Medical Managment of Hyperglycemia - Diabetes Core Update Special Editon January 2015

Summary

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Diabetes Core Update: Special Edition – Medical Management of Hyperglycemia (January 2015)

Podcast: Diabetes Core Update
Date: January 30, 2015
Host: Dr. Neil Skolnik
Guest: Dr. Silvio Inzucchi, Co-chair of the ADA/EASD Hyperglycemia Management Position Statement, Yale Diabetes Center

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Overview

This special edition of the Diabetes Core Update podcast covers the January 2015 ADA/EASD position statement “Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach.” Dr. Neil Skolnik interviews Dr. Silvio Inzucchi, a co-chair of the committee that authored the update. The episode reviews highlights of the 2015 update, focusing on individualized glycemic goals, the role of lifestyle modification, updates on pharmacologic options, and the rationale behind new recommendations.

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Key Discussion Points & Insights

1. Patient-Centered Approach to Glycemic Targets

Timestamps: 03:53–05:46

• The guidelines reinforce individualization of glycemic goals based on patient characteristics.
• Aggressiveness of treatment should consider age, comorbidities, duration of diabetes, and life expectancy.
• For younger, healthier patients, stricter goals (A1c ≈ 7%) are reasonable. For elderly and those with significant comorbidities, less stringent targets are safer.
• The main benefit of glucose control is reduction in microvascular risk. The effect on macrovascular risks remains less certain.
• Special emphasis on avoiding hypoglycemia in high-risk groups.

"The approach in a newly diagnosed individual in their mid-40s will be different from someone who begins treatment in their mid-80s."
— Dr. Silvio Inzucchi (03:57)

2. Role of Lifestyle Modification and Initial Pharmacotherapy

Timestamps: 06:31–07:42

• The 2015 update softens prior recommendations that all patients start metformin immediately upon diagnosis.
• Lifestyle modification is strongly encouraged as first-line when possible.
• If a patient can attain target glycemia with lifestyle alone, pharmacologic therapy may be delayed.

"If you have patients who are doing well with lifestyle changes alone, [there’s] no reason to move to pharmacotherapy until you have to."
— Dr. Silvio Inzucchi (07:28)

3. Metformin Use and Renal Function

Timestamps: 08:55–12:20

• Discussion of metformin’s safety profile in patients with chronic kidney disease (CKD).
• The panel recommends using estimated GFR (eGFR) over creatinine for dosing decisions, aligning with UK’s NICE guidelines.
  • Continue metformin if eGFR >45.
  • Halve dose if eGFR 30–45.
  • Discontinue if eGFR <30.
• FDA guidelines (based on serum Cr) may be too conservative.

"Many of us have petitioned the FDA to reassess these guidelines to see if, number one, could we base them more on estimated GFR as opposed to simply creatinine."
— Dr. Silvio Inzucchi (10:21)

• The risks with metformin are far lower than historic concerns (mainly attributed to the older biguanide, phenformin).

4. Approach to Marked Hyperglycemia

Timestamps: 12:56–15:26

• For newly diagnosed patients with very high A1c (>9%) or significant hyperglycemia, consider dual therapy from the outset.
• Basal insulin is preferred if blood glucose is very high (e.g., >350 mg/dL or A1c >10–11%), or if symptomatic.
• Once stabilized, can attempt to transition to oral agents.

"We don't want people to start metformin monotherapy in patients who present with blood sugars of 400. That just doesn't make sense and it's potentially dangerous."
— Dr. Silvio Inzucchi (15:15)

5. Updates on Specific Drug Classes

Timestamps: 16:35–23:49

a. Thiazolidinediones (TZDs) and Bladder Cancer

• Early data suggested bladder cancer risk with pioglitazone, but more recent long-term studies (Kaiser Permanente, European data) do not support this risk.
• The potential for benefit remains for appropriate patients, especially now that TZDs are generic and affordable.

