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Diabetes Core Update
Diabetes Core Update March 2015
00:24:52
Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association’s four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and...
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- [00:04]
A
Welcome to the American Diabetes Association Diabetes Core Update, where we will regularly keep you up to date on the latest clinically relevant articles from the American Diabetes Association's four science and medical journals, Diabetes, Diabetes Care, Clinical Diabetes and Diabetes Spectrum. Joining us for this program are Dr. Neal Skolnik, who is a professor of family medicine at Temple University School of Medicine and and associate director in the Family Medicine Residency Program at Abington Memorial Hospital. Welcome, Dr. Skolmik.
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B
Thank you. It's a pleasure to be here.
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And Dr. John Russell, who is a professor of family medicine at Temple University School of Medicine and director in the Family Medicine Residency Program at Abington Memorial Hospital.
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C
Thank you. I'm looking forward to going over this week's articles.
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A
And now for the articles.
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B
We have a really exciting, wonderful issue this month all about SGI LT2 inhibitors. We'll start our discussion with an introduction of the class and then we'll talk about six different articles. The first article will be about canagliflozin versus glimepiride in addition to metformin. Next, canagliflozin in addition to insulin, then dapagliflozin in addition to metformin and sulfonylureas together. Then an article, all of these articles from Diabetes Care on dapagliflozin for type 1 diabetes. We'll finish with two articles on the combination of empagliflozin and linagliptin, first in addition to metformin and then as first line agents. Before going into the articles this month, we're going to do an overview of the SGLT2 inhibitor class of medicines to tee up our understanding of these articles. And John, you were going to first give us a bit of history on the development of SGLT2 inhibitors.
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John, the SGLT2 inhibitors have been around for close to 200 years. They were discovered in the 1830s in France. And at that period of time, people were looking to the barks of various trees to develop lots of medicine. So in 1835, French scientists isolated fluorizin from bark and they really weren't sure what to do with it. For a long time they were using it for fevers and malaria. About 50 years later, they found that it induced glucosuria, polyuria, weight loss, and started using the diabetes model around 1900. And for a long time people worked on this particular substance. And really by the early 1970s, research with Fluyzin really had began and there was a resurgence in the 1980s and 1990s in using it clinically for diabetes. After some Animal models showed that it worked for diabetes in diabetic dogs that had had their pancreas removed. Neil, how do they work?
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Well, it's really an exciting new class of medicines that wasn't around John when we were in medical school, and we never thought of the kidney as being instrumental for diabetes glucose control. But every day approximately 180 grams of glucose are filtered through the glomeruli and almost all of that glucose is reabsorbed. 90% of it is reabsorbed by SGLT2, which is located in the proximal tubules. In type 2 diabetes, renal glucose resorption is increased due to upregulation of SGLT2. This class of agents, the SGLT2 inhibitors, reduce A1Cs in general by about 0.5 to 1% by increasing the amount of glucose that goes out through the urine due to inhibition of reabsorption of glucose. The mechanism of action basically involves inhibiting the SGLT2 in the proximal Nephron, and it reduces glucose resorption and increases glucose excretion by up to approximately 80 grams a day. Because the action is independent of insulin, SGLT2 inhibitors may be used at any stage of type 2 diabetes even after insulin secretion has decreased. And interestingly, as we'll see in one of the articles that we'll review, there's a question about whether it might also be useful in type 1 diabetes. Additional potential advantages of this class of agents include modest weight loss, about 2 kg that stabilizes over 6 to 12 months, consistent lowering of systolic and diastolic blood pressures, roughly in the order of 2 to 4 millimeters of mercury systolic and 1 to 2 diastolic. The side effects also come logically from the mechanism of action. With increased glucose in the urine, there's increased genital mycotic infections at a rate about 11% higher in women and 4% higher in men compared to placebo. In some studies, a slight increase in urinary tract infections was shown. The medications also possess a slight diuretic effect due to increased glucocuria, so symptoms related to volume depletion may occur. SGLT2 inhibitors are also less effective when the estimated GFR is below 45-60ml per minute because they're going to be less effective at causing glucose inhibiting glucose resorption. Currently, there are three approved SGLT2 inhibitors on the market. Canagliflozin, also called invocana, which was FDA approved in March of 2013. Dapagliflozin or Farziga FDA approved in January of 2014 and empagliflozin, also called Jardiance, FDA approved in August of 2014. There are also additional SGLT2 inhibitors in the pipeline. The American Diabetes Association's recent update on the management of hyperglycemia and if our listeners are interested in hearing about that statement in detail just for the podcast where Silvio and Zucci goes over the management of hyperglycemia and the new update in a recent podcast shows that they can, as is true of many other agents, fit in a broad area as second line agents after Metformin. John now let's go over our articles.
