Welcome & Introductions
1 What are your criteria for starting ? insulin in patients with type 2 diabetes?
1. A1C level
2. Blood glucose level
3. C-peptide level
4. Family history
5. Duration
Today I am going to talk about when and why to initiate insulin, the use of analog therapy in type 2 diabetes, indications, and rationale.
2 Let’s see the answers. Interesting. Most of you look at the A1C level, and I am pretty sure that the speakers today are going to agree with you. Looking at blood glucose levels is also important. If we have a chance at the end we will talk about why C-peptide levels might not be a good way of doing it. And of course, family history does not have much, and duration probably is not that important. Very good.
3 How do you usually initiate insulin ? in a patient with type 2 diabetes?
1. Basal insulin alone (1 injection)
2. Premixed insulin (1 or 2 injections)
3. Long-acting insulin in the evening
4. Short-acting insulin to cover dinner/evening meal
5. Intensified basal/bolus regimen
Today I am going to talk about when and why to initiate insulin, the use of analog therapy in type 2 diabetes, indications, and rationale.
4 Well, we see that number 3, long-acting insulin in the evening, is the most popular among you. Basal insulin alone, one injection 24%. 17% of you are using premix insulin. Only 8% use short-acting insulins to cover dinner and evening. Which, by the way, is a very common program in Germany. And 5% use intensified basal bolus regimens from the beginning.
5 When and Why to Initiate Insulin Analog Therapy in Type 2 Diabetes: Indications and Rationale
Arturo R. Rolla, MD Consulting Endocrinologist Beth Israel Deaconess Medical Center Assistant Clinical Professor of Medicine Harvard Medical School and Tufts University School of Medicine Boston, Massachusetts
Today I am going to talk about when and why to initiate insulin, the use of analog therapy in type 2 diabetes, indications, and rationale.
6 Outline of Presentation
• Failure to meet glycemic goals in the majority of patients with type 2 diabetes • Goals of therapy and the central role of glycemic control • When should insulin therapy be initiated?
During my presentation I am going to explain why there is a failure to meet glycemic goals, in part because of the nature of the type 2 diabetes, but in great part because of failure of physicians to progress to insulin. I am going to remind you of what the glycemic goals are in the treatment of type 2 diabetes, and I am going to tell you when insulin should be initiated. Later on, Drs. Tibaldi and Cooppan are going to give you all the details about how to do it in practice.
7 Diabetes Control Is Bad …
…and Getting Worse
I do not need to tell you that control of diabetes is bad, and it is getting worse. In part, we are to be blamed because we should keep educating our patients. But diabetes is not an easy disease to control because it requires a number of changes in life habits; these are not easy. I always say that if I have to follow a diet, I do not know what I am going to do.
8 The Diabetes Epidemic: 2 of 3 Patients With Type 2 Diabetes Are Not Achieving Goal
I also have to remind you of the number of patients with diabetes—I am not going to give you the gory details—you know them very well. But following the increased prevalence of obesity all over the planet, we are now having an explosion in the number of patients with type 2 diabetes. These patients are also now appearing with higher blood sugars at younger ages, and this is going to lead to a number of chronic complications in the near future.
9 Fundamental Premise: Glucose Control Is Important
I do not want you to think that I am glocucentric, but the pancreas is the center of the universe, with the exception that insulin resistance is also important because it is the mother of all clinical problems that you see. Just remember that this interaction between insulin secretion and insulin resistance in skeletal muscles, liver, and adipose cells is the basis of the pathogenesis of type 2 diabetes.
10 Diabetes Control and Complications Trial: Absolute Risk of Retinopathy
Conventional Therapy Intensive Therapy 24 24 11% 10% 20 9% 20 Mean A1C 16 Level 16
12 12 Mean A1C 8% Level 8 8 9% 7% 8% 4 4 Rate per 100 Patient-years 100 per Rate Rate per 100 Patient-years 100 per Rate 7% 6% 0 0 0 123456789 0 123456789 Time During Study (years) Time During Study (years)
*DCCT = Diabetes Control and Complications Trial Diabetes Control and Complications Research Group. Diabetes. 1995;44:968–983.
Very important studies—Kumamoto, UKPDS, and particularly the DCCT—have shown us in a very clear way that glycemic control decreases the rate of complications, particularly microvascular complications. For every 1% in A1C that you decrease in your patients, you have a decrease in microvascular complications—such as retinopathy, nephropathy, and neuropathy—of approximately 35%. Also, with the prolongation of the DCCT study, EDIC, this control that you have for 5 or 6 years creates a metabolic memory in your patients, and they tend to have less macrovascular complications later on.
11 Targets for Glycemic Control*
• ADA target (for patients in general) A1C < 7.0% • Eur IDF and ACE targets A1C ≤ 6.5% • Normal A1C < 6.0% • ADA 2006: “The A1C goal for the individual patient is an A1C as close to normal (< 6%) as possible without significant hypoglycemia” • Realistic target: lowest A1C level possible without unacceptable adverse effects
*DCCT referenced assays: normal range 4%–6%.
What are the targets for glycemic control? It is important to remind you because this target has been changing. The classic target of the American Diabetes Association of 7% is not tenable anymore. The American College of Endocrinology, the International Diabetes Federation, the World Heath Organization, etc., have changed, and now we are requiring 6.5%. Normal, of course, with the new ways of determining A1C as less than 6%. The ADA this year have changed their position a bit and they said that “as close to normal as possible without significant hypoglycemia.” We should be realistic because we cannot have this same very strict A1C target for all our patients. From a practical point of view, the best control that you can have in your patients is the best control they can have without ruining the rest of their life, particularly without having unacceptable side effects. We are talking mostly about hypoglycemia.
12 Targets for Glycemic Control
Measurement Eur IDF (mg/dL) Normal “Low Risk”ADA Goal ACE Goal
Preprandial < 100 < 11090–130 < 110
Postprandial < 140 < 145*< 180* < 140 (2 hour)
*Peak value
The targets you know well. Before meals, less than 100 is normal. After a meal, even with very large carbohydrate meals, blood sugars do not go above 140 mg. Mother Nature abhors hyperglycemia and tries to keep it, with a very complicated system, as normal as possible, even after large carbohydrate meals. For the IVF in low-risk patients, less than 110 mg/dL and postprandial less than 145 is normal. The ADA is still vague with between 90 and 130 fasting and less than 180 any time after the meal. The ACE is more specific, requiring less than 110 mg/dL and postprandial less than 140. Remember that type 2 diabetes is called type 2 because it requires 2 determinations of blood sugars a day: fasting in the morning and 2 hours after the main meal, which is usually dinner or supper. So when you’re following your patients, it is very important to know the fasting blood sugar every day and then the 2-hour postprandial blood sugar to be able to follow these patients. In any patient with diabetes, every day is metabolically different, and for that reason we have to check this.
13 What to Do When OADs Fail to Maintain Control in Type 2 Diabetes
• Reemphasizing diet and exercise produces at most a 1% reduction from baseline; maximum effect is at 3 months • If on 2 first-line oral therapies, a third oral agent will result in a further reduction of A1C levels of only 1% or less – Do not add a third agent if A1C > 8.0% – Chances are that most patients will not reach target level – It’s time to consider insulin
What do you do when oral agents fail? Most of us still think: Mrs. Jones is going to start running the marathon, follow a very strict diet, and drop her glycohemoglobin with diet and exercise. In reality, this does not work. Diet and exercise do work, human nature does not work. You have to understand that because you might just sit there waiting for the patient to change their life habits. Nuns and monks change habits, humans do not. Therefore, you can waste a lot of time with glycohemoglobin of 9, 10, and 11%. Be realistic. If one oral agent fails you can use 2. If 2 fail, you can use 3. But remember that as you add an oral agent, the most you’re going to get in the drop of A1C is 1%. So if your patient on 2 oral agents has an A1C of more than 8%, it will be very unlikely that adding a third oral agent is going to bring them to target. Because of this, we need to realize that we have to start these patients on insulin earlier. The entire paradigm of diabetes means having to move everything much earlier. We have to diagnose diabetes much earlier, start oral agents much earlier, and we have to start insulin much earlier.
14 Therapies for Type 2 Diabetes Glucose-lowering Potential
Therapy ↓ Fasting Glucose ↓ A1C
Secretagogues 30–70 mg/dL Up to 2.3%
Metformin 30–64 mg/dL Up to 2.2%
Thiazolidinediones 28–80 mg/dL Up to 2.6%
Incretins 20–25 mg/dL Up to 1.0%
Insulin > 100 mg/dL Unlimited
Kendall DM. Data adapted from multiple references.
These are the armamentarium that we have. The secretagogues, mostly sulfonylureas, can decrease—in this review, up to 2.3%. It is really too high. In general, with sulfonylureas, you get decreases of A1C of 1.5 or 1.8%. Same with metformin. In monotherapy, probably not that strong. But it is a great company to all the other treatments. Thiazolidinediones, you can get drops again, 1.5, 1.8%. We now have the incretins, such as Byetta; they’re not very powerful antihyperglycemic agents, but they have the added benefit of weight loss. Finally, insulin is the most potent of them all—you can use them in any patient and you can get very significant drops.
