mallow family, such as hibiscus or cotton, may also be allergic to okra.
• Even if okra proves to be ineffective in fighting diabetes, it remains a safe snack for people with diabetes. A single serving of 100 grams contains just 30 calories, but offers a number of nutritional benefits:
  • Okra contains no saturated fats or cholesterol
  • Okra is rich in fiber, containing 9 percent of the recommended daily value (RDV)
  • Okra contains 8 percent of the RDV of calcium, 43 percent of the RDV of manganese, 10 percent of the RDV of iron and copper, and 44 percent of the RDV of vitamin K
  Okra is rich in protective substances known as antioxidants, including myricetin. According to the National Center for Complementary and Integrative Health, antioxidants may reduce oxidative stress, a process that damages cells in the body. Oxidative stress plays a role in the development of diabetes, as well as diseases such as:
  • Parkinson's disease
  • Alzheimer's disease
  • Cataracts
  • Macular degeneration
  • Heart and blood vessel disease
  • Cancer
  In addition to its antioxidant benefits, okra may also reduce tiredness. A 2015 study published in Nutrients found that substances found in okra seeds known as polyphenols and flavonoids could reduce fatigue.

Metformin along with chemotherapy/radiation improves outcomes in head and neck cancer patients

In continuation of my update on metformin

Researchers at the University of Cincinnati (UC) College of Medicine have found that adding increasing doses of an approved Type 2 diabetes drug, metformin, to a chemotherapy and radiation treatment regimen in head and neck cancer patients is not well tolerated if escalated too quickly, but allowing slower escalation could be beneficial.

These findings are being presented via poster June 4 at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting: Collective Wisdom, being held June 3-7 in Chicago.

Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute and principal investigator on this study, says retrospective studies have shown improved outcomes in tumors treated with chemotherapy and radiation if they were also on metformin for diabetes.

"In head and neck squamous cell carcinoma, which develops in the mucous membranes of the mouth, nose and throat, diabetic patients taking a medication called metformin had better overall survival compared to those not on metformin when also treated with chemotherapy and radiation," she says. "Additionally, pancreatic cancer patients treated with chemotherapy and metformin required higher doses of metformin--1,000 milligrams twice a day--to experience positive results.

"In basic science studies, metformin has been shown to stop mTOR, a molecular pathway present and active in this type of head and neck cancer, and pretreatment with metformin resulted in a decrease in the occurrence of oral cavity tumors in animal models. In this study, we wanted to see if the combination of escalating doses of metformin with the chemotherapy agent cisplatin and radiation for head and neck cancer tumors in non-diabetic patients would be effective."

Wise-Draper says that metformin, which is an approved Type 2 diabetes medication, was provided by their investigational pharmacy. Metformin was administered orally in escalating doses for 7 to 14 days prior to starting the cisplatin and radiation and continued throughout standard treatment. Blood samples were collected before and after metformin treatment as well as during chemotherapy. Flow cytometry, a technique used to count cells, was used to detect the percent of circulating immune activated cells, and clinical laboratory tests including glucose, B12 and C-peptide (an amino acid that is important for controlling insulin) were performed.

"This is part of an ongoing clinical trial," says Wise-Draper. "We found that eight patients with advanced head and neck cancer have been enrolled so far; we plan to have 30 total. Due to the relatively quick escalation of metformin, the patients' tolerance was poor with higher doses of metformin when initiated 7 days prior to their chemotherapy and radiation therapy regimen.
"Therefore, the protocol was modified to allow slower escalation over 14 days. The most common toxicities observed included nausea (71 percent of patients) and vomiting (43 percent of patients), increase in creatinine (57 percent of patients), decreased white blood cell count (43 percent of patients) and pain when swallowing (43 percent of patients) with only nausea being directly attributed to metformin and the rest attributed to cisplatin and radiation."

She adds that there wasn't a substantial change in T cell or glucose levels with administration of metformin in the small sample of patients but that there were increased C-peptide levels in response to metformin administration.

"These results show that the combination of metformin and cisplatin and radiation was poorly tolerated when metformin was escalated quickly. However, there has been no significant increase in side effects thus far with the addition of metformin," Wise-Draper says. "The trial is continuing with escalation of metformin over a longer period of time to provide more data; we will also try to increase our sample size."