"So I think at this point there are more papers suggesting no risk at all than those that had indicated a small increase in risk."
— Dr. Silvio Inzucchi (18:42)

b. Incretin Therapies (DPP-4 inhibitors, GLP-1 receptor agonists)

• Recent reviews by the FDA and EMA do not support an increased risk for pancreatic neoplasia or pancreatitis.
• More long-term data pending, but current evidence lessens concern over pancreatic risks.

c. SGLT2 Inhibitors

• Recognized as a class with evidence for A1c reduction, modest weight loss, and blood pressure lowering.
• Now equally considered as an option for dual therapy after metformin, alongside sulfonylureas, TZDs, DPP-4 inhibitors, GLP-1 agonists, and basal insulin.
• Expense and individual patient factors should be weighed.

"Now we have six credible drug choices after metformin."
— Dr. Silvio Inzucchi (22:41)

• Cost remains a significant concern, especially as newer agent classes are 100x more expensive than generics but not 100x more effective.

6. When to Add Insulin, and the Role of Combinations

Timestamps: 23:49–29:59

• Insulin can be considered after metformin (dual therapy), but many patients prefer to exhaust oral options first.
• Basal insulin is the initial recommended insulin strategy.
• For patients uncontrolled on multiple agents, adding basal insulin is usually necessary.
• GLP-1 receptor agonist + basal insulin is now a highlighted combination:
  • Similar (even superior) efficacy to basal-plus-mealtime insulin.
  • Less risk of hypoglycemia.
  • Greater benefit for weight loss.

"Basal insulin plus GLP1 receptor agonist... this combination has now been demonstrated to be as effective and without as many side effects as adding three mealtime insulin injections."
— Dr. Silvio Inzucchi (27:22)

• Practical consideration: high cost for GLP-1 agonists, balanced against reduced complexity (e.g., weekly injections) and improved side effect profile.

7. Summation and Paradigm Shifts

Timestamps: 30:06–31:14

• The 2015 update introduces significant shifts:
  • Reinforced emphasis on individualized care.
  • Expanded options after metformin.
  • Major role for basal insulin/GLP-1 agonist combination in complex cases.
  • Cost and patient preferences are central to all decisions.

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Notable Quotes & Memorable Moments

• On patient-centered care:
  "We first have to have a very frank discussion with the patient and their families as to how aggressive to be."
  — Dr. Silvio Inzucchi (03:58)

• On lifestyle:
  "All of us who take care of patients can think of those individuals who really did a marvelous job of finally attending to diet and exercise and were able to control their diabetes without medicines."
  — Dr. Neil Skolnik (07:46)

• On metformin safety:
  "The incidence of lactic acidosis in metformin-treated patients is significantly lower than with phenformin. In fact, most studies have demonstrated that the risk is essentially the same as in untreated diabetic patients."
  — Dr. Silvio Inzucchi (10:58)

• On evolving drug options:
  “They [SGLT2 inhibitors] are about 100 times more expensive, and they're certainly not 100 times more effective... but I think we just have to be very realistic and incorporate these financial issues into our treatment decisions.”
  — Dr. Silvio Inzucchi (23:18)

• On GLP-1 and basal insulin combination:
  "The hemoglobin A1C reductions were essentially identical. In fact, in some studies there was a slight favor to the A1C reductions with the GLP1 basal insulin combination. In addition, there seem to be less hypoglycemia, which makes sense and also marked differences in weight."
  — Dr. Silvio Inzucchi (28:13)

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Recommended Listening Segments (Timestamps)

• Patient-centered goal setting: 03:53
• Lifestyle therapy vs. immediate metformin: 06:31
• Metformin and renal function: 08:55
• Managing marked hyperglycemia: 12:56
• Drug safety updates (TZDs, incretins, SGLT2i): 16:35
• Advanced pharmacologic options and paradigm shifts: 24:20
• New strategies after basal insulin: 27:22

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Conclusion

This episode provides a practical, current overview of the 2015 ADA/EASD hyperglycemia management guidelines, highlighting a patient-centered, flexible approach. It acknowledges the expanded armamentarium of diabetes medications, the need for individualized care, the newfound role of the basal insulin/GLP-1 agonist combination, and a frank discussion on the realities of cost and flexibility in therapy.

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For more details, the full position statement is available at the American Diabetes Association’s website.

Transcript

[A]

Welcome to the American Diabetes Association's Core Update. While we usually go over the most important articles from the core journals published by the American Diabetes association, today we will cover the 2015 position statement titled Management of Hyperglycemia in patients with type 2a patient centered approach, published in the January 2015 issue of Diabetes Care. Joining us today will be our usual host, Dr. Neal Skolnik, as well as one of the co chairs of the position statement, Dr. Silvio Inzucci. Dr. Skolnick.