15 INSULIN: THE MOST POWERFUL AND VERSATILE AGENT WE HAVE WITH WHICH TO CONTROL GLUCOSE
Insulin, then, is the most powerful and versatile, and we will see later today you can use them in many different programs in your patients according to their metabolic needs.
16 If You Think Your Patients Need Insulin…
They Probably Do!
If you think your patients need insulin, they probably do; and you just have to avoid the procrastinations when starting them on insulin. It is a big obstacle for you and the patients, the initiation. But once you learn how to do it, and they are going to show you how, it is very simple.
17 Type 2 Diabetes Is a Progressive Disease: Over Time, Increasing Numbers of Patients Require Insulin
Patients 40 Requiring Additional Insulin (%) 20
0 1236 45 Years From Randomization
Adapted from Wright A, et al. UKPDS. Diabetes Care. 2002;25:330–336.
Patients on oral agents—and this is data from the UKPDS—about 10% per year of patients with sulfonylureas are going to fail. They have a secondary failure, and they go on to require insulin. I am going to call your attention now to the first year. About 15% of patients will fail oral agents from the beginning. These patients really do not have type 2 diabetes. They have autoimmune type 1 diabetes presenting in the adult, masquerading as type 2. You can recognize these individuals as LADAs, late-onset autoimmune diabetes of the adult. Number one, they are not that overweight. Blood sugars are very high. They do not respond well to oral agents, they go on to require insulin within the first year or so, and they have a marker in the blood, an anti-GAD, glutamic acid decarboxylase. The anti-GAD antibody you can get in any commercial laboratory. That is a very important marker for type 1 diabetes because it is the most common anti–islet cell antibody that we have. You check the anti- GAD. If it is positive, that patient requires insulin.
18 Indications for Insulin Therapy in Type 2 Diabetes
• Persistent hyperglycemia with oral agents • Uncontrolled weight loss • Latent autoimmune diabetes in adults (LADA) • Advanced renal or hepatic disease • Contraindications to oral agents • Intercurrent events: MI, CVA, acute illness, surgery • Women planning pregnancy • Gestational diabetes
Chan JL. Mayo Clin Proc. 2003;78:459–467.
When do we start a patient on insulin? Number one, and most important, when the A1C level is above the limits that you set as a target—6.5%, 7%, whatever. This is the most important indication. Fortunately, C-peptide does not help you as much. Remember, type 2 diabetes is a progressive disease that gets more and more hyperglycemic every year. Your wishful thinking that life habits and nature of the disease is going to change does not work. Type 2 diabetes gets more hyperglycemic because of the failure of the beta cells. The number of beta cells continues to decrease in these patients, and for that reason blood sugars continue to go up. If the patient has weight loss, that is a clear indication that they are too insulin dependent, they need insulin. If they have some contraindication to oral agents because of renal failure, liver failure, or congestive heart failure, and during acute events such as myocardial infarction, CVA during surgery, or women planning surgery who require a preconceived idea of control—these patients can use insulin. Also during gestational diabetes.
19 Why Start Insulin in Type 2 Diabetes?
• Timely initiation of insulin optimizes blood glucose and improves prognosis • A1C levels consistently > 7% indicate that a patient may benefit from insulin • After oral antidiabetic drug (OAD) failure, combination insulin + OAD can improve glycemic control with less weight gain than insulin alone • Some patients may benefit from insulin therapy as soon as diet becomes inadequate
Why do you have to start insulin in type 2 diabetes? We used to call it non–insulin- dependent diabetes mellitus, NIDDM, until very recently. We need to optimize the control of blood sugars in these patients, and type 2 patients deserve the same degree of control and monitoring as patients with type 1 diabetes. If the levels of A1C are consistently above 7%, for the ADA, the patients will require insulin. Also, if you are thinking about adding an oral agent and A1C is more than 8%, that patient will not get under control. You can consider as a transition or a more permanent treatment, the combination of insulin with oral agents. That has more of a psychological impact on the patient than a true metabolic impact. But about 30% of patients in the United States take insulin for type 2 diabetes. They are also taking oral agents. So this combined treatment, oral agents and insulin, can be used. Some patients, as I said, may require insulin very early, particularly if you are making the diagnosis of type 2 diabetes. The key question is their weight. If the patient tells you that they are losing weight at the time of diagnosis, you have to seriously consider that the patient is going to require insulin. If the patient’s weight is stable or gaining, you can use oral agents, diet, etc.
20 When Should Insulin Be Considered in Type 2 Diabetes Patients Naïve to Therapy?
Initial Intervention(s) A1C (%) Combine therapies as needed
Target: Oral therapies: metformin, TZD, SU 8–9 Insulin analog strategies: PPG and FPG basal, rapid-acting
Target: Oral therapies: metformin, TZD, SU 9–10 Insulin analog strategies: PPG and FPG basal, rapid-acting
Target: Insulin: rapid-acting insulin > 10 with NPH or basal analog or PPG and FPG premixed insulin analogs
http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf
These are some guidelines from the American Association of Clinical Endocrinologists. They are a little bit complicated. What it is telling you is that you start with one oral agent. If that does not work you go to 2 oral agents, or if that does not work you go to 3 oral agents. Adjust according to the levels of A1C that you have. In the transition you can use the combination of oral agents with insulin. My preference is when I start insulin immediately I stop sulfonylureas to prevent hypoglycemias and more weight gain. I keep the patients on thiazolidine and metformin for the next 3–6 months. Then I drop the thiazolidinediones, and I maintain the patient on metformin for a long period of time, especially if they are very insulin resistant and requiring more than 40 or 50 units of insulin a day. Again, these are different guidelines and you can start maximizing them.
21 When Should Insulin Be Considered in Type 2 Diabetes Patients Not Responding to Current Therapy? Initial A1C (%) Current Therapy Intervention Initiate Combination Therapy If on monotherapy: Metformin +SU or meglitinide meglitinide, SU, AGI, TZD +SU 6.5–8.5 metformin, TZD Incretin mimetic + metformin Premixed insulin analogs and/or SU or basal insulin Basal or premixed insulin analogs
If on combination Maximize Combination Therapy Maximize Insulin Therapy therapy: If elevated FPG, add basal SU, AGI, metformin, If elevated PPG, add bolus 6.5–8.5 TZD, incretin mimetic, If elevated FPG and PPG, Premixed insulin add basal-bolus therapy analogs QD or BID, or premixed insulin analogs tid basal insulin Add incretin mimetic to patients on SU and/or metformin Adaptation of: http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf
Another very important concept is that when you start insulin in a patient with type 2 diabetes, it is not the same system that your patient is going to follow for the rest of the disease. In the very early stages of insulin therapy in type 2 diabetes, even one injection of basal insulin is going to control 40– 50% of them.
22 When Should Insulin Be Considered in Type 2 Diabetes Patients Not Responding to Current Therapy?
Initial A1C (%)Current Therapy Intervention
Initiate insulin therapy that If on monotherapy or includes both FPG + PPG coverage: > 8.5 combination therapy Long-acting plus rapid-acting insulin, Premixed insulin analogs
Adapted from: ACE/AACE Diabetes Recommendations Implementation Conference. Road map for the prevention and treatment of type 2 diabetes. Available at : http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf
As the type 2 diabetes progresses, becomes more hyperglycemic, they lose more beta cells and are going to require more intensified treatment. You will have to go from just a basal injection to more than one injection. That is where you have to learn to make that change. Because increasing basal insulin to doses that are very high is only going to bring you more hypoglycemia, and it is not going to win your control. So the first big barrier is initiation of insulin. The second one that appears later, because of the intrinsic nature of type 2 diabetes, is the intensification of insulin therapy.
23 Conclusions
• Effective intervention begins with an uncompromising insistence to treat to glycemic goal • This involves early initiation of appropriate therapies, including insulin when appropriate • Treatment of type 2 diabetes, overall, needs to be intensified to bring more patients to goal and to reduce the burden of this disease
In conclusion, we need to take type 2 diabetes more seriously. It is a very common disease, and type 2 diabetes is not handled by us endocrinologists. It is handled by you internists. Eighty to 90 percent of patients with type 2 diabetes in this country and all over the world are being treated by internists, not by endocrinologists. You also know that we have to diagnose these patients much earlier. We have to start the treatment of these patients with oral agents much earlier, and we have to start insulin therapy much earlier. The treatment overall of type 2 diabetes needs to be intensified. I will finish by saying that type 2 diabetes is a multifactorial disease. Diabetes is bad because it has a lot of sugar, but is also worse because of the bad company it keeps. And you have to think of these patients not only in terms of their blood sugars, but also their weight, cholesterol, and you have to look at the blood pressures, etc. It is about multicontrol. As a recent Danish study has shown, all of this multicontrol of blood pressure and cholesterol is relatively easy with the medications that we have now. But glycemic control remains very difficult, mostly because you need to make very significant changes in your lifestyle, and human nature prevents prevention. Thank you very much.