Study finds no added benefit of empagliflozin alone or in combination for type 2 diabetes

In continuation of my update on Empagliflozin

Empagliflozin (trade name: Jardiance) has been approved since May 2014 for adults with type 2 diabetes mellitus in whom diet and exercise alone do not provide adequate glycaemic control. In 2014, the German Institute for Quality and Efficiency in Health Care (IQWiG) concluded in its dossier assessment that an added benefit of the drug in comparison with the appropriate comparator therapies was not proven. Partly, the drug manufacturer had presented no relevant data; partly not only the drugs, but also the therapeutic strategies differed; in addition, the indirect comparisons were based on studies unsuitable for the assessment.

The manufacturer now requested a new benefit assessment due to "new scientific findings", and submitted two dossiers: one for empagliflozin alone, and one for empagliflozin in combination with metformin. IQWiG determined in both early benefit assessments that the dossiers still contained no data and analyses relevant or suitable for the research questions. Hence an added benefit of empagliflozin alone or in combination with metformin in comparison with the appropriate comparator therapies is still not proven. The analyses of the large study EMPA-REG-Outcome additionally submitted were unsuitable for an assessment of the added benefit in Germany.

Same studies, same problems

Both the single agent and the combination of empagliflozin with metformin are approved alone or in combination with other blood-glucose lowering drugs including insulin. According to the Federal Joint Committee (G-BA), this resulted in three and four research questions respectively. The manufacturer again presented no relevant data for five of these seven research questions so that an added benefit is not proven. One study of direct comparison as well as several studies for indirect comparisons, all of which had already been cited in the dossier or in the commenting procedure in 2014, were available for the other two research questions.

The assessment of the data from the indirect comparison was incomplete with regard to content, although it had been known to the manufacturer since the first dossier assessment which patient-relevant outcomes were important. In particular, there was no information on specific adverse events for which a disadvantage of empagliflozin versus the comparator therapy was shown. The information provided on one of the indirect comparisons had the same deficiency; furthermore, there were contradictions to the clinical study reports. The second indirect comparison was not evaluable because the studies compared were not sufficiently similar and because therapeutic strategies instead of drugs were compared with one another again.

Hence there was no hint of an added benefit of empagliflozin in comparison with the appropriate comparator therapies for the single agent or for the fixed combination.

Study EMPA-REG-Outcome unsuitable for the assessment of the added benefit

Both dossiers additionally contained a description of the EMPA-REG-Outcome study used by the manufacturer to answer a question posed by the manufacturer itself, i.e. whether empagliflozin (alone or with metformin) in addition to standard treatment offers an added benefit for patients at high cardiovascular risk in comparison with standard treatment alone plus placebo.

The antidiabetic therapy in this study cannot be considered standard treatment, however: The blood-glucose lowering treatment was not escalated appropriately and the upper threshold values mentioned in guidelines were not consistently respected. And even if treatment was escalated, this was mostly done as emergency treatment, but not as part of a planned treatment expansion.

Effects in favour of empagliflozin mainly in Latin America and Asia

Moreover, marked regional differences were notable: Effects in favour of empagliflozin mainly occurred in study centres in Latin America and Asia, whereas in Europe, partly advantages and partly disadvantages of empagliflozin were shown. Finally, the study addressed neither the G-BA's research questions nor the appropriate comparator therapies specified there.

Thomas Kaiser, Head of the IQWiG Drug Assessment Department, commented on this attempt by the manufacturer to prove an added benefit for at least certain patients: "This is a wasted opportunity. It should be welcomed that studies of this size and this duration, which are therefore potentially informative, are conducted. But it was conducted with obvious deficiencies. Experts had pinned high hopes on this study, particularly as, in contrast to other large outcome studies, it appeared to produce positive results at first glance. A thorough analysis of the study and the results in European participants did not confirm this impression, however."