[B]

Thank you Amy, and welcome to this special edition of Diabetes core update. In 2012, the American Diabetes association and the European association for the Study of Diabetes published a positional statement titled Management of Hyperglycemia in patients with type 2A patient centered approach. January 2015 the committee released an update of that report. The original report was really fantastic in offering a less prescriptive approach to choosing medicines than the previous guidelines had, and it really emphasized an individual approach to both setting glycemic targets and choosing medicines for patients to help us achieve the targets that we set with them. The original position statement, in my opinion has been, and the opinion of others has been incredibly helpful for giving all of us a well thought out, organized approach utilizing individual patient characteristics to help choose among the increasing numbers and classes of medicines in order to tailor our approach to individual patients. Given the continued emergence of both new medicines and clinical trial data, both the ADA and the ESDA requested an update to the position statement, so the committee met over the last summer a number of times. Joining us today, one of the co chairs of the committee that developed the position statement, Dr. Silvio Anzucci, is joining us. Dr. Anzouchi is a professor of medicine and Director of the Yale Diabetes Center Section of Endocrinology, Yale University School of Medicine, Yale New Haven Hospital in New Haven, Connecticut welcome Dr. Anzutchi.

[C]

Thanks very much Neil for having me to update you on the new position statement from the ada and the EASD.

[B]

Since we only have about 20 minutes to discuss the statement, we'll really narrow our discussion to the highlights of the statement and we really encourage our listeners to go to the American Diabetes Association's website at www. Diabetes.org to download and read the full position statement as we talk about the update. Since it's an update to the previous position statement, but not a complete rewrite of it, we'll try to review some of the most important points from the previous that are still applicable. For our first question, While clearly glucose control is the major focus in management of patients discussed in the position statement, we don't want to forget that management of glucose occurs in the context of our comprehensive management of patients, particularly management of their cardiovascular risk factors, including smoking cessation, healthy lifestyle, blood pressure control, lipid management with statin medicines, and for some patients, antiplatelet therapy, but relevant to glucose control. Silvio, can you discuss the patient centered approach that the guidelines emphasize and how individual patient characteristics should influence our decision, particularly with regard to goal setting of glycemic targets?

[C]

Sure. So this is the first aspect to the original position statement. We tried to reiterate this with the 2015 update that before you even start talking about which medical strategies we use, we first have to have a very frank discussion with the patient and their families as to how aggressive to be. So the approach in a newly diagnosed individual in their mid-40s will be different from someone who begins treatment in their mid-80s. And much of this has to do with the long term benefits of glycemic control. For the most part, this is related to the reduction in microvascular risk we've discussed previously. The impact of glucose control on macrovascular risk, such as stroke and myocardial infarction remains controversial. And as you nicely pointed out, we can do a lot better by focusing on blood pressure and lipids and healthy lifestyles in order to reduce the incidence of cardiovascular disease. So glucose control is, I wouldn't say solely something we do to prevent microvascular complications, but that's where the, a large part of the evidence rests. So in someone with limited life expectancy, someone with many comorbidities, I think that glucose control, while I wouldn't say takes a back seat to other issues, may not be the central focus of their care. So if controlling hemoglobin A1c down to a euglycemic level were easy, then this would be a no brainer. We invoke tight glucose control in everyone, but we all know that, particularly in the elderly individuals, achieving a very tight hemoglobin A1C is very, very difficult, particularly difficult to do without hypoglycemia. So we just have to have a realistic and logical approach to the management of glucose in all of our patients.

[B]

That makes sense. So the guidelines really go over that nicely. And it's become something that my sense is that people are finally getting that while there's that average a 1C of 7 for younger people, lower, maybe better, and as you said for our elderly, much less stringent goals than 7 make, make a lot of sense because of really what has emerged as critical issues around problems with hypoglycemia let's move on to therapeutic choices. Can you say a few words about the place of lifestyle management when we see patients with newly diagnosed diabetes? Is it important? And do medications always need to be started right upon diagnosis?

