The Management of Patients With Diabetes: An Overview
In this episode, Dr Harrison and Deny Sung, MD, discuss diabetes case presentations, the diagnostic criteria for diabetes, and the advantages and disadvantages of therapy options, including metformin, glucagon-like peptide 1 agonists, sodium-glucose transport protein 2 inhibitors, and more.
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Anil Harrison, MD, is the Program Director and Chair of the Internal Medicine Residency Program at the University of Central Florida and HCA Florida West Hospital (Pensacola, FL). Dr Harrison is board certified in India and the United States.
Deny Sung, MD, is an internal medicine resident at St Joseph's Medical Center (Stockton, CA).
TRANSCRIPTION:
Moderator: Hello everyone and welcome to Multidisciplinary Dialogue: Clinical Rounds and Case Reviews with your host Dr Anil Harrison, who is the program director and chair of the Internal Medicine Residency Program at the University of Central Florida and HCA, Florida West Hospital in Pensacola, Florida. Today we have diabetes case presentations that Dr Harrison and Dr Deny Sung will analyze and provide treatment insights. Dr. Sung is an internal medicine resident at St. Joseph's Medical Center, Dignity Health in Stockton, California. The views of the speakers are their own and do not reflect the views of their respective institutions or the views of Consultant360.
Dr Deny Sung: Good morning everyone. Good morning, Dr Harrison.
Dr Anil Harrison: Good morning everyone. I am Anil Harrison, and with me is Dr Deny Sung.
Dr Deny Sung: Today we intend to talk about a couple of scenarios with diabetes and perhaps go over its management in general and its impact.
Dr Anil Harrison: Let's start. What questions do you have for me?
Dr Deny Sung: Before we start discussing our cases on diabetes, what are the diagnostic criteria for diabetes mellitus?
Dr Anil Harrison: That's a great question, Deny. So the diagnostic criteria for diabetes mellitus are if a person has a hemoglobin A1C greater than 6.5 or a fasting blood sugar that is more than 126-milligram percent, or if on a random blood sugar, if it's more than 200-milligram percent. On a glucose tolerance test, if you have any number that is over 200-milligram percent, that tells one that the person has diabetes.
Dr Deny Sung: Thank you for that, Dr Harrison. Now let's start with our patient. This case is about a 60-year-old with a history of coronary artery disease who was recently admitted with a diagnosis of heart failure and has an ejection fraction of 30%. Laboratory evaluation shows a hemoglobin A1C of 8.5%. Her medications include Atorvastatin, 40 milligrams once a day, lisinopril 40 milligrams once a day, and on physical exam, her blood pressure is at target, which is below 130 over 80 millimeters of mercury. And she has nonproliferative retinopathy. Her labs include an LDL cholesterol, which is less than 70 milligrams percent, and a GFR of 60. What will we do next?
Dr Anil Harrison: Thank you, Deny. That is a great scenario. So before we begin talking about our patient, it is imperative that each treatment plan for a diabetic must be individualized. So let us first take a look at the glycemic targets. The ADA recommends a hemoglobin A1C of less than 7%, and they would like for a fasting blood sugar to be between 80 to 130 milligrams percent and postprandial blood sugars less than 180-milligram percent. The American Association of Endocrinology recommends an A1C of less than 6.5%, a fasting blood sugar that is less than 110 and a two-hour postprandial blood sugar of less than 140-milligram percent. So when we talk about lowering the hemoglobin A1C, what really are we trying to achieve? Is it just a number that we have to get down or has this proven to reduce, number one, deaths related to diabetes, microvascular complications, and myocardial infarctions?
The answer is yes. So giving you an example, a reduction in the hemoglobin A1C by 1% reduces myocardial infarctions by 14%, deaths and microvascular complications by 37%. So it is important, therefore, to get one's hemoglobin A1C below, and as I mentioned with the 1% drop, there is a significant reduction in MIs, deaths, and also in microvascular complications. This, therefore, tells us that the approach to the management of diabetes must be individualized for every patient. If the risk for hypoglycemia is low, one would recommend one would be more stringent with diabetes control as opposed to if the risk for hypoglycemia and adverse events was high, one should be less stringent in diabetes control. Similarly, depending on the disease duration. For example, if the diabetes is newly diagnosed, one should be more stringent as opposed to someone with long-standing diabetes where one can be less stringent.