FDA Expands Indication of Invokamet (canagliflozin/metformin HCl) to Include First-Line Treatment of Type 2 Diabetes

In continuation of my updates on INVOKANA® (canagliflozin) and metformin hydrochloride,

Janssen Pharmaceuticals, Inc. (Janssen), announced the U.S. Food and Drug Administration (FDA) has approved Invokamet, a fixed-dose combination therapy of INVOKANA® (canagliflozin) and metformin hydrochloride, for first-line treatment of adults with type 2 diabetes. With this new approval, Invokamet may now be prescribed in adults with type 2 diabetes who are not already being treated with canagliflozin or metformin and may benefit from dual therapy.

 metformin    canagliflozin

Invokamet, the first combination of a sodium glucose co–transporter 2 (SGLT2) inhibitor and metformin available in the United States, was previously approved by the FDA in August 2014 as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes not adequately controlled by either canagliflozin or metformin, or who are already being treated with both medications separately.

“Physicians increasingly try to achieve greater initial blood sugar control by using dual therapy at the outset, versus single-agent therapy alone, especially for patients with higher A1C levels,” said John Anderson, M.D.*, Frist Clinic, Nashville, Tenn. “Invokamet combines two effective, complementary medicines—canagliflozin and metformin—into one convenient pill, to lower A1C significantly more than metformin alone.”

A1C is a measure of average blood glucose over the past two to three months; the American Diabetes Association recommends most adults with type 2 diabetes maintain A1C levels of 7 percent or less.[2]

The new Invokamet indication aligns with recent type 2 diabetes treatment guidelines, which recommend dual therapy for patients with higher A1C levels. Specifically, guidelines recommend dual therapy for patients who have an initial A1C level of 7.5 percent or higher;[3] and for those who have an initial level below 7.5 percent and do not achieve an A1C treatment goal after about three months on single therapy, often metformin.3,[4] In addition, dual or triple therapy is recommended as first-line therapy in asymptomatic patients with an initial A1C level above 9 percent.3

Studies have demonstrated that administration of Invokamet results in the same levels and effects of canagliflozin and metformin in the body as co-administration of corresponding doses of both drugs as individual tablets. Canagliflozin works with the kidneys to help adults with type 2 diabetes lose some sugar through the process of urination, and metformin decreases the production of glucose in the liver and improves the body's response to insulin. Invokamet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.1

Invokamet is available in four dose strengths, in tablets containing canagliflozin 50 milligrams (mg) or 150 mg, and metformin 500 mg or 1000 mg. The recommended dosing is twice daily. The prescribing information for Invokamet also contains a boxed warning for lactic acidosis, a rare, but serious complication that can occur due to metformin accumulation.1

“The available doses of Invokamet allow physicians to tailor therapy for individual patient needs and offer an alternative for people living with type 2 diabetes who may be able to reduce the number of pills they take each day,” said Paul Burton, M.D., Ph.D., Vice President, Medical Affairs, Janssen. “This expansion marks an important milestone as we continue to study Invokamet and INVOKANA®—the number-one prescribed SGLT2 inhibitor with more than 8 million prescriptions to date—for the treatment of type 2 diabetes.”

Phase 3 Study Supports Expanded Indication

The expanded indication for Invokamet was based largely on a 26-week, double-blind, active-controlled, multicenter Phase 3 study in 1,186 adults with type 2 diabetes inadequately controlled with diet and exercise, and who had not been treated previously with any glucose-lowering medications. The participants were assigned randomly to one of five treatment groups: metformin hydrochloride extended release (MET), canagliflozin 100 mg (CANA100), canagliflozin 300 mg (CANA300), canagliflozin 100 mg + MET (CANA100/MET), or canagliflozin 300 mg + MET (CANA300/MET). The mean baseline A1C across all groups was 8.8 percent. The primary endpoint was the change in A1C. A report on the study findings was published in Diabetes Care in March 2016.[5]

After 26 weeks, participants in the CANA100/MET and CANA300/MET groups had significantly greater decreases in A1C compared to those in the CANA100, CANA300 and MET groups: 1.77 percent and 1.78 percent vs. 1.37 percent, 1.42 percent and 1.3 percent, respectively (p-values for all differences between the combination therapies vs. individual therapies less than 0.001). Additionally, significantly more participants in the CANA100/MET and CANA300/MET groups compared to the MET group achieved the goal of reducing A1C to less than 7 percent: 47 percent and 51 percent vs. 38 percent, respectively (p less than 0.05 for both combination groups vs. MET).1

Other Phase 3 Studies of Canagliflozin-Metformin Therapy

The co-administration of canagliflozin—INVOKANA®—and metformin has been evaluated in six other Phase 3 clinical studies that enrolled 4,732 patients with type 2 diabetes and who were already taking glucose-lowering medications. The studies showed that the combination of INVOKANA® and metformin lowered blood sugar and, in pre-specified secondary endpoints, was associated with significant reductions in body weight and systolic blood pressure.