24 Initial Insulin Strategies: Once- or Twice-daily Therapy With Insulin Analogs
Joseph M. Tibaldi, MD, FACP Assistant Clinical Professor of Medicine Albert Einstein College of Medicine Bronx, New York Director of Endocrinology Flushing Hospital Center Flushing, New York
Dr. Rolla: Being here gives me many pleasures, and one of them is to be able to share the podium with two very good friends—not only good friends, but also great speakers. The first speaker is Joe Tibaldi. He is an Assistant Clinical Professor of Medicine at Albert Einstein College of Medicine at the Bronx. He is also Director of Endocrinology at the Flushing Hospital Center in Flushing, New York. It gives me great pleasure to introduce Dr. Tibaldi to you.
25 Overview of Presentation
• Overview of insulin analogs and role in patients with type 2 diabetes • Role of basal (long-acting) insulin analogs in patients with type 2 diabetes • Role of biphasic (premixed) insulin analogs in patients with type 2 diabetes
Thank you, Arturo. Good morning, everybody. It is my pleasure to try to take you through insulin therapy, 1–2 shots per day. Our limit is going to be 2 shots a day. I am going to go up to 3 or 4 just briefly. So the overview will include the use of insulin analogs and the advantages. In particular, we are going to discuss the basal as well as the biphasic, or what I like to call the premixed insulin analogs, in people with type 2 diabetes.
26 Current Practice Insulin Initiation in Insulin-naïve Patients With Type 2 Diabetes
1 injection/ Other 64% Basal insulin day 95% 5%
Basal 2 Premix Other 31% Insulin injections/ 69% 1% 30% day
>2 Basal bolus Other injections/ 5% 84% 16% day
Source: NNPI Hybrid Segmentation Study; September 2002.
Let’s look at current practice. What we see here is very similar to what we did with the survey. In terms of insulin initiation in type 2 diabetes, the majority of people will choose a basal insulin. So that is why we are going to discuss starting with one injection and advancing onward. Two injections a day are less common, and a multiple dose regimen—it was 5% here, and it was 5% in our survey. It is very difficult to get somebody on 4 injections all at once. In general, with type 2 diabetes, most people are adding insulin onto orals. That is what we are going to see with the clinical trials.
27 Insulin Preparations
Class Agents
Human Insulin Regular, NPH
Insulin aspart, insulin glulisine, Insulin Analogs insulin lispro, insulin glargine, insulin detemir
Premixed Insulin Human 70/30, 50/50
Premixed Insulin Insulin lispro 75/25 Analogs Biphasic insulin aspart 70/30
In terms of the preparations, I trained over 20 years ago. I learned how to use human insulin. So I used regular and NPH, and I thought they were great. However, we now have insulin analogs, and the fast-acting ones are aspart, glulisine, and lispro. We also have basal analogs, such as glargine and detemir. The premixed insulins I learned to work with were human 70/30 and human 50/50. But what we are going to be discussing today are the premixed insulin analogs, lispro 75/25 and biphasic insulin aspart 70/30, and we are briefly going to mention lispro 50/50 as well.
28 Insulin Analog
Insulin produced by technology that uses recombinant DNA to produce an insulin molecule that is slightly different from human insulin in structure as well as pharmacokinetic/pharmacodynamic properties.
All right. So what is an analog? An analog is produced by technology that uses recombinant DNA to produce an insulin molecule that is slightly different from human insulin in structure as well as in pharmacokinetic/pharmacodynamic properties. So what does that mean?
29 Advantages of Insulin Analogs
• More physiologic time–action profiles • Lower postprandial glucose values • Mealtime dosing of rapid-acting analogs • More reproducible serum levels • Less variability • Less hypoglycemia
Disadvantages • Cost
First of all, in terms of advantages, you are able to get insulin that gives you a more physiologic time– action profile. This will also grant us, with the rapid analogs, lower postprandial glucose values. You can actually give insulin at the meals. You can give mealtime dosing of rapid-acting analogs. In terms of importance, we will later discuss reproducible serum levels, which have less variability. These go hand in hand because they lead to less hypoglycemia. What is the disadvantage? The cost. They are approximately twofold more expensive.
30 ACE Treatment Recommendations for Initiating Insulin Therapy in Patients Not Achieving Goals with OADs
• Premixed insulin analogs or A1C ≤ 8.5% basal + OAD
• Premixed insulin analogs A1C > 8.5% • Long-acting plus rapid-acting insulin
American College of Endocrinology. ACE road map to achieve glycemic goals: treated patients (type 2). Available at: http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf Accessed January 26, 2006.
So let’s come back to the concept Dr. Rolla talked about in terms of guidelines. AACE came out with recent guidelines looking at diabetes, and they used that magic number, 8.5. What 8.5 actually is, in my mind, is a surrogate measurement. These are going to be 8.5 in people already on orals. When the A1C is greater than 8.5, more than likely you are going to have somebody with fairly advanced diabetes. When the A1C is less than 8.5, it is less advanced. Let’s see what the recommendations are, and I’ll go through clinical studies trying to describe all of this. So if the A1C is less than 8.5 in people on orals, the recommendations are to use a premixed insulin analog or a basal plus oral medications. When the A1C is greater than 8.5, we can use premixed insulin analogs, but with long- acting insulin you need to add rapid-acting insulins with it at mealtime. I’ll come back to why that is the case.
31 When A1C > 8.5%
• Adding another pill probably will not work to reach goal • Higher success rate getting to goal with a basal–bolus approach • GLP 1 analog addition won’t reach goal
To summarize what Dr. Rolla said: If your A1C is over 8.5, he used a slightly lower number, by adding another pill it will not work. You are not treating the patient. You are going to get that higher success rate with a basal–bolus approach, as we will discuss. Lastly, there is a GLP analog addition. You won’t reach goal because the A1C drops with those medicines are about 1%.
32 Time–action Profiles of Insulin Products
Insulin Aspart, Insulin Glulisine, Insulin Lispro 4–6 hours
Regular 6-8 hours NPH 12–20 hours
Plasma Insulin Glargine, Insulin Detemir Insulin up to 24 hours Levels
0123 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hours
Skyler JS. Insulin treatment. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. 3rd ed. Alexandria, Va: American Diabetes Association; 1998:186–203.
Let’s take a look at the time–action profile of insulin products. I learned with regular insulin. I thought it was great. It takes an hour to peak; let’s look at what that duration of action is. It is about 6 hours. So, regular insulin lasts a quarter of a day. Let’s contrast it to the rapid analogs, aspart, glulisine, and lispro. They peak rapidly within 20 minutes, and most of the biological action is gone within 2 hours. This very much more closely simulates normal insulin physiology. What did I learn when I was a resident? NPH was great. Let’s take a look at NPH. It starts to work hours later and has a peak action at about 6 hours or so. Duration of action is about 16 hours, but what I did not know when I was a resident is how variable the serum insulin levels are with NPH. They jump up and down like crazy. Part of the reason my patients were getting poor blood sugar control was not that they were not being adherent to their therapies. It is because I was not giving them an insulin that worked quite as well as I thought it would. Now we have the new, slow-acting basal insulins, glargine and detemir, which last 24 hours. The beauty with them, in contrast to NPH, is reproducible serum insulin levels.
33 Correlation Between Insulin Variability and Incidence of Hypoglycemia
90 80 70 60 Hypoglycemia 50 (episodes per person per 40 year) 30 20 10 0 0 10203040506070
Within-patient Variability (CV) of Fasting Blood Glucose (FBG)
Heller SR, et al. Diabetologia. 2004;47(suppl 1):A303.
Let’s take a look at the study of hypoglycemia. Because what is it that patients fear when you begin insulin therapy? They fear low blood sugar. So if we look at the x-axis, the within-patient variability of the fasting sugar, versus hypoglycemia on the y-axis, the less variable the fasting is, the less likely you are to have hypoglycemia. You want to use insulins that are reproducible. You want to have patients that are happy. You want patients who are going to adhere to their therapies.
34 Long-acting Insulin Analogs
• Insulin glargine Gly(A21),Arg(B31),Arg(B32)-Insulin • Insulin detemir Lys(B29)-N-ε-Tetradecanoyl,Des(B30)-Insulin
The newer insulin analogs are much more stable in terms of their serum levels. When we think of the long-acting insulins, the first one that came out in the states was glargine. There were a few amino acid modifications made with the molecule. It was acidified. Upon injection it gets precipitated, and then there is a slow linear release over time. The newest addition in the states is detemir, with a minor amino acid modification in the molecule, but a free fatty acid is added. What does that free fatty acid do? Upon injection it binds in the soft tissues to albumin, and that protracts the effects. Upon release it never precipitates; it then binds in the serum to albumin, and that albumin binding is what gives it a protracted effect over 24 hours.