You'd agree, Deny, it makes sense, also, if a person has fewer comorbidities. One could be more stringent as opposed to someone who has several comorbidities where one would be careful and less stringent in their diabetes control. Also, if a person does not have vascular complications, one should be more stringent while if on the other hand, if a person has significant vascular complications, bad CAD, bad PAD, bad kidneys, then one has to be less stringent in their diabetes control. Also, I'd like to mention if resources are abundant, one can be more aggressive with diabetes control, as opposed to if the resources are lacking.
Therefore, the individualized glycemic target has to be balanced with the benefits of stringent control versus the adverse events including hypoglycemia along with the cost of treatment. As you know, Dr Sung, there are 12 choices of medications for diabetes. We have the sulfonylureas, the glinides, insulin, the GLP-1 analogs. GLP-1 is a glucagon-like peptide, DPP-4 inhibitor. We've got the amylin analogs, we've got alpha-glucosidase inhibitors, we have colesevelam, we have Bromocriptine, we have SGLT2 inhibitors, which stands for sodium-glucose-like transporter two inhibitors. We have Biguanides, we have Thiazolidinediones called TZDs. So of the 12 choices of current anti-hypoglycemic medications, remember there are two categories, namely insulin and sulfonylureas, which need to be remembered, which can cause hypoglycemia.
Dr Deny Sung: Thank you very much for that, Dr Harrison. Now we'll briefly get in touch with the algorithm on how to control a patient's blood sugar. Okay, so if you could explain a little bit about that, Dr Harrison.
Dr Anil Harrison: Sure, Dr Sung. Out of all these guidelines, recommend metformin as first-line therapy for type two diabetes, whether a person has atherosclerotic cardiovascular disease or not. The next thing to consider after putting a person on metformin is what is the patient's hemoglobin A1C? If it is less than nine, then one should consider using a GLP-1 agonist or an SGLT2 inhibitor.
The other choices going down the line would be a DPP-4 inhibitor, and I have put an asterisk against the TZDs sulfonylureas and basal insulin for reasons that we will discuss later. If the hemoglobin A1C is more than nine, then one might consider a GLP-1 agonist before going to treating the person with insulin. Otherwise, starting with basal insulin is what is recommended If the hemoglobin A1C is more than nine.
After you've done this, you might want to consider a GLP-1 agonist and/ or an SGLT2 inhibitor. And if you go down the list, you could add a DPP-4 inhibitor or a Thiazolidinedione, also called TZD. Remember Dr Sung, if cost is a consideration, which does happen on occasion, then along with lifestyle modifications and metformin, those would be your first line. Other medications, which cost less, would be your sulfonylureas, your TZDs, also called Thiazolidinediones, and human insulin.
Dr Deny Sung: Dr Harrison, what would be a reason for choosing metformin as a first-line agent?
Dr Anil Harrison: That's a great question Dr Sung. You see the advantages of metformin being that it reduces the hemoglobin A1C by one to 2%. Also, it is inexpensive. It has a high initial response rate. It does not cause weight gain, and as a matter of fact, it causes modest weight loss. It also has advantages with cholesterol and reduces macrovascular complications, which was observed in studies.UKPDS mentioned that it is cardioprotective. This should always of course, be accompanied by lifestyle changes, which can also achieve reductions in hemoglobin A1C by 1 to 2%.
Dr Deny Sung: Does it have any disadvantages?
Dr Anil Harrison: Absolutely, Dr Sung. Anything that you take has its advantages and disadvantages. So the disadvantages of metformin would be, that it can cause gastrointestinal side effects, such as, and the most common one is diarrhea, and it usually happens with higher doses of metformin. Remember, metformin is contraindicated if the GFR is less than 30. One has to half the dose when the GFR is between 30 to 45. And remember, it is contraindicated when a person has congestive heart failure. Similarly, one must withhold metformin before surgery and imaging studies using Iodinated media. By the way, it has a very small risk of causing lactic acidosis as well.
Dr Deny Sung: Thank you, Dr Harrison. And what if after you start Metformin, your hemoglobin A1C is still high? What would you do then?