In two studies comparing INVOKANA® plus metformin to current standard treatments plus metformin—one studying sitagliptin and the other studying glimepiride—INVOKANA® dosed at 300 mg provided greater reductions in A1C levels and body weight than either comparator. The overall incidence of adverse events was similar with INVOKANA® and the comparators.

Results from the Phase 3 studies showed that INVOKANA® was generally well tolerated, and the most common adverse events include genital yeast infections, urinary tract infections, and changes in urination. The most common adverse reactions due to initiation of metformin, as noted in the prescribing information for that medication, are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use. INVOKANA® can increase the risk of hypoglycemia when combined with insulin or a medication that increases insulin levels (e.g., a sulfonylurea). Therefore, a lower dose of insulin or insulin-raising medication may be required to minimize the risk of hypoglycemia when used in combination with Invokamet.

About Type 2 Diabetes

Of the approximately 29 million people who have diabetes in the United States, 90 to 95 percent of them have type 2 diabetes, which is chronic and affects the body's ability to metabolize sugar (glucose), and is characterized by the inability of pancreatic beta cell function to keep up with the body's demand for insulin

Cardioprotective effect proposed for metformin

In continuation of my update on metformin

 

A large retrospective analysis suggests that metformin could be cardioprotective in insulin-dependent patients with Type 2 diabetes.

The findings, based on data from the UK Clinical Practice Research Datalink, found a reduced risk of major adverse cardiac events (MACE) and all-cause mortality among patients taking the drug.

To minimise the effects of confounding by indication, Craig Currie (Cardiff University, UK) and co-workers analysed only patients who had been started on insulin, with metformin started simultaneously or added later.

None of the 12,020 patients analysed had prior MACE or cancer at baseline. During an average 3.5 years of follow-up, the MACE rate among the 5536 patients taking insulin plus metformin was 15.9 per 1000 person-years, compared 26.3 with per 1000 person-years among the 6484 patients taking insulin monotherapy. The all-cause mortality rate was also lower, at 21.2 versus 61.3 deaths per 1000 person-years.

After accounting for multiple confounders, including cumulative insulin exposure, patients given metformin had a significant 25% reduced risk of MACE and a 40% reduced risk of mortality, the team reports in  PLoS ONE

Among patients matched for the propensity to be prescribed metformin, outcome rates were 14.9 versus 22.2 per 1000 person-years for MACE and 23.1 versus 44.4 per 1000 person-years for mortality. The mortality difference persisted after accounting for confounders, at a 30% reduction, although the difference in MACE became nonsignificant.

The team found no association between cancer risk and metformin treatment, despite previous suggestions that it may have a protective effect.

Currie et al note that the various contraindications and cautions for metformin treatment, such as tissue hypoxia and renal impairment, mean that "the population of people receiving insulin in combination with metformin may be healthier than the monotherapy group."

Given this, and other drawbacks of a retrospective study, they conclude that more research is needed "to determine the risks and benefits of insulin in type 2 diabetes and the possible benefits associated with the administration of concomitant metformin."

 Ref : http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0153594

Diabetes drug found no better than placebo at treating nonalcoholic fatty liver disease: But randomized, double-blind clinical trial suggests better way to conduct future trials

A diabetes medication described in some studies as an effective treatment for nonalcoholic fatty liver disease (NAFLD) works no better than a placebo, report researchers at University of California San Diego School of Medicine, after conducting the first randomized, double-blind, controlled clinical trial of sitagliptin, an oral antihyperglycemic marketed by Merck & Co. under the name Januvia.