[C]

You know, I actually feel no previous statements have suggested that as soon as someone's diagnosed that metformin should be used basically on day one. And we kind of backtracked a little bit from that in the original position statement using the terminology that Metformin should be used as first line therapy at diagnosis or soon thereafter. And I think the point we're trying to make is that we've all seen patients who really embrace lifestyle once they're diagnosed and make wonderful lifestyle choices and are able to reduce their hemoglobin A1C significantly. I think in that individual it would be a mistake to use Metformin, not allowing them the opportunity to control their glucose through lifestyle. Remember that Metformin is a generally safe medication. It's also incredibly inexpensive, but in most circumstances it's has to be taken twice a day. It's a large pill, it has some GI side effects. And my own feeling, and I think that of the group is that if you have patients who are doing well with lifestyle changes alone, no reason to move to pharmacotherapy until you have to.

[B]

I was thrilled to see that decision, the change from previous guidelines, because it always made sense to me to emphasize lifestyle. That emphasis on lifestyle, even if someone doesn't fully achieve it, helps them for years to come, sets the right stage. And while it's a minority of patients that are able to turn things around, I think all of us who take care of patients can think of those individuals who really did a marvelous job of finally attending to diet and exercise and were able to control their diabetes without medicines. Once the decision to use medicines is made clearly Metformin is the initial medication of choice. Can you say a few words specifically about the issue of metformin use in patients with mild to moderate renal insufficiency? I know you recently wrote a wonderful systematic review of the topic that was published in December in jama. And it's something that comes up fairly frequently. And could you say where Metformin, how we should view metformin use in that fairly large group of patients?

[C]

Absolutely. The popular drug Metformin has been used in the US since 1995. It remains the most popular anti hyperglycemic drug in the country and indeed in the world. And I think we all know as clinicians that we have many patients who are into their 70s and 80s and many doing well on metformin. But of course, with aging, there comes a natural decline in renal function. And according to the current package label, which is endorsed obviously by the fda, we're supposed to stop the drug when the serum creatinine hits 1.5 in men, 1.4 in women. I think many of us in the diabetes community have had some problems with that. It's a set of guidelines that was initially developed in 1994 when metformin came before the FDA. And I think that the taste, the sour taste of fenformin was still in the mouths of the FDA regulators at that time. You might recall that in the 1960s and 70s there was a drug called fenformin which is in the same class, the biguanide class. It's kind of an older cousin of metformin, but it was associated with higher rates of lactic acidosis. And therefore there was a lot of concern at the level of the FDA that we would basically be approving another drug that was going to have the same problems. As it turns out, the incidence of lactic acidosis and metformin treated patients is significantly lower than with fenformin. In fact, most studies have demonstrated that the risk is essentially the same as in untreated diabetic patients, that is, patients who are not taking metformin at all. So many of us have petitioned the FDA to reassess these guidelines to see if, number one, could we base them more on estimated GFR as opposed to simply creatinine. We know that EGFR is a better estimate of renal function, particularly in the elderly population. And we've also asked the FDA to relook at the use of metformin in those patients with mild to moderate ckd. So, just as a reminder, in England, there's a group called the NICE Coalition, which I believe stands for the National Institute for Clinical Excellence, and they feed guidelines to the National Health Service of the uk. And according to the NICE guidelines, they continue to endorse the use of metformin once the EGFR falls under 60, so long as the creatinine is not above 1.7. And a reduction in the dose of metformin is recommended once The EGFR hits 45. And the drug is not supposed to be stopped until the EGFR hits 30. So we've kind of adapted those guidelines to recommend that the FDA considered the following. Metformin is based on GFR. It's fine under 60. In fact, it's fine under 45. But at that point, you might consider halving the dose. Instead of 2 grams, just give 1 gram and then to stop the medication once the EGFR hits 30. Of course, this implies that the patient is reliable, attends their office visits, you have regular blood work, and understands the need for the discontinuation of that medication as their renal function declines further.

[B]

That's fantastic. And it really opens up the use of this important first line medicine to a lot of other people who might not otherwise have it and for whom there often are not other optimal choices either.

[C]

Yeah, that's the point, is that sometimes you have to move to something else to control glucose. And very often that's either a sulfonylurea that particularly in the aging population and especially those with declining renal function, may be more dangerous in terms of hypoglycemia risk, or one of the newer medications, which are extraordinarily expensive. So there's limited options, particularly those on fixed budgets.