Dr Anil Harrison: So what I would do after having begun metformin, if the hemoglobin A1C is still not at goal, starting either a GLP-1 agonist or an SGLT2 inhibitor would be my next step, especially if the patient has risk factors for atherosclerotic cardiovascular disease. Subsequently, if the hemoglobin A1C does not still come down, another choice would be to add a DPP-4 inhibitor. The above choices would precede the usage of TZDs, your Thiazolidinediones, sulfonylureas, glinides, and basal insulin, etc.
Dr Deny Sung: Thank you very much for that, Dr Harrison. Now, could you talk a little bit more about the GLP-1 agonist and the SGLT2 inhibitors, please?
Dr Anil Harrison: Absolutely, Dr Sung. So, while deciding between a GLP-1 agonist or an SGLT2 inhibitor, besides insurance coverage, the important thing while making a decision is whether the patient would like oral formulations or injectable formulations. So the SGLT2 inhibitors are mostly oral preparations while the GLP-1 agonist are mostly injectables. The GLP-1 agonist can lower hemoglobin A1C from 0.5 to 1.5, whereas the SGLT2 inhibitors lower the hemoglobin A1C from between 0.5 to 2.7. The GLP-1 agonists work by reducing gastric emptying. They cause early satiety and they also increase insulin secretion while reducing glucagon secretion. So as we know, the DPP-4 inhibitors increase the halflife of GLP-1 agonists by inhibiting the enzyme that destroys GLP-1 agonists.
The glucagon-like peptide GLP-1 agonist mimic the natural hormone that is produced by the intestines would stimulate the beta cells of pancreas to produce more insulin. And while doing this to have an inhibitory effect on the glucagon production. This will also reduce gastric emptying to enable carbs being absorbed slowly. So while talking about the GLP-1 agonist in patients with type two diabetes, the short-acting ones are exenatide and lixisenatide, while the long-acting ones are liraglutide daily, exenatide weekly, albiglutide, dulaglutide, semaglutide, which comes in the subcutaneous and oral forms, the GLP-1 agonist and with glutide except for exenatide.
Dr Deny Sung: And what are some things that one might consider when using a GLP-1 agonist, Dr Harrison?
Dr Anil Harrison: Sure, Dr Sung. So the advantages of a GLP-1 agonist are that it causes weight loss. Along with the benefits with the cardiovascular system, there is a reduction in cardiovascular events and it ranges from 13 to 25%. The GLP-1 agonists are also renal protective, which means they protect the kidneys. And it's also been shown that the GFR decline gets lowered as time goes by. So in summary, a GLP-1 agonist helps reduce the incidence of heart attacks, strokes, and helps slow down the progression of kidney disease while intensifying to the injectable therapies in type two diabetes, which is before thinking of adding basal insulin.
So it makes sense to consider a GLP-1 agonist before delving into using insulin. I'd like to also mention the injectable forms come in a pen form and are dosed either once daily or once weekly. As mentioned, Semaglutide also has an oral form, pill form. Now it has disadvantages. I'm talking about the GLP-1 agonist. They are expensive. Most of them are in the injectable form. They can cause GI side effects such as nausea, bloating, and fullness. The contraindications for GLP-1 use would be if there is a history of pancreatitis or if a person has a family history of a multiple endocrine neoplasia type one syndrome or if the patient has a personal or a family history of medullary thyroid cancer.
Dr Deny Sung: Thank you Dr Harrison. Now you mentioned another category of diabetic medications, something called an SGLT2 inhibitor. Could you tell us a bit about how they work, ts benefits, and some of its side effects please?
Dr Anil Harrison: Sure, Dr Sung. So the SGLT2 inhibitors work by inhibiting the absorption of glucose in the proximal convoluted tubule at the S1 segment. Therefore, it gets rid of the body's sugar along with calories. So it's a winner. As mentioned, SGLT2 inhibitors as monotherapy cause a drop in hemoglobin A1C between 0.5 to one. Because you're losing sugar along with calories, SGLT2 inhibitors cause weight loss as well. With the SGLT2 outcome trials, it was found that SGLT2 inhibitors reduce cardiovascular risk for MI, stroke and death by about 14% and they're also useful for heart failure by reducing it from 20 to 30%. So therefore the SGLT2 inhibitors like the GLP-1 agonist are renal protective. The SGLT2 inhibitors, Dr. Sung, they end with the letters flozin, such as empagliflozin, canagliflozin, dapagliflozin, canagliflozin. So the disadvantages, it has disadvantages. I'm talking about the SGLT2 inhibitors, they cause glycosuria and so there is a higher incidence of urinary tract infections as well as genital fungal infections.