35 Basal Insulin Therapy
Breakfast Lunch Dinner
Plasma Insulin
Glargine or Detemir
4:008:00 12:00 16:00 20:00 24:00 4:00 8:00 Time
Let’s take a look first at normal physiology. What we see here is how somebody without diabetes makes insulin. In between meals there is always that basal insulin on board. What is the purpose of that basal insulin? To keep the blood sugar down between meals. But with every meal there is a rapid spike of prandial or mealtime insulin, and the purpose of that mealtime insulin is essentially to prevent the blood sugars from rising. If you do not have mealtime insulin, as soon as you eat your blood sugar goes up to 400, even though it started off normal. So when we add a basal insulin on board, this is what we are doing. We are re-creating the basal, and what are we hoping for in type 2 diabetes? We are hoping that the beta cells come back. If the person has adequate beta-cell reserve, which are being poisoned by the sugars, it is called glucotoxicity. As we lower the blood sugars and if the beta cells come back, then you are going to get these spikes of insulin secretion and the basal insulin is going to work. The only surrogate measurement that can tell you right now is from the ACE guidelines. When the A1C is greater than 8.5, the odds are you are not going to get these spikes back, and you are going to need to consider more than one injection per day. Again, to summarize, for basal insulin to work you need to have the prandial insulin come back produced by the body. Those spikes have to be endogenous. If not, then we have to give exogenous.
36 Long-acting Insulin Analogs: Anytime Administration of Insulin Glargine or Evening Administration of Insulin Detemir
• Patient considerations – Variable mealtimes, but no major meals – Fear of nocturnal hypoglycemia – Always eating • Administration considerations – Start with 10 units – Pen devices available – Does not provide postprandial coverage
When would I choose a basal insulin analog? The way that I would choose it, I can give glargine any time of day, and detemir has really only been studied in the evening. So for patient considerations, when I am looking at that individual and I am thinking of insulin, what I would like is variable mealtimes but no major meals. Why no major meals? Because if somebody has a very large carbohydrate-containing meal, they may not make enough prandial insulin on their own. I would consider a basal insulin when I fear nocturnal hypoglycemia because, as I’ll show you, it is less. For the nibbler, somebody who is always eating, I would give them a basal insulin because I think that is the appropriate therapy. How would I start? Usually with 10 units. Pen devices are available. However, unless the body produces endogenous insulin, there may not be any postprandial coverage. So these insulins, per se, do not lower postprandial blood sugars.
37 Insulin Glargine vs NPH Insulin Added to Oral Therapy
Methods: Forced-titration Schedule Start with 10 IU/d bedtime basal insulin dose and adjust weekly Self-monitored FPG (mg/dL)* Increase Insulin Dose (IU/d) ≥ 180 8 140–180 6 120–140 4 100–120 2 Treat-to-target FPG ≤100 mg/dL
*2 consecutive days with no episodes of severe hypoglycemia or PG < 72 mg/dL. Small ↓ (2–4 IU/d adjustment) in dose allowed when self-monitored PG < 56 mg/dL or severe hypoglycemic episode occurs.
Riddle MC, et al. Diabetes Care. 2003;26:3080–3086.
This is a study done by Dr. Riddle. It is a wonderful study called Treat to Target. It is important because, number 1, he showed that you could add insulin to oral medicines. Number 2, you could tell the patients to titrate up their own insulin. You can take care of your diabetes. He empowered them. This is the algorithm. I do not use this algorithm. I will show you the algorithm I use. But it began the concept that people can take care of their own diabetes.
38 Insulin Glargine vs NPH Insulin Added to Oral Therapy Mean A1C Levels During Study
9 Insulin glargine NPH insulin 8 Mean A1C (%)
7 Target A1C (%)
6 0 4812 16 20 24 Time (weeks)
Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.
With this trial they compared nocturnal, bedtime NPH to bedtime glargine. What we see here is that glargine was shown to be noninferior. There was no difference in A1C reductions between glargine and NPH.
39 Treat-to-Target Study Mean FPG During Study
200
Insulin glargine NPH insulin FPG 150 (mg/dL)
120
117 100 04812162024 Time (weeks)
Riddle MC, et al. Diabetes Care. 2003;26:3080–3086.
The point I want to make with the study is the following. NPH only lasts 16 hours. So with type 2 diabetes, you do not need a 24-hour insulin to get comparable glucose control. So the question arises: Why not use NPH, because it is half the price compared with glargine? Fastings were identical.
40 Insulin Glargine vs NPH Insulin Added to Oral Therapy - Symptomatic Hypoglycemia by Time of Day -
Glargine 1.4 Basal insulin * * NPH insulin 1.2 * Events 1.0 * * per 0.8 * * *P < 0.05 vs glargine patient- 0.6 year 0.4 0.2 0 20 22 24 2 4 6 8 10 12 14 16 18 Time of Day (hour)
Hypoglycemia defined as PG ≤ 72 mg/dL, by hour
Riddle MC, et al. Diabetes Care. 2003;26:3080–3086.
However, when we look at hypoglycemia, nocturnal hypoglycemia in the glargine arm was significantly less than that in the NPH arm shown in the green. Much less nocturnal hypoglycemia. In this clinical trial, however, there was no overall reduction in hypoglycemia. As you can see at that 12-hour point, glargine has a slight increase. There was clear-cut evidence of diminished hypoglycemia at nighttime with glargine.
41 Insulin Glargine vs NPH Insulin Added to Oral Therapy Target A1C ≤ 7%, Without Documented Nocturnal Hypoglycemia (PG ≤ 72 mg/dL)
35 33*
30 27 25 Patients 20 (%) 15 10 5 0 Insulin NPH ITT analysis; *P < 0.05 Glargine Insulin
Riddle MC, et al. Diabetes Care. 2003;26:3080–3086.
When we look at target A1Cs under 7%, without documented nocturnal hypoglycemia, you can see that 33% of the people with glargine were able to attain it and only 27% with NPH.
42 Mean A1C Levels During Study
9.5
Morning insulin glargine Bedtime insulin glargine 9.0 Bedtime NPH insulin
A1C (%) 8.5 8.3
8.1 8.0 7.8 * 7.5 04 812 16 20 24 Time (weeks)
*Decrease in A1C level from baseline for morning glargine: P < 0.001 vs bedtime NPH and P = 0.008 vs bedtime glargine.
Adapted from Fritsche A et al., and 4001 Study Group. Ann Intern Med. 2003;138:952–959.
Now, they began looking at glargine given at other times of the day. In this trial, they compared morning glargine to bedtime glargine to bedtime NPH. What we see in green is the following—that the morning glargine was superior to the evening glargine. The question is, why would that be if it is a 24-hour insulin? One thought is, if you are taking insulin in the daytime and you do not worry about going to bed, you are going to increase your insulin more aggressively. So maybe the titration was better. The other nuance from this study is that perhaps the insulin may actually have a slight peak. By having that slight peak, maybe the numbers are a little better during the day. Another point I want to make is, let’s look at the starting A1Cs in this study. They are a little above 9. What is our final A1C? 7.8. Did they reach goal? No. These patients at the end of the trial need to progress their therapy. If the basal insulin alone does not work, we go to step 2, which I will come to very shortly. If they were 8.5, they clearly would have made goal.
43 ATLantus: A Trial Comparing Lantus (Glargine) Algorithms to Achieve Normal Blood Sugar Targets in Patients with Uncontrolled Blood Sugar • Primary objective: to compare two titration algorithms in terms of the incidence of severe hypoglycemia • Randomized, open-label 24-week, prospective multicenter trial (N = 4,961) involving poorly controlled T2DM patients on once- or twice-daily insulin (~70%) ± OADs • Treatment: once- or twice-daily insulin glargine ± OADs • Target FBG < 110 mg/dL
Algorithm 1: Algorithm 2: Clinic Driven Patient Driven Clinic-based titration using Patient self-titrate 2-U increments 2- to 8-U increments weekly every 3 days 10-U start dose for FBG-based* start dose for insulin- insulin-naïve patients naïve patients
*Numerically equivalent to the highest FBG value in mmol/L over the previous 7 days.
Davies M, et al. Diabetes Care. 2005;28:1282–1288.
I will not go over the ATLantus trial in detail. However, what they did is they compared 2 different algorithms in type 2 diabetes. A fairly big study, about 5000 people. Algorithm 2 is my way of treating this. I will start the patient on 10 units at night or at daytime. Every 3 days, bump your insulin dose up by 2 units until you get to goal. The goals can change, and for our third part of the lecture we will talk about goals. By having patients titrate up very slowly it is extremely safe, and I agree with everyone in the room it is slow. But if it is slow and safe I think that is fine, because we are going to get to goal.
44 Insulin Glargine: Significantly Greater Reduction in A1C With Patient- Than With Physician-driven Titration Algorithms
Physician-driven Patient-driven Algorithm Algorithm (n = 2,315) (n = 2,273) 0
-0.25
A1C Level -0.50 (%) -0.75
-1.00
-1.08 Baseline -1.25 -1.22 A1C = 8.9% p < 0.001
Davies M, et al. Diabetes Care. 2005;28:1282–1288.