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C
Our first articles from Diabetes Care and it compared canagliflozin on its improvement in glycemic control and body weight over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin. So in this particular study there were 1400 patients that were randomized in a double blinded fashion to either canagliflozin 100 or 300 milligrams or glimepiride during a 52 week core period and that was followed by a 52 week extension at the end of 104 weeks. The decrease in a 1C was minus 0.65 and minus 0.74 in the two canagliflozin arms and minus 0.55 in the glimepiride arm. They also showed reductions in body weight of about 4% in the two canagaliflozin arms and an increase of about 1% in the glimepiride arm. Decreases in blood pressure were found in the canagulaflozin arm with a decrease of 2 to 3 millimeters of mercury, but there was an increase of 1.7 millimeters of mercury in the glimepiride arm. The overall adverse event incidence was in the 70 percentile for all three arms and the incidence of discontinuation was 6% in the 100 milligram arm, 9.5% in the 300 milligram arm and 7.3% respectively in the glimepiride arm. The incidence of genital mycotic infections, UTIs, osmotic duresis related adverse events were higher in the canagulafozin than the glimepiride arm, but they were generally mild to moderate intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with the canagliflozin 6 to 8% versus 40% that was found in the glimeporide arm.
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Neil John this article nicely illustrates some of the real advantages of SGLT2 inhibitors. The article showed that canagliflozin decreased weight by about 4% or roughly 10 pounds versus an increased weight with the sulfonylurea, less hypoglycemia by a lot. That's an impressive number 8% versus 40% and a slight decrease in blood pressure versus increase in blood pressure. So really all with equal or non inferior A1C control. So the article as you went over it really illustrates nicely some of the benefits of this class of agent. Our next article is on the efficacy and safety of canagliflozin when used in conjunction with insulin therapy in patients with type 2 diabetes. There's limited data about the effects of SGLT2 inhibitors when used with insulin. This study was a double blind placebo controlled trial that randomized participants to Prevent Placebo Canagliflozin 100 or 300 milligrams once daily in addition to a range of therapies. The primary endpoint of the study was a 1C change from baseline at 18 weeks. 52 week effects were also examined. Over 600 individuals were randomized in each arm of the trial who were on insulin at baseline and then randomized to placebo. Canagliflozin 100mg and canagliflows in three 300mg. The mean A1C on entry to the trial was 8.3. The mean BMI was 33 and mean GFR was 75mls per minute. The median daily insulin dose for these people was 60 units. Most were using basal bolus insulin. A1C reductions with canagliflozin 100 and 300mg versus placebo were negative 0.62 and negative 0.73 at 18 weeks and negative 0.58 and negative 0.73 at 52 weeks. There were significant falls in fasting plasma glucose, about a 2% decrease in body weight and a decrease in blood pressure at both time points and a greater incidence of hypoglycemia, genital mycotic infections and hypovolemia with both canaglifloz and doses.