[B]

Yeah. So it's pretty clear metformin is first line therapy for most patients. How about patients who come in with very elevated blood sugars, who present initially with very elevated blood sugars and a 1Cs of 9, 10, 11 and above? What would be the recommended approach for those patients?

[C]

Well, they're hyperglycemic, but not necessarily catabolic, so they're not losing weight, they don't have any ketones in their urine. So you're not concerned about them potentially slipping into DKA? I think as long as the hemoglobin A1C is above 9%, you could consider beginning with two drugs. Now, is there any immediacy to controlling a hemoglobin A1C of 9.5%? Not really. But I think we all know that these Drugs lower hemoglobin A1C about 1%, maybe 1.5%, rarely up to 2%. So that you can do the math. If you're trying to get somebody down to 7% from 9.5%, you're probably going to need two drugs. So the question is whether you start stepwise, beginning with one drug and then another, or move right to combination therapy. And I think the committee felt that it would be not unreasonable to start with two drugs. But certainly if you prefer a stepwise approach, as long as you're moving in the right direction, that's fine too. Now, when you're talking about people with very high glucoses greater than 300, 350, hemoglobin A1C's of 10, 11, 12% at that point, basal insulin at the very least becomes a really important option. It's unlikely that you will be able to get these patients down to target just with oral agents. And, and insulin is probably going to be at least part of the therapeutic program in that individual. So early insulinization is key. It'll get the blood glucose down. The nice thing about insulin is that it almost always works where with these oral agents, some patients are non responders. You really don't want to waste a lot of time if somebody is very polyuric and getting dehydrated with that higher glucose. So move to insulin right away and then consider even mealtime insulin or other strategies as well. And you can always have the opportunity, as the patient's blood glucose improves, to back off on the insulin and maybe transition them back to oral agents. But I think that's important. We don't want people to start metformin monotherapy in patients who present with blood sugars of 400. That just doesn't make sense and it's potentially dangerous.

[B]

Those are great points. I think one point worth emphasizing is that when you start with basal insulin in that group of patients with very elevated A1Cs, it doesn't mean you have to be on it forever. As you said, there's that issue of glucose toxicity. And once the glucose goes down, it may be easier to keep it down than getting it down. And those are patients who, if they also then begin paying attention to diet, exercise, and their blood sugars are down a little bit, they might be able to be maintained on oral agents. But initially, for those with very high glucoses, basal insulin makes, makes the most sense and most predictably lowers their blood sugars. Before we discuss what medicines to use next after metformin, the position statement specifically discusses the place of a new agent since the last statement, the SGLT2 inhibitors. Some new information about TZDs and bladder cancer, as well as information about the incretin mimetics and pancreatic safety. Can you review some of that information for our listeners?

[C]