You can see with this, the patient-driven algorithm, the A1Cs were superior in reduction to the physician-driven algorithm. However, the point I am going to make is that the baseline A1C was 8.9. The patients did not reach goal. When A1Cs are greater than 8.5, you have to think of the next step.
45 Insulin Detemir vs NPH in Type 2 Diabetes With a Treat-to-Target Design
10 9.5 Insulin detemir 9 NPH insulin 8.5 A1C (%) 8 7.5 7 6.5
-2 0 12 24 Weeks
Hermansen K, et al. EASD. Munich, Germany; 2004; Poster 754:PS 064.
The new insulin on board is insulin detemir. In this clinical trial, they compared insulin detemir to NPH, adding it on to oral medicines to people which are type 2. Treat-to-target design. You can see that the A1Cs started off a little greater than 8.5, and came under 7. The NPH and detemir were identically effective with lowering the A1C.
46 Proportion of Patients Using Detemir Reaching Goal A1C Without Hypoglycemia
Reaching goal without hypos = 70 A1C ≤ 7.0% with no PG reading < 56 mg/dL and no confirmed 26% 60 (PG < 72 mg/dL) symptomatic hypoglycemia 59 50 16% 40
30 36
20
10
0 Detemir NPH Insulin (N = 230) (N = 232)
Hermansen K, et al. EASD. Munich, Germany; 2004; Poster 754:PS 064.
However, overall—this is not nocturnal hypoglycemia. This is a 24-hour period. The hypoglycemia was significantly reduced with detemir compared with NPH. Again, with basal insulins compared to NPH there is much less hypoglycemia.
47 Insulin Detemir: Weight Profile in Phase III Studies
3 *p < 0.05, insulin detemir vs NPH Insulin detemir insulin 2.5 NPH insulin
2 ****** *** * ** 1.5 Weight Change (kg) 1
0.5
0
-0.5 Studies in Type 2 Diabetes -1 Standl Vague De Pieber Pieber Home Home Russell- Her- Rašlová Haak Her- Leeuw Jones mansen mansen
The other thing with detemir, this will need to be investigated more. The studies on the left, you see, are detemir studies with type 1 diabetes. There is really no weight gain. The detemir studies on the right are with type 2 diabetes, and there is very little weight gain. When you compare detemir in these trials to NPH, there was much less weight gain. So the question is, will this insulin be more “weight friendly” to our patients with type 2 diabetes who already suffer from obesity? I think we are going to need further studies, but it is interesting.
48 Options When Not at Goal With One Injection of Basal Insulin
• Add an injection of a rapid-acting analog before the biggest meal • 6 units or 0.1 U/kg OR • Switch to a premixed insulin analog • Divide dose in half and give twice daily (breakfast and dinner)
What happens when we do not reach goal? As Dr. Rolla mentioned, if you have a fasting of 100, if you do not increase your basal, you are going to get hypoglycemic. We can do 1 of 2 things. This is where you are going to get some reticence from the patients, but the most reticence you are going to get is the first injection; the second injection is a little easier. One thing that can be done is you add an injection of a rapid-acting analog before the biggest meal. This is especially pertinent if it is somebody from the Midwest, where the biggest meal is in the middle of the day. Starting doses can either be a fixed number such as 6 units, or you can give 0.1 unit per kg. Many patients, physicians, and healthcare providers will subtract a little off the basal to try to prevent hypoglycemia. At this point, what the person can do is begin to titrate up. If you have somebody you can work with, as Dr. Rolla mentioned, you have to do blood sugars after the meals. They can slowly increase the insulin until they can get a postprandial value. If you want to use the 180 number of the ADA, fine. If you want to use the 140 of AACE, fine. But 6 units can go from 8 to 10. The best thing for them to learn is carbohydrate counting. Not everybody wants to do it. If one shot does not work, what do you need to do eventually? Go on to 4 shots. Three prandial injections of insulin and one basal. But if you have somebody who is not willing to comply too much, usually by adding one shot on top of a basal, I have seen A1C reductions of about a point. An additional shot will get you an additional point of A1C reduction. The other thing that you can do with a person if they are refusing—if they do not want to use 2 types of insulin, or they are fairly simple, and you are never going to get them to carb count—I would take the insulin and the basal, divide it up into half, and give a premixed insulin analog. Half the dose before breakfast, half the dose before dinner. That will also require titration up, and we will discuss titration in just a moment. You can choose one of 2 ways, and the way that you choose depends a lot upon the patients. Again, the best way is going to be the 4-shot regimen, ultimately, with 3 prandial insulins and 1 basal.
49 Biphasic Insulin Analogs
• Protaminated insulin aspart Biphasic insulin aspart 70/30 • Protaminated insulin lispro Biphasic insulin lispro 75/25 Biphasic insulin lispro 50/50`
Biphasic insulin analogs include protaminated insulin aspart with a ratio of 70/30, protaminated insulin lispro with a ratio of either 75/25, or the newest addition of 50/50. I do not have clinical experience. It has just been released in the states.
50 Human Insulin Time–action Patterns
Normal insulin secretion at mealtime Human insulin 70/30 premix Biphasic insulin 70/30 or 75/25
Theoretical representation of the profiles associated with human insulin 70/30 premix and biphasic insulin aspart 70/30 Change in Serum Insulin Serum Change in Baseline Level
Time (hours) SC Injection
What are the advantages of these insulins? Look at white. That is normal insulin secretion. Look at blue. That is human 70/30 injected at the time of the meal. So when is it peaking? Well after the meal. If we look here, we see tons of insulin action when we do not want it because it has NPH. With this insulin, if you were to use human 70/30, it has to be administered 30–45 minutes before the meal, but this component you still have to worry about. When you use the analog mixtures, administering them at the meal, you can see it fits the insulin physiology pretty well with the meal, and then it trails off to a basal. But there is much less insulin action out later on. If you are injecting it at dinner, you do not want a lot of unwanted insulin action at 3:00 in the morning.
51 Rationale for Biphasic Insulin Analogs
• More physiologic profile –Low rate of hypoglycemia; no NPH • Convenient dosing –Once a day with option to intensify –Mealtime administration • Coverage of FPG and PPG –Better A1C control and PPG control than with basal insulin analogs • Three products available: aspart 70/30 and lispro 75/25 or 50/50 • One- or two-injection regimens
The rationale for the biphasic insulin analogs includes the following. It is more physiologic than the older human insulins. When you compare the analogs to the human 70/30s, there is a lower rate of hypoglycemia for the factors I just mentioned. Convenient dosing. You could start this once a day, and I will talk about the rationale in a moment, but you can intensify with the same type of insulin. You can give this insulin at a meal. You do not have to wait 30–45 minutes. We went out to a restaurant last night, and I do not think any of us could have predicted 45 minutes before the food would have come. If anybody had taken the insulin when they thought it was 45 minutes before the food was going to come, they would have been very severely hypoglycemic with my dinner party. Coverage. You get better A1C control. Why? Because you are also now getting an insulin that is targeted at the postprandial, not just at the fasting. I have already mentioned the products.
52 24-Hour Plasma Glucose Curve
400
300 Diabetic
Glucose (mg/dL) 200
Normal 100
0 06001000 1400 1800 2200 0200 0600 Time of Day
Adapted from Polonsky KS, et al. N Engl J Med. 1988;318:1231–1239.
Let’s take a look at somebody with diabetes in red comparing them to a person without diabetes below in blue.
53 24-Hour Plasma Glucose Curve
400
300
Glucose (mg/dL) 200 Diabetic
100
Normal 0 06001000 1400 1800 2200 0200 0600 Time of Day
If we give a basal insulin, this is all we are going to see. You are still going to see high postprandial blood sugars. Why is that important?
54 Increasing Contribution of PPG as A1C Improves
100% 70% 60% 55% 50% 30%
80%
Contributio 70% FPG n to 60% PPG A1C 50% (%) 45% 40% 40%
30% 20%
0% > 10.2 10.2–9.3 9.2–8.5 8.4–7.3 < 7.3 A1C (%) Quintiles
Monnier L, et al. Diabetes Care. 2003;26:881–885.
If we look at the Monnier data, the data basically says that if we look at A1Cs closer to our goal of around 7%, when we take the A1C apart, that is, when the A1Cs come down, they are predominantly postprandial in nature: 70% postprandial versus only 30% fasting. For us to get our patients from an A1C of 7.5 down to 6.5, your therapeutic approach really has to encompass a lowering of the postprandial, not just the fasting.
55 Better PPG Coverage With Biphasic Insulin Analogs Than With Human Premix 70/30
p < 0.05 p < 0.0001 400
300
Serum PPG Excursions 200 (mg•h/dL)
100
0 Biphasic Biphasic Human Insulin Insulin Premix Lispro Aspart 70/30 75/25 70/30
Hermansen K, et al. Diabetes Care. 2002;25:883–888.