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John so in our first article we looked at using canagalaflozin plus metformin. In this article we look at using canagalaflozin with insulin and it really seems to do a nice job. Has a nice A1C reduction. People have lower blood pressures, people lose weight. So it seems to be a possible medicine to add on to insulin. Remember, this is our medicine that is completely insulin independent and really shouldn't really be expected to have hypoglycemia. So I think we can, as we're kind of putting together a kind of a spreadsheet in our mind of medicines. I think we're going to say the SGLT2s in type 2 diabetics and this study did well with an add on medicine meeting all the metrics we look for in an add on medicine. Our next article is from Diabetes Care and it looked at dapagliflozin on glycemic control and body weight reduction as an add on therapy to metformin plus sulfonylurea. It was a 24 week randomized double blind clinical trial. So in this particular trial looked at patients who had a 1Cs between 7 and 10.5 who were already on sulfonyurea and metformin were randomized to receive dapagliflozin 10 milligrams per day or placebo for 24 weeks with roughly about 220 patients in the total study. What they found is compared to placebo the plagliflozin lowered A1C 0.69. A larger percentage of patients got their glycemic control to an A1C below 7 with the pegliflozin being close to 32% versus 11% for placebo. The reductions in body weight and systolic blood pressure with a decrease in about 2.1 kilos and 3.8 millimeters of mercury of blood pressure. They did find that the patients who received dapagliflozin had increases in their total and LDL cholesterols of about 11 and an increase of their HDL cholesterol about 2.2. There were no changes in the LDL to HDL cholesterol ratio or triglycerides. Adverse events occurred in 48% of the patients receiving dapagliflozin and 51% receiving placebo. Significantly more patients with topagliflozin compared with placebo experienced hypoglycemia approximately 13% versus 4% in genital infections 5.5 versus 0. The events of urinary tract infections were reported by 6% of patients in both groups.
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Neil John, I think this trial is interesting and it rounds out some of the discussion we've been having. So in the first article that you reviewed we saw canagliflozin used as add on to metformin versus a sulfonylurea and showed it doing quite well, having the same A1C control but decreasing weight and less hypoglycemia. Now we're seeing, so we see it working well, an SGLT2 inhibitor working well as a second agent in addition to metformin. Here we're looking at a different SGLT2 inhibitor, dapagliflozin, working very nicely as a third line agent added to metformin anisulfonyuria. Both of those circumstances are ones which we commonly encounter. So when we use it as add on to metformin anasulfonylurea, what we see is that it has a very nice A1C, very nice A1C control. We see that. Remember in our first study we saw very low incidence of hypoglycemia in comparison to the sulfonylurea. Here we're seeing excellent weight loss, a weight loss of about five pounds. And one of the things that I think is important when we think about A1C control and this trial illustrates nicely is that people entering into the trial had slightly over hemoglobin A1C slightly over 8%. There was an average decrease in A1C in the dapagliflozin group of about 0.7. I've heard residents sometimes say, well, if it only gets a 0.7 decrease and they're over 8, we're not going to reach goal. It's important to always remember clinically that the numbers that we hear mean numbers, which means patients as individuals respond individually. So a third of the patients entering with a mean A1C of 8 actually achieved the goal A1C of less than 7. So it really serves nicely as a third line add on agent after metformin and sulfonylurea in patients who are not controlled with a 1C somewhere around 8, a bit above 8 with a third of patients reaching goal and having very nice A1C control with a low incidence of hypoglycemia and the additional benefit of some weight loss. Our next study is titled exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes. This was a two week dose ranging randomized double blind placebo controlled proof of concept study enrolling 70 stable adults with type 1 diabetes with A1C7.10% who are receiving treatment with insulin with one of four dapagliflozin doses 1mg, 2.55 or 10mg versus placebo changes from baseline with administration of dapagliflozin 10mg by day 7 were negative 41mg per deciliter for 24 hour daily average blood glucose levels negative 63mg per deciliter for mean amplitude of glycemic excursion. For every efficacy parameter. The 95% confidence intervals for all dapagliflozin doses overlap those for placebo. Those strongly suggested a response, John.