By the way, the SGLT2 inhibitors can also cause non-hyperglycemic diabetic ketoacidosis and they've also been found to increase the risk of fractures. Therefore, in the management of type two diabetes, GLP-1 agonists as well as the SGLT2 inhibitors are recommended for cardiovascular and renal protection. The beauty of using the GLP-1 agonists or the SGLT2 antagonists is they should be considered independently of what the patient's baseline hemoglobin A1C is or in trying to attempt an individualized hemoglobin A1C target. So you'd agree Dr. Sung, taking the above three categories of medications, namely metformin, GLP-1 agonist, and SGLT2 antagonists, it would make sense to start with metformin, an independent of glycemic control, if there is established atherosclerotic cardiovascular disease or the patient is at high risk in folks with CKD or chronic kidney disease stage three, or folks who have heart failure with reduced ejection fraction. You have to think about starting either a GLP-1 agonist or an SGLT2 inhibitor. In some cases the question might arise if the cost is a major issue. In that scenario, you start with metformin and consider sulfonylureas, TZDs and human insulin.
Dr Deny Sung: Now getting back to our case, and I'll briefly read again about this case. It is about a 60-year-old patient with a history of coronary artery disease who was recently admitted with a diagnosis of heart failure and an ejection fraction of 30%. Laboratory results review a hemoglobin A1C of 8.5. Some of her medications include Atorvastatin 40 milligrams, Lisinopril 40 milligrams, and physical exam shows a blood pressure which is at target and that is below 130 over 80 milliliters of mercury. And she also has nonproliferative retinopathy. And lastly, her LDL cholesterol has been less than 70 milligrams percent and she has a GFR of 60. Now for this patient, Dr. Harrison, how would you go about treating her diabetes and her management of diabetes?
Dr Anil Harrison: Sure, great question, Dr Sung. So what I would do is we will start with lifestyle changes along with starting on metformin at 500 milligrams, let's say twice a day, and then consider either adding a GLP-1 agonist or an SGLT2 antagonist. And of course we should also add low-dose aspirin. I'm glad that on Atorvastatin, her LDL is below 70-milligram percent. That is where we want it. So our thoughts being with lifestyle changes, we could reduce the hemoglobin A1C in our patient by one to 2%. We hope to reduce hemoglobin A1C by one to two with metformin, 0.5 to 1.55% with a GLP-1 agonist and 0.5 to 0.7% with an SGLT2 inhibitor taking into consideration that the latter two are being instituted once again independent of the patient's hemoglobin A1C.
Dr Deny Sung: That sounds great, Dr Harrison. Thank you very much for that. Now, could we discuss about some of the other medications that can be used in the treatment of type two diabetes and what is the order in which you should use these different classes of medications?
Dr Anil Harrison: Most certainly Dr Sung. While insulin can reduce hemoglobin A1C up to 3.5%, sulfonylureas can reduce hemoglobin A1C by one to 2% while the long-acting insulins might be expensive. The other formulations of insulin along with sulfonylureas are inexpensive though remember both insulin and sulfonylureas can cause weight gain and hypoglycemia. With sulfonylureas, we are not sure about the cardiovascular safety and they have to be used with caution in patients with hepatic and renal dysfunction. As far as the lipid goes or the lipid panel goes, with blood sugar lowering, this might help in reductions with triglycerides. We also have the DPP-4 inhibitors. The advantages of these medications being that they are weight neutral. They also have a favorable adverse effect profile. They do not cause hypoglycemia. They have no contraindications in folks with heart failure and renal insufficiency, and they can be used as monotherapy and also with sulfonylureas, TZDs, metformin, and even insulin.
The disadvantages of the DPP-4 inhibitors being that it can cause nasopharyngitis, upper respiratory infections, and the cost, on occasion, can be prohibitive. The DPP-4 inhibitors reduce hemoglobin A1C between 0.5 to 0.8% and they end with gliptin such as alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin. Remember the TZDs, the one that is available in the market is pioglitazone and it has the advantages of reducing the hemoglobin A1C by one to 2% and they also reduce insulin resistance. By the way, they do not cause hypoglycemia.