When we look at the biphasic insulin analogs, comparing them to the right with human premix 70/30, they are better postprandial numbers, both with aspart 70/30 and the lispro 75/25. You can see that the aspart 70/30 is somewhat superior, because it is 30% fast versus only 25%.
56 Biphasic Insulin Analogs
Breakfast Lunch Dinner
Plasma Insulin
4:008:00 12:00 16:00 20:00 24:00 4:00 8:00 Time
So one of the advantages of using the analog, as I mentioned before, is less hypoglycemia. The other advantage is better postprandials. If we take a look at administering a biphasic insulin analog just at dinner for an individual, you can see it fits the curve fairly nicely.
57 Biphasic Insulin Analogs
Breakfast Lunch Dinner
Plasma Insulin
4:008:00 12:00 16:00 20:00 24:00 4:00 8:00 Time
What is the advantage of this over just giving a basal? You are going to also lower the blood sugar after dinner. I come from the Northeast. The working individual in the Northeast currently has a very big dinner, with a small breakfast and lunch. By giving this insulin you are going to lower the highest blood sugar of the day, which is after dinner. So you are going to continue with the basal component to lower the fasting. But it turns out that breakfast and lunch are not much of a challenge for the pancreas. A lot of these patients may do very well with one injection alone, especially if their major meal is dinner. If it does not work, then you can add a second injection at breakfast, and that will control the post-breakfast blood sugar. If people look, you can miss lunch, so a big lunch may not necessarily work. I’ll come back to approaching lunchtime by just using this one type of insulin.
58 Twice-daily Split-mixed Regimen or 70/30 Conventional Insulin
Breakfast Lunch Dinner
Insulin Action REGNPH REG NPH
4:008:00 12:00 16:00 20:00 24:00 4:00 8:00 Time
. Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker; 2002:87. Nathan DM. N Engl J Med. 2002;347:1342–1349.
This is the insulin I trained with, human insulins. If we take a look—regular in the morning. It peaks around noon, so that is why patients have to have their mid-morning snack. The NPH you give in the morning peaks at 4:00, which is why they have to have their mid-afternoon snack. The regular you give at dinner peaks at midnight. That is why they have to have their bedtime snack. Then the NPH peaks at 3:00 in the morning, which is why you pray that they wake up in the morning. This is the reason I have gotten away from the older insulins and now use the analogs.
59 Pre-dinner Biphasic Insulin Analogs
• Patient Considerations – Obese – Late, large dinner – High FBG and bedtime glucose but reasonable dinner glucose – Failing basal insulin use • Administration considerations – Addresses post-dinner glucose – 12 U initial dose – However, no fine-tuning; may wear off by morning; nocturnal hypoglycemia – Use analog mix if possible
So in terms of the pre-dinner, this will be the one-shot regimen using a mixture, an analog mixture. When do I consider it? In the person who is obese who tends to have a large, late dinner. They typically have a high-fasting, high bedtime blood sugar, but reasonable dinner. Because they don’t eat much during the day the glucotoxicity abates, and they can make enough insulin during the day. You can even consider the switch in somebody failing a basal. How do you start? You start with 12 units just before the evening meal. Disadvantages include the following: no fine tuning; it is a premix, and it may wear off by the morning. Typically if dinner is at 5:00 or later, no problems. Nocturnal hypoglycemia exists with every insulin. However, if you use the analog mix, hypoglycemia is much less likely. It goes down significantly.
60 The 1–2–3 Study: Using Biphasic Insulin Aspart 70/30 Achievement of A1C Targets (completer analysis)
A1C ≤ 6.5% A1C < 7.0%
100 100 87.8 80 77.0 80 78.4 66.2 % of Patients 60 60 45.9 40 40 28.4 20 20
0 0 QDBIDTID QD BID TID
Garber AJ, et al. Diabetes Obes Metab. 2006;8:58–66.
Let’s take a look at the 1-2-3 trial published by Dr. Garber. They looked at individuals breaking through oral medicines. About 28% of the patients actually were ready on basal. They started them on 1 shot a day, 12 units at dinner, and they also empowered the patients. By empowering the patients they said, titrate up your own insulin, a very rigorous titration scheme. They were only allowed 16 weeks to reach goal. The goal was an A1C under 6.5. What we can see after 16 weeks, about 28% of the patients got their A1C under 6.5 with one injection, under 7 it was 45%. What did they do at that point? A second injection was added at breakfast. So this time, rather than 12 units they added 6 units at breakfast. How did they titrate it up? They titrated up their morning insulin based on their pre-dinner blood sugar. Titration goals will be discussed in the third part. By adding a second shot, titrating it up, what do we see? Sixty-six percent of the patients got their A1Cs under 6.5 and almost 80% under 7%. In the minority, a third shot was added. But essentially, with this one insulin almost 90% of the patients can get under control. The beauty of it is they are not using 2 different types of insulin. It is just one type of insulin. You could start with one, advance to 2, and if necessary, go to 3.
61 Biphasic Insulin Aspart 70/30: Initiation and Titration in Actual Clinical Practice
• Once daily – 12 units at dinner – Titrate 2 units every 3 days • Adding a second dose when needed – Add second dose at breakfast as needed (6 units) – Discontinue secretagogues • Can add a third dose
So the titrations again: Once a day you start with 12 units at dinner, and you titrate up 2 units every 3 days until you reach your fasting goal. I typically wait 3–6 months, since I do not do clinical research, to get my A1C. If I am not at goal, and their pre-dinner blood sugars are high, you add 6 units at breakfast. They titrate it up to get their pre-dinner down. At that point you can discontinue the secretagogues and if necessary, a third dose can be added.
62 Effect of Glargine + Metformin vs BID Insulin Lispro 75/25 + Metformin
8.8
8.6 Glargine Glargine 8.4 * * * Mean 8.2 A1C (%) 8 ± SEM 7.8
7.6
7.4 Premix Premix 7.2 0 4 8 12 16 20 24 28 32 32-week crossover study Weeks on Study
Malone JK. Diabet Med. 2005;22:374–381.
Just briefly, for 2 clinical trials. The question comes up, which is superior, a basal or a premix? It depends upon the patients. I think you need to use the A1Cs as a guide. In this clinical trial, lispro mix 75/25 was compared with metformin. A crossover trial. Same patients used 2 different insulins, and you could see where the premix was used there was superiority. Again, it is 2 shots versus one shot. But why was there superiority? There were better postprandial numbers. The other thing I want to mention about the study is that the goals were not so good. They did not get down to 7%.
63 INITIATE Trial Primary Endpoint (A1C)
Biphasic insulin aspart 70/30 BID P = 0.478 Insulin glargine QD 11
10 9.7 9.8 P = 0.001 9 A1C (%) 8 7.4 6.9 7
6
5 Baseline 28 Weeks
Raskin P, et al. Diabetes Care. 2005;28:260–265.
This was physician driven and patient driven. I will show you here with the INITIATE trial. The INITIATE trial was aspart 70/30. Same idea—comparing glargine to 2 shots a day of aspart 70/30, and you see superiority. Actually, these are better A1Cs. Why? This was patient driven. It was from this clinical trial where we got that A1C difference of 8.5 as a dividing point.
64 Conclusions
• For optimal glycemic control, attention must be paid to both fasting and postprandial glucose as well as to A1C level • Insulin is effective therapy in type 2 diabetes • A number of insulin treatment strategies can be used in type 2 diabetes • Unfortunately, insulin often is initiated later in the course of the disease than is desirable
In summary, for optimal glycemic control, attention must be paid to both fasting and postprandial glucose, as well as to the A1C. Insulin is an effective therapy in type 2 diabetes. A number of insulin treatment strategies can be used in type 2 diabetes but, unfortunately, we usually wait too late because the patients try to talk us out of it. Thank you very much for your attention.
65 Applying Clinical Trial Data to Practice: Implementing Therapy With Insulin Analogs
Ramachandiran Cooppan, MBChB, FRCP(C), FACE Senior Staff Physician, Joslin Diabetes Center Senior Attending Physician, Beth Israel Deaconess Medical Center Assistant Clinical Professor of Medicine Harvard Medical School Boston, Massachusetts
Dr. Rolla: Many years ago, when I was a very young medical student, I came to the Joslin Clinic where I first met Dr. Cooppan, who was already a senior established physician back then. I was always very impressed with him, and over the years I came to appreciate him, not only as a physician but as a great teacher and a great friend. It gives me great pleasure to introduce Dr. Chan Cooppan from the Joslin Clinic in Boston. Dr. Ramachandran Cooppan: Good morning, everyone. Thank you, Arturo. You know, this is what happens when you get old together. You are allowed to take liberties, right? I think Dr. Tibaldi has given us a wonderful science background, so at this point you are going to have fun. So we will do this based on a case history and apply some of these principles to a patient.