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So now as we're kind of putting together SGLT kind of work box, I think this particular study now we can look at adding it to type one diabetics. So the question is, why would you, if you already have someone whose type 1 diabetes has to be on insulin and they're taking basal bolus insulin, why do you need to add on a particular medicine? Well, I think interestingly, within a week we saw that there was an overall decrease of about 20% for the need for bolus insulin. So I think as a very practical level for our patients to have to do less coverage with meals I think is a good thing. And certainly we're seeing basically all the other things that we saw in different studies. So it is effective. A1C wise lowers blood pressure, lowers body weight, and certainly I don't think is a bad idea. Our next article from Diabetes Care looked at the combination of empagliflozin and linagliptin as second line therapy in subjects with type 2 diabetes that was inadequately controlled on metformin. In this particular study of around 500 patients that were already on metformin, subjects were randomized to a combination of either empagliflozin 25 and linagliptin 5, empagliflozin 10 mg and linagliptin 5 empagliflozin 25 mg, empagliflozin10 mg or linagliptin5 mg as add on to metformin for 52 weeks. The primary endpoint was baseline A1C change at 24 weeks. At 24 weeks, a reduction in A1C in the combination medicines were superior to those in either medication alone. The Change from baseline A1C was minus 1.19 in the 25.5mg combination, minus 1.08 in the 105 combination. There was a decrease of 0.62 in the empagloflosin 25mg pill, a decrease in 0.66 in the empagliflozin 10mg pill and a decrease in 0.7 in the linagliptin 5mg pill. In the combination group, 61% and 57% of folks who had A1Cs greater than 7 achieved an A1C less than 7 compared to 32 and 28% in the two empagliflozin groups and 36% in the linagliptin group. Efficacy was maintained at week 52 and the proportion of subjects with adverse events over 52 weeks was similar across all the different treatment arms with no hypoglycemic adverse events requiring assistance.
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Neil John this combination of an SGLT2 inhibitor and a DPP4 really provides a nice additional option. Recently actually just a few weeks ago FDA approved for use in the United States. We really see that the combination potentially can give you greater than on the average greater than 1%, 1.2% decrease in a 1C and in that group the highest dose group looked at over 60% of patients achieved the A1C goal of less than 7. So we really live in exciting times with lots of options and when someone isn't controlled on metformin alone, this really is a nice option. A single pill combination SGLT2 DPP4 with good outcomes in this study. Our next study is on initial combination therapy with empagliflozin and linagliptin in subjects with type 2 diabetes. The study looked at individuals not receiving any therapy for greater than 12 weeks randomized to empagliflozin 25 mg, linagliptin 5 mg, combination empagliflozin 10 mg, linagliptin 5mg, empagliflozin 25mg or empagliflozin 10mg or linagliptin 5mg all for 52 weeks. The primary endpoint was a change from baseline A1C at 24 weeks. Mean A1C at baseline was 7.99 to 8.05% at week 24. Adjusted mean changes from baseline in A1C with the combination empagliflozin 25, linagliptin 5mg, empagliflozin 10mmg, linagliptin 5mg, combination empagliflozin 20 5mg alone, empagliflozin10mg alone and linagliptin 5mg alone were negative 1.08%, negative 1.24%, negative 0.95%, negative 0.83% and negative 0.67% Reductions in A1C were significantly greater for empagliflozin 25mmg linagliptin 5mg combination compared with linagliptin 5mg but not compared with empagliflozin 25Mg and were significantly greater for empagLiflozin 10Mg linagliptin 5Mg combination compared with the individual components.
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John so our final paradigm of the day is using these medicines in a combination as first line agents for folks with type 2 diabetes, and certainly these medications work. I think my takeaway from this article isn't that I would forego using metformin to use this add on combination that's now available, but certainly it is an alternative to folks who cannot tolerate metformin as a first line therapy. But certainly we've looked at SGLT2 inhibitors in all these different situations and it's been kind of an interesting new class of medicines that hopefully we will be using safely and taking better care of our patients for a long time. I want to finish with A quote from J.R. tolkien, the author who wrote few can foresee whither their road will lead them until they come to its end. So certainly we are on the SGLT2 road. We've had a couple stops along the way in this article and we'll kind of find out where it ends.
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For more information and links to the articles that we discussed in this issue, just go to www.diabetesjournals.org. until next week, keep listening and keep learning. Sam.