They are inexpensive and can be dosed as once daily and these medications also have cardiovascular protection. The disadvantages being weight gain, slow answer of action. They can cause edema, they can worsen heart failure and they do cause osteopenia and bone fractures. So you'd agree Dr. Sung, what we have learned with the management of type two diabetes with lifestyle modifications, which are very important, Metformin would be the first medication to be added with care being instituted when the GFR drops below 45.
And in that scenario you have the dose of metformin and you definitely stop metformin if the GFR falls below 30. The next thing to consider is if the patient has significant atherosclerotic cardiovascular disease or is at high risk such as age greater than 55 or the patient has coronary carotid or lower extremity stenosis greater than 50%. Or if the patient has left ventricular hypertrophy, it is advised to start the patient on a GLP-1 agonist or an SGLT2 inhibitor. If further intensification is required to lower the A1C after using a GLP-1 agonist or an SGLT2 inhibitor, the next choice would be a DPP-4 inhibitor followed by basal insulin, followed by TZDs, followed by sulfonylureas.
On the other hand, if heart failure or CKD, chronic kidney disease predominates especially for heart failure with reduced ejection fraction less than 45% and GFR between 30 to 60, an SGLT2 inhibitor will predominate. If one cannot use an SGLT2 inhibitor or further hemoglobin A1C lowering is required, then add a GLP-1 agonist. SGLT2 inhibitors should be avoided if the GFR is less than 30. Having said that, TZDs should be avoided in folks with heart failure and therefore a DPP-4 inhibitor would be the next medication to be added followed by basal insulin. And last of all, sulfonylureas.
Dr Deny Sung: So this case is a 22- year- old female with a history of type one diabetes that was diagnosed over 15 years ago, who's presenting with multiple episodes of hypoglycemia that happens during the night. Her fingers stick, blood sugars range from 70 to 280-milligram percent. She takes insulin glargine 30 units a night and six units of lispro before meals. And she also has a correctional factor with insulin scale insulin. She also has a correctional factor with sliding scale insulin for blood sugars greater than 180-milligram percent. Labs include a blood glucose of 180-milligram percent, hemoglobin A1C of 8.5% and GFR of 60 milliliters per minute.
Dr Anil Harrison: So the two important things that we realize with our patient are suboptimal glycemic control since her hemoglobin A1C Is at 8.5 along with our patient who also happens to have multiple episodes of nocturnal hypoglycemia, which is not cured. Studies have revealed that only 10 to 30% with type one diabetes have optimal glycemic control, and that is a shame. The other thing is the occurrence of severe hypoglycemia is at about 6%. For folks receiving insulin after the age of 50, it goes up to 10%.
Another important aspect is what is the occurrence of diabetic ketoacidosis in relation to a person's hemoglobin A1C? With the hemoglobin A1C ranging from seven to 8%, the incidence is less than 2%. However, if the hemoglobin A1C is at 10, the incidence of DKA goes up to about 10%. And if the hemoglobin A1C is 11 or more, the chances of DKA are at about 17%. It is also a well-known fact that intensive insulin therapy versus conventional therapy provides a greater reduction of the development of retinopathy. Therefore, Dr. Sung, you'd agree goals of treatment are to prevent acute and long-term complications while maintaining target glucose.
Dr Deny Sung: Thank you, Dr. Harrison. So how do we proceed from here? Should we institute multiple daily injections of rapid-acting insulin with meals combined with a daily basal insulin, or do you think a continuous subcutaneous insulin infusion using an insulin pump or a closed-loop system like an artificial pancreas if this method would be better?
Dr Anil Harrison: That's a great question, Dr, Sung. So let's take our patient first. Our patient was checking fingerstick blood sugars four to five times a day. How feasible is that? What are the limitations? And remember, fingerstick blood sugars only measure blood glucose levels in a single point in time and provides no indication of the direction or the velocity of changing glucose levels. For example, if a fingerstick blood sugar done right now is 100-milligram percent, it doesn't tell one, how have the sugars been in the past several hours, and where are the sugars headed in the future? Fingerstick blood sugars also frequently miss hypoglycemic events in particular when the patient might be asymptomatic or asleep. Therefore, Dr. Sung, it makes sense that we institute continuous subcutaneous insulin infusion via an insulin pump or a closed loop system, also called an artificial pancreas with very importantly, along with continuous glucose monitoring, which is also called CGM.