66 The Decision to Implement Insulin - Patient Profile -
Female with 10-year history of type 2 diabetes • Age: 60 yrs • Weight: 168 lbs, BMI 28 • Works full-time in sales; mealtimes not set, little time or energy for exercise Therapy history • Initially treated with metformin 500 mg BID; repaglinide 2 mg TID was added. Two years ago, pioglitazone 15 mg QD was started • With each additional oral antidiabetic drug (OAD), she achieved a 0.5% to 1% reduction in A1C values • Her most recent OAD regimen included metformin 1000 mg BID, repaglinide 4 mg with meals, and pioglitazone 45 mg QD
We will start with a lady who is 60 years old, who has had a 10-year history of type 2 diabetes. She weighs 168 lbs with a BMI of 28 and works full-time in sales. Mealtimes are not set, and she has very little time for exercise, nor is there energy to do exercise. Her therapeutic history is very typical of the staged approach one uses today. You start with one medication, metformin 500 mg twice a day, and then a secretagogue is added. In this case it is repaglinide, 2 mg taken 3 times a day. And with the progression of the disease, finally a thiazolidinedione, pioglitazone, is started at 15 mg once daily. As you have heard in the prior lectures, with each additional oral medication she achieves a modest reduction in her A1C values. At her most recent therapeutic regimen, she maxed out on 1000 mg of metformin twice daily. That is an important clinical point, that these are the optimal doses for each one of these classes of medication: 1000 mg of metformin, repaglinide 4 mg with meals, and the pioglitazone is now at 45 mg. We have achieved what is an optimal dose response.
67 The Decision to Implement Insulin - Patient Profile -
• At a regular visit several months ago, she complained of nocturia, polyuria, and polyphagia. Also, over the previous 6 months, her body weight had increased by 15 lbs • Fasting blood glucose (FBG) levels: 160–180 mg/dL; postprandial glucose (PPG) values > 300 mg/dL. Her A1C value was 8.2% • The patient sent back to nutritionists and nurse educator
So she comes back for a visit, and she is now complaining. She is becoming symptomatic. She has nocturea, polyuria, polyphagia, and in the last 6 months her weight has increased. She brings some blood glucose reports with her—self-glucose monitoring. Her fasting glucose is about 160–180, and there are postprandial values that go up to 300 or above. Her glycosylated hemoglobin is 8.2%. Like all of us believers do, we send the patient back to the nutritionist, to the nurse educator, to see if we can once again get her to follow the program and move from that point on.
68 ? What is the A1C goal in this patient?
1. 7%– 8% 2. 7% 3. 7% or less
What should the A1C goal be in this patient? These are going to be very simple questions, so everyone ought to get them right. What is the A1C? If it is 8.2, what should it be?
69 The answer is 93%. So there are some people we still have to train. The goal is, as you know, less than 7%. But that is a transition. These goals are progressively going lower.
70 ?
What is the FBG goal?
1. 100–120 mg/dL 2. 90–130 mg/dL
We have another question for you. What is the fasting blood glucose goal in this patient? Remember, we are restricting this. We are practicing in North America under the aegis of the ADA, so look at those criteria from that viewpoint. Is it 100–120 or 90–130? Choose one answer.
71 Whenever we do these programs, I am always waiting to see if I can get 100% on an answer. It has not happened yet despite prompting. Obviously, if you are going to use the ADA criteria, it is 90–130. But 100–120 does not cut it.
72 ?
What is the 2-hour postprandial goal?
1. < 180 mg/dL 2. < 140 mg/dL
Let’s go to the next one, and I think this is the postprandial goal. Remember, it is a 2-hour postprandial goal. Are we shooting for less than 180 or less than 140? I emphasize that it is a 2-hour value. You got your prompt. Can we vote?
73 We have 80%. Obviously, the ADA goal of 180 is not specified, and that is important to recognize. Dr. Rolla made that point. It is a peak value. But when one looks at a 2-hour value internationally, looking at the ACE guidelines and European guidelines, 140 or less is where we want to be.
74 ?
What is the cause of the poor control?
1. Increasing insulin resistance? 2. Decreasing beta-cell function? 3. Both?
Finally, the issue of physiology. What is the cause of poor control in this patient? Is there increasing insulin resistance, is there decreasing beta-cell function, or do you believe it is a combination of both? Let’s vote on this. This question is a little tricky, but let’s see how we do.
75 Most people said, both these defects. She is on a max dose of a TZD and she is taking metformin. It is true she has gained a few pounds that may make insulin resistance a little worse. Fundamentally, what is going on here is her beta cells are becoming less effective in making insulin. That is the key in the situation, especially when these medications are on board. The 15-lb weight gain is a physiological effect of the thiazolidinediones. That is the way they work, improving insulin sensitivity.
76 Assessment
• Control is inadequate on combination OAD therapy • FBG is high; post-meal readings are markedly abnormal • A1C level of 8.2% suggests that hyperglycemia may be related to high post-meal excursions • Meals are inconsistent in both timing and portions • It’s time to initiate insulin
So now, we make an assessment. Obviously, this woman is not well controlled. She has a high fasting glucose, and her postprandials are even higher. We have all agreed that this A1C is much too high, and as you saw from the Monnier data, much of this is driven by the postprandial. We have assessed from her history that her meal timing and portions are somewhat inconsistent. Obviously, we need to go to the next step, and that is to initiate insulin. This is when the rubber meets the road. We need to do something.
77 What treatment options would you recommend for this patient who is ? reluctant to begin insulin therapy?
1. Start NPH at bedtime, with the option to add regular insulin at largest meal 2. Long-acting analog (glargine or detemir), with the option to add a rapid-acting insulin analog at mealtimes if PPG is not controlled 3. Premixed analog at dinnertime, with the option to add a second dose if needed 4. Adding exenatide injection twice daily
She is sitting there, and she is looking at you. So what are you going to do? She is reluctant. In all my 30-plus years at Joslin, I have never had a patient who came to me and said, “Please, Dr. Cooppan, start me on insulin.” I felt like I was always an insurance salesman, saying, “What kind of policy do you want?” The best one I have is 4 shots, and we go down from there. You could start this patient at NPH at bedtime with an option to add a fast-acting insulin. Two, you could use a long-acting analog, such as glargine or detemir. Once again, you have the option of adding some rapid insulin, an analog, if the postprandials are not controlled. You also could use a premixed analog before dinnertime with an option to use a second dose. More recently, you have the option of adding the exenatide, the incretin, to this patient’s program. So choose one of these options because the patient is looking at you expectantly and wondering what is happening.
78 This is what you expect. This is typical. We have a wide distribution. Most people here are looking at #2 and #3, with some people in the fringes. The point is that when you look at insulin therapy, you look at your patient, but to make this decision we lack some major pieces of information.
79 Which regimen?
• There is no one “right” choice, and one regimen is not necessarily forever
The point I want to make is, there is no one right choice. The regimen that we start with does not always last forever. The key to making this decision will come with the data that we have.
80 The Decision to Implement Insulin - Overcoming Concerns -
Initial anxiety – Provide education and support Feelings of personal failure – Inform patient that type 2 diabetes is a progressive disease Fear of hypoglycemia – Provide education about signs and symptoms as well as prevention and treatment Fear of injections – Advise of availability of fine needles and injection devices Weight gain – Adjust diet and exercise as needed
But before we can actually implement this, we need to also convince this patient. As I mentioned, over the years we talked about physiological insulin resistance, but psychological insulin resistance is even greater an issue. Patients are afraid of insulin injections. They feel like they are failing. Insulin is not to be used as something that is punitive. I never tell a patient, “If you do not do this, then I will start you on insulin.” It is a progression. I think patients need to understand the physiology. They are afraid of hypoglycemia. They have seen others with diabetes; they have diabetes in their families. They have seen the adverse effects. They have read about it. People do not like injections. People who volunteer to take injections, I can assure you, do not take insulin in them. People do not like insulin. The fingersticks are far more painful today than taking a shot. Also, weight gain is an accepted effect of this particular compound we are using. It is a physiological action, especially if there is excessive calorie intake. But adjusting diet and exercise can mitigate that.
81 The Decision to Implement Insulin - Overcoming Concerns -
Communicate benefits of insulin therapy! • Insulin therapy is safe, effective, and flexible; it can reduce the risk of diabetes complications • New delivery systems are available – Insulin pens – Insulin dosers – Insulin pumps – Inhaled insulin
So you need to also know, as you heard from Dr. Tibaldi and Dr. Rolla, the benefits of insulin therapy. It used to be said that if you came to Joslin, you always went on insulin. Indeed, we always promoted that if your own insulin did not work very well for you, we would try and increase it. When you lacked that, we would give you insulin eventually. There are 2 major institutions in Boston for diabetes: Joslin, and another hospital that had a nice CPC in the New England of Journal of Medicine every week. We never saw eye to eye on the question of insulin, oral agents, and how we used them. Nonetheless, we have very good data today of the benefits of insulin. Even more importantly, we have better delivery systems. When I started at Joslin, it was at the time when we still had big needles, glass syringes, and people worshiping the blue shrine, Benedict’s solution and urine tests. The changes that have occurred in 3 or 4 decades are outstanding. It is just unbelievable the kinds of things our patients have today.