Sure. Let's start with the TZD question. You know, the TZDs had become quite popular in the mid 2000s. And then the controversy began with the rosiglitazone meta analysis that suggested that these drugs that came to market in large part because they were suspected of reducing cardiovascular risk, the question was whether rosiglitazone could actually aggravate the risk of at least myocardial infarction. So the story became very, very confusing. And then we had other issues, obviously with weight gain and edema and an increased risk of heart failure with any tzd. And then the bone fracture question was risen in a couple of the studies with rosiglitazone and then confirmed with pyoglitazone. So there was a lot of baggage with these drugs. And the straw that kind of broke the camel's back was this suspicion of bladder cancer with pioglitosome but not rosiglitosome. Many of us in the diabetes community looked at the initial data with great suspicion. The relative risk, or the hazard ratio, I should say, for bladder cancer was quite modestly increased, something in the 20 to 30, maybe 40% range. In epidemiological research, we're taught that anything above, or I should say below, a twofold increase in risk may be just as likely related to uncontrolled confounding issues such as the what's known as allocation bias, which is the reason a person is allocated to a certain drug in clinical practice and may not have anything to do with the drug itself. In addition, we all know in practice that people who get prescribed TCDs tend to be more advanced in terms of their diabetes. And diabetes itself is felt to be by many a risk factor for bladder cancer. So some of us were a bit suspect of the initial data. And what's happened is that the large study, the Kaiser Permanente of Northern California study that initially raised the question of bladder cancer in a, I believe it was a 2011 manuscript that was a five year analysis of a 10 year planned study showing this 20 to 40% increase in risk that has come to a conclusion, that study. So now they have the 10 year data and although it's not been published yet, I think it's imminently going to be published. The top line announcement from the researchers and the company who makes pioglitazone was that the 10 year results showed no increased risk, which was relief to many of us who still use this medication. And there's been a large meta analysis as well, suggesting that the risk is minimal, even if it is there. And finally, a large retrospective study that was just published last month in diabetologia showed no increase in risk. So I think at this point there are more papers suggesting no risk at all than those that had indicated a small increase in risk. So we felt as a committee that we would alert the prescribing physicians to this fluctuating database now, suggesting that the original concerns about bladder cancer and pioglitazone are rapidly evaporating. So I have continued to prescribe this medication. I would point out that it is now generically available and while not as inexpensive as a sulfonylurea or metformin. It is exceedingly cost effective. So I think that's an important point, particularly in those who are paying out of pocket for their medications. The other safety issue that we thought we needed to comment on was that involving the incretin based drugs. So These are the DPP4 inhibitors and the GLP1 receptor agonists. Obviously the concern has been with the pancreas, both with pancreatitis as well as with pancreatic cancer. And we highlighted the FDA and the European version of the FDA called the EMA that they co published the paper in the New England Journal, reviewing extensive data on these drug classes. And their conclusion is that there was really no evidence of significant increase in the risk of either pancreatic neoplasia or pancreatitis. Does this close the door on this potential link? No, I think we have to wait for some of the well controlled clinical trials that are currently underway or in fact closing out over the next year or two before we truly understand whether there is a risk. But I think the concerns that had arisen over the past two to three years are also diminishing and I think that's good news for us that continue to prescribe these medications. And then the final, I'm sorry, the final update was regarding the SGLT2 inhibitors. This is a new drug class and we thought we had to comment on it because it has been increasing in popularity, mainly because it's one of the few classes that is associated with some weight loss, although that weight loss is relatively modest. We felt that the SGLT2 inhibitors, which lower glucose through inducing glucosuria, so patients essentially urinate out their glucose with significant reductions in hemoglobin A1c and also some impact on body weight, as mentioned in blood pressure, that this drug class seems to be as good as others that have been used after metformin. And we actually included it as a dual therapy potential drug for patients who are not being controlled with metformin monotherapy. So it was kind of on par with a sulfonyria, a TZD, a DPP4 inhibitor, a GLP1 receptor agonist or basal insulin. Now we have six credible drug choices after metformin. And again as you mentioned, consistent with what we felt in 2012, the group in 2015 says that you really have to think about your patient, what do they need? How much glucose lowering effect do they need? What are the issues in terms of adverse effects with the drug class in terms of hypoglycemia weight gain, other side effects. I mean, we know our patients the best, we know which drugs are probably not good choices for this individual. And also costs. I mean, costs are extremely important. We talked about the generic versions of sulfonylureas, metformin, now TZDs. These other agents, DPP4 inhibitors, the GLP1 agonists, and the SGLT2 inhibitors, are about 100 times more expensive, and they're certainly not 100 times more effective. They may have some side benefits, they may have some decreases in certain adverse effects, but I think we just have to be very realistic and incorporate these financial issues into our treatment decisions.

[B]

The algorithm really is a wonderful one. Looking at drugs through the lens of efficacy, hypoglycemia, side effects, weight effect, and cost, and then deciding for the individual patient what to use when, and then the question, so you start with metformin, you add an additional drug, maybe a third medication. When should physicians consider the use of insulin and how should it be started?