 

Januvia (sitagliptin)

Writing in the Journal of Hepatology, a multidisciplinary team headed by study senior author Rohit Loomba, MD, professor of medicine in the Division of Gastroenterology and director of the NAFLD Translational Research Unit at UC San Diego School of Medicine, found that sitagliptin was not significantly better than a placebo in reducing liver fat, as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and other technologies.

The team included Claude Sirlin, MD, professor and vice chair (translational research) of radiology at UC San Diego School of Medicine, and Richard Ehman, MD, professor of radiology at Mayo Clinic. The labs, led by Sirlin and Ehman, invented and validated the advanced noninvasive imaging techniques applied in this study.

NAFLD is the accumulation of fat in the livers of people who drink little or no alcohol. It is the leading cause of chronic liver disease in the United States. Roughly one-quarter of Americans -- an estimated 100 million adults and children -- have NAFLD, which can progress to a more serious form called nonalcoholic steatohepatitis, which in turn can develop into cirrhosis, liver cancer and liver failure.

Currently, there are no approved, specific therapies for NAFLD. However, it is commonly associated with diabetes, which has prompted researchers to test diabetes medications, such as metformin, rosiglitazone and liraglutide, as potential treatments.

Sitagliptin is another possibility. In clinical trials conducted in patients with type 2 diabetes, sitagliptin has been shown to be effective in improving glycemic (blood sugar) control, cholesterol, lipoproteins and other health measures compared to placebo.

"But human trials of sitagliptin have been limited to date because they have lacked important tools like a placebo arm and allocation concealment (in which researchers do not know what the next treatment allocation will be, further preventing selection bias in testing)," said Loomba.

In the new study, 50 NAFLD patients with pre-diabetes or early diabetes were randomized into two groups: one received a 100 milligram oral dose of sitagliptin daily for 24 weeks, the other received a placebo. Primary outcome was assessed by changes to liver fat measured by MRI-PDFF, conducted by the Liver Imaging Group in the Department of Radiology at UC San Diego Health.

At end-of-treatment, Loomba and colleagues found no significant differences between sitagliptin and placebo across a range of measures. Neither study group experienced any adverse effects.

While the study did not support earlier findings that sitagliptin was an effective treatment for NAFLD, Loomba said it provided new evidence that clinical trials with patients at higher risk of diabetes do not necessarily need a liver biopsy to be efficiently screened for potential therapeutic agents.

"Biopsies present their own complications, such as possible pain and infection," said Loomba. "MRI-PDFF, and magnetic resonance elastography (a non-invasive imaging technique that measures the stiffness of soft tissues) proved to be accurate, quantitative, and useful over the study duration in measuring the state and progression of disease. These technologies should be further investigated in clinical trials, especially those of longer duration."

Drug combination could help reduce risk of death in type 2 diabetes

In continuation of my update on metformin

People with type 2 diabetes treated with insulin plus metformin had a reduced risk of death and major cardiac events compared with people treated with insulin alone, a new study by Cardiff University shows.

Led by Professor Craig Currie of the University's School of Medicine, the retrospective research looked at people with type 2 diabetes who were treated with insulin with or without metformin from the year 2000 onwards.

12,020 people were identified from a general practice data source, and the research team tracked them for three and a half years on average, from the time they were first prescribed insulin.

The researchers found than when used in conjunction with insulin, metformin had the potential to reduce mortality and heart attacks. They also found that there was no difference in the risk of cancer between people treated with insulin as a single therapy or in combination with metformin.

Professor Currie said: "Since 1991, the rate of insulin use in type 2 diabetes increased more than six-fold in the UK. In more recent years, metformin has also been used alongside insulin as a treatment.

"Previously, our work showed that increased insulin dose is linked with mortality, cancer and heart attacks. Existing studies have also shown that metformin can attenuate the risks associated with insulin.

"In this research we examined insulin dose along with the impact of combining insulin with metformin. We found that there was a considerable reduction in deaths and heart problems when this cheap and common drug was used in conjunction with insulin.

Around 3.9m people live with diabetes in the UK, with more than 90% of those affected having type 2 diabetes.

"While this research indicates the potential of using these treatments together, further studies are needed to determine the risks and benefits of insulin in type 2 diabetes and the possible benefits associated with the administration of metformin alongside insulin," added Professor Currie.