Dr Deny Sung: That makes sense. However, what should we do?
Dr Anil Harrison:
So to circumvent these issues, a continuous form of monitoring would be better. This would tell one the blood sugars at any point. It should tell one the history and the graph with presets for low blood sugars and high blood sugars. It'll also tell you your daily, your weekly, your monthly averages, and hence the advent of, and the use of CGM or continuous glucose monitoring, which tells one your average glucose, what is the pattern, what percent is in range, what percent is below range or above range. Meta-analysis of continuous glucose monitoring has shown great evidence and utility. If one can monitor the blood sugar continuously, wouldn't it make more sense that the insulin supply should also be in tune? The insulin pump, also called continuous subcutaneous insulin infusion offers a continuous administration of rapid-acting insulin analogs via a small subcutaneous plastic catheter with the amount of insulin to be administered predetermined by the provider and then included in the pump settings.
Dr Deny Sung: That sounds great. Dr. Harrison. Could you talk a little bit more about the subcutaneous insulin pumps?
Dr Anil Harrison: Absolutely. So the anatomy of the insulin pump offers a small flexible plastic cannula, which is inserted into the subcutaneous tissue by a small retractable needle. There is a tubing that connects to the insulin reservoir, which holds about 200 to 300 units of insulin. For pump therapy, the glucose on the meter transmits the readings to the pump to assist with bolus-calculated dosing. The sensor talks to the pump to suspend when it reaches hypoglycemic threshold or before low glucose occurs. With a hybrid closed-loop system, in recent years, the development of closed-loop systems, which links insulin delivery to sensor glucose levels have started to transform management of type one diabetes.
These closed-loop systems utilize an algorithm that automatically adjusts insulin delivery via an insulin pump based on real-time sensor glucose levels. So Dr. Sung, in conclusion to improve care in type one diabetes, the major advances in diabetes technology include the ability to use CGM or continuous glucose monitoring values to make treatment decisions, remote monitoring, data reporting and management platforms, and progressive integration of continuous glucose monitoring along with insulin pumps for type one diabetes.
Dr Deny Sung: Thank you very much, Dr. Harrison. Now, could you talk a little bit about basal and bolus insulin and how does one go about calculating the amount to be given to a patient?
Dr Anil Harrison: That's a good question again, Dr. Sung. So you'd agree it is worthwhile to discuss the basal and bolus doses of insulin required in a patient. The total daily insulin requirement equals 0.55 or 55% times the total weight in kilograms, and off the total amount that you calculate 40% can be given as basal insulin, whereas 60% can be given with meals. The prandial calculation is done using carb counting. Once you think of one unit of insulin for about 12 to 15 grams of carbohydrates, one should also take care of the correction factor. Now, how do you do that? The correction factor is the patient's blood sugar minus 100 divided by the total amount of insulin calculated for the day. Which means, for example, if the patient's blood sugar is 300, so 300 minus 100 equals 200, and you divide this by the total amount of insulin, which for example was calculated at 55 units in 100-kilogram person. This would equal something in the range of receiving three to four units of insulin as a correction factor.
So on our patient, what I would recommend on the 22-year-old that you mentioned with a history of type one diabetes for over 15 years, presenting with multiple episodes of hypoglycemia during the night with fingerstick blood sugars ranging from 70 to 280-milligram percent who takes insulin glargine 30 units at night and six units of lispro before meal, and a correction factor according to the sliding scale insulin for blood sugars greater than 80 milligrams, 180-milligram percent. What I would recommend is the institution of a continuous glucose monitoring and using an insulin pump because it would make more sense to help better control of diabetes in this patient and also avoid episodes of hypoglycemia and also help prevent progression of complications related to poorly controlled diabetes. So those are my thoughts, Dr. Sung.
Dr Deny Sung: Thank you, Dr. Harrison, for your great knowledge and your insights on diabetes management. Thank you everyone for listening in. Thank you very much.
Dr Anil Harrison: Thank you everyone