[C]

Well, insulin can be used as a phase two drug, so it could be the first drug you add to metformin. I personally don't move to insulin that early. I think that just being realistic, most patients, if they can take an oral medication, they would prefer that. But in those patients that are quite a far distance from their hemoglobin A1C target, particularly if they're getting frustrated with managing their diabetes and just would like an effective agent and don't want to try a drug and see how they respond and adjust the dose and maybe move to a third drug, if they just say, hey, I just want the next strategy to be effective, then I think that's a good basal insulin candidate as long as they're willing to inject. So it's certainly a strong contender as a phase two drug. Realistically, however, most patients, particularly now with the fixed dose combinations, which are essentially one pill, even though you're getting two drugs, most patients would like to stick to two oral medications first and certainly beyond dual therapy. Once you start getting into triple therapy, while many patients might prefer three drugs, the options start running out, particularly if you have some contraindications where you can't use a certain drug class, and then basal insulin becomes a stronger contender as a triple therapy, a part of triple therapy. And of course, if even at three oral drugs, the patients are not well controlled, then at that point, I think the writing's on the wall that their beta cell secretory capacity is so impaired that you just need to supplement their insulin. And that is a very effective way of getting them under control. There is this other injectable class known as the GLP1 receptor agonists. Those are increasing in popularity to some degree, at least in specialty circles. I'm not sure how the drug is doing in primary care circles, but this is an incretin based therapy that has the advantage of weight loss more than you see with the SGLT2 inhibitors. And in some patients it can be substantive. There have been patients at least in my practice that have lost 10, 15, 20 pounds, although on average the weight loss is relatively modest, somewhere in the three to five pound range. This is now a that at least in this position statement update, we tried to underscore that the evolving evidence base is now emphasizing that this drug class GLP1 receptor agonist in combination with basal insulin is quite effective. It's something that could have been done with the 2002 algorithm. You could get to GLP1 plus insulin or insulin plus GLP1. But in the 2015 update we thought that the evidence base was so strong that we decided to underscore this potential combination of basal insulin with the GLP1 receptor agonists. @ the bottom of the chart that we call Figure two. This combination has now been demonstrated to be as effective and without as many side effects as adding three mealtime insulin injections. This is something that I never thought would be shown because I've always thought that the so called Cadillac treatment for insulin requiring diabetic patients would be basal insulin once a day and then mealtime insulin. One of these rapid acting analogs such as lispro or aspart three times a day. Almost like a type 1 diabetes patient. I mean how could you get more potent than four injections a day? As it turns out, much to my surprise, when the studies were done showing basal insulin plus the GLP1 receptor agonist in combination compared to basal insulin plus three additional mealtime injections, the hemoglobin A1C reductions were essentially identical. In fact, in some studies there was a slight favor to the A1C reductions with the GLP1 basal insulin combination. In addition, there seem to be less hypoglycemia, which makes sense and also marked differences in weight. So with mealtime insulin you gain a few pounds. With GLP1 receptor agonist you lose a few pounds and the difference is quite substantial. So a large meta analysis was recently published when we were preparing the document. It just been published showing that this Strategy, basal insulin plus GLP1 receptor agonist, is something to be considered. It's not for all patients, for sure. There are. Not everyone's going to respond to a GLP1 drug. And also there's some GI side effects that you have to be careful of. And then there's this price issue, which is extremely an extreme concern of mine, particularly with the GLP1 receptor agonists that are in the range of 400 to sometimes, depending on dose, $600 a month. I'm not sure that can be justified based on how equally effective they are to other agents. But I think we pointed out that if that is not a concern in terms of someone's insurance status, that it's maybe a simpler combination after basal insulin, as opposed to having to check blood sugars three times a day and adding mealtime insulin three times a day, maybe just once a day. Some of these are now once a week. GLP1 receptor agonist with basal insulin could be just as good. So it's just something to keep your eye on in terms of an evolving treatment strategy that we focused on in the physician statement update from 2015.

[B]

Yeah, I thought that was incredibly exciting. It really represents in many ways a paradigm shift for what to do after basal insulin and an incredibly less complicated approach, particularly, as you said, with the weekly GLP1 agonists, to have one shot a week instead of three extra shots a day, and with that, get less hypoglycemia and achieve some large difference in weight. It's pretty amazing. Well, thank you, Dr. Anzutshi, for going over things in such detail. I think this is incredibly helpful for our listeners. We covered a lot of ground from glycemic targets to new medicines to new information on old medicines to how to start with lifestyle and or metformin, what medicines to use, then insulin, and a whole new approach with GLP1 agonists when basal insulin alone isn't working. I think this was fantastic for our listeners, A lot of learning and really want to thank you for joining us.

[C]

Well, thanks for having me. It was fun.

[B]

For the American diabetes association, I'm Dr. Neal Skolnick.

[C]

Thanks for listening, Sam.

[A]

It.