82 The Decision to Implement Insulin - Steps to Insulin Initiation -
1. Define blood glucose target for this patient 2. Should they remain on their oral antidiabetic agents (OADs)? 3. Insulin formulation, number of injections, delivery system
So we have this woman. We need to define the goals, set targets, and communicate these to our patients. We need to make a decision on the medication she is taking. This lady may have other comorbid conditions, and she may be taking a host of other drugs. So what are we going to do with these oral agents? Then we have to choose a formulation, the number of injections, and how we want to deliver this.
83 Insulin Regimen and Delivery Methods - Patient Profile -
• How symptomatic is the patient? • What is the duration of diabetes? • What are the blood glucose patterns? FBG > PP PP > FBG ALL BG high • What is the current A1C level? • What are the comorbid conditions?
This is an interchange between you and that patient. This part is so critical because you are building up trust. One question that we use to make these decisions is, how symptomatic is this patient? What if, as Dr. Rolla mentioned, you have a patient with type 2 diabetes to whom you have been saying every visit, “Please lose weight,” now loses weight without trying? They are ecstatic. You are not looking so happy because that means their beta cells are starting to decline profoundly. They lose weight, and they are becoming more hypoglycemic. In general, the longer the duration of diabetes, the more likely you are to see some beta-cell decline. Remember that the data from the UKPDS is done in a different era with different medications. Looking at glucose patterns is absolutely critical. This is what we use to determine how we are going to implement an insulin program. Is it a fasting issue? Is it a postprandial? Is it throughout the day? What is the current A1C level? It is going to be impossible to take someone with an A1C of 10 or 11 and add a single injection to get to less than 7. That is not going to happen in our wildest dreams. Look at where you are: an 8 to a 7 is very doable with one modification. What are the comorbid conditions?
84 Insulin Delivery Insulin pens • Faster and easier than syringes •Improved patient attitude and adherence •More accurate dosing
This is an unusual lady. Most of these patients have dyslipidemia and hypertension. Many of them are cigarette smokers. They have microalbuminurea, etc. All of this plays into the decision making. Today, our approaches are facilitated by these delivery systems. In the United States, we do not use these pens as extensively as they do in Europe, and these pens are wonderful. They are very easy to use, very user friendly. Patients have less of an option to make errors with them. They are portable, provide accurate dosing, and are a useful tool for initiating therapy.
85 SMBG Results
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 149 150 250 162 280 Tue 162 160 320 280 Wed 156 160 275 Thu 190 190 155 290 Fri 138 143 270 Sat 170 178 257 Sun 160 200 143 172 326
It all comes down to looking at blood glucose monitoring results. I am going to walk you through this. You may say, “When was the last time I saw a patient with type 2 diabetes who did this for me? He probably made this all up.” The answer is, they are not going to do this for you every day. But when you see a patient in this situation where you have to set new goals, this is your opportunity to say, “Look, for the next 2 weeks, test more frequently for me. I have sent you to the nutritionist, I have sent you to the nurse educator. Bring me this data because we are going to look at this together, and we are going to determine how to treat your diabetes at the next level.” So looking at blood glucose patterns is extremely important. Getting fasting and postprandial glucoses is critical in decision making.
86 SMBG Results
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 149 150 250 162 280 Tue 162 160 320 280 Wed 156 160 275 Thu 190 190 155 290 Fri 138 143 270 Sat 170 178 257 Sun 160 200 143 172 326
If you look at this chart, this patient has done about 75% of the tests I have asked her to do. When you look at these charts, have your patients take them from their meters and write them down. Bring in those little meters; punching those buttons is not useful. I always ask them to write it down, and if I see little bits of blood stuck on the paper, it is even better for me. I know it is real. When you look at blood glucose patterns, the tendency is to look across. However, I would suggest, look this way. One of the key things you want to ask is, how does this day start? Where is the fasting glucose? Once the day starts well, you could look at how it progresses. If you look at this, she has an elevated fasting. We know this. Look at these pre-lunches, pre-dinners, and even right up to the evening meal—not too bad. Then comes this big meal. Notice that. Very clearly there is a pattern here, and this one is in the patient with type 2 diabetes. These are easier to see. Patients with type 2 diabetes do not vary that much in terms of the fluctuation, except as they progress. So you have a post-dinner period of hyperglycemia, going to bed high, and still an elevated fasting glucose.
87 How would you treat this patient? ?
1. Add pre-supper rapid-acting analog 2. Add pre-supper premixed insulin analog 3. Add long-acting basal insulin at supper 4. Add NPH at supper
You need to choose a therapy at this point. You have a chance now to decide on what you are going to do. We have 4 choices here for you. You could add pre-supper, fast-acting insulin, an analog. You could add a premixed insulin, an analog preparation. Add a basal insulin at supper or add NPH at supper. Choose one option from this, because this lady is looking at you expectantly. It is like a sentence coming down: “What is he going to do?”
88 Seventy-four percent of you decided that you would use a premixed insulin analog. Some people went for the other options. Reflect back on those results that I showed you, as well as Dr. Tibaldi’s lecture. The choice between an analog mix and a human insulin analog mix is very important in this patient. Remember that her postprandials are very high after dinner. But as you get to the morning hours, there is a decrease in her blood sugars. It does not have the markedly elevated fasting glucoses that you sometimes see as beta-cell function deteriorates. She is also on metformin, a drug that we know reduces hepatic glucose output and suppresses that glucose level. Using the analog here gives you the 30% you would need to take care of dinner, and then the tail end of that long- acting preparation is much less than with the human, so you do not develop a problem with nocturnal hypoglycemia. So it is a very good choice.
89 Dosing and Titration ? - Initial Dosing for Premixed Insulin Analog Regimens -
12 U biphasic insulin aspart 70/30 started before dinner
Would you continue OADs in this patient once insulin is started? 1. Yes 2. No
How many units should one start? He has given you ways of doing it. I think the key is to have the patient engage with you in adjusting this. We used to teach our patients to inject in oranges. Today you see the nurse, first shot goes in, and most patients will tell you this is far less painful than doing the finger sticks. So a premixed insulin is wonderful for this patient. What can you expect if you did this? You would start with 12 units before dinner, and you would incrementally increase that. You can choose with your patients whether it is 2 units every 3 days, 4 days—as long as that patient is monitoring and you have a means of keeping in touch with them. Now comes the big question: You have initiated insulin. What are we going to do with these oral medicines? She is on 3 pills at max dose. The question is, should we continue this or should we not?
90 All of them? Audience: One. Dr. Cooppan: Which one? Audience: The secretagogue. Dr. Cooppan: Yes. When? Stopping the secretagogue makes a lot of sense just before dinner. You are giving a rapid-acting insulin, which will already take care of that. The other issue would be, what do you do with the thiazolidinedione? She is on max doses. You are initiating insulin. As you know, when you start to use insulin, there is a higher rate of patients who may develop edema. There is a potential for more weight gain. You have the option to watch this a little while, see where it goes. If you chose to stop it at this time, I would not have any argument with it. You need to simplify this program within the context of the initiation of insulin. However, to stop the earlier doses of the secretagogue would be a major error. Because there is nothing else in the morning from breakfast to carry her, or from lunch to dinner.
91 SMBG Results: Pre-dinner Mix
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 130 238 190 250 179 160
Tue 140 231 222 140 135
Wed 122 210 150 Thu 260 190 193 147 Fri 112 189 201 133 Sat 131 276 178 123 Sun 126 200 220 240 166
So we initiate insulin. She gets to a reasonable dose, which on average in these patients is about 40 units or so.
92 SMBG Results: Pre-dinner Mix
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 130 238 190 250 179 160
Tue 140 231 222 140 135
Wed 122 210 150 Thu 260 190 193 147 Fri 112 189 201 133 Sat 131 276 178 123 Sun 126 200 220 240 166
We also have this profile. If you look at that again, we have achieved our goals here. We have done what we set out to do, and we have done fairly well. However, now something starts to happen in her testing, and you can see as I highlight that. She is now progressing. She is getting postprandial hypoglycemia after breakfast with very reasonable fasting sugars.
93 SMBG Results: Pre-dinner Mix
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 130 238 190 250 179 160
Tue 140 231 222 140 135
Wed 122 210 150 Thu 260 190 193 147 Fri 112 189 201 133 Sat 131 276 178 123 Sun 126 200 220 240 166
We also see a carryover to the other parts of the day. This is expected in the natural history of type 2 diabetes. You ought to anticipate that this is coming along. At this point, you can see there are far more peaks in other times of the day, so a decision needs to be made.
94 ? How would you treat this patient?
1. Add pre-breakfast rapid-acting analog 2. Add pre-breakfast and pre-lunch rapid-acting analog 3. Add pre-breakfast premixed insulin analog 4. Add exenatide before breakfast
What would you do here? You can add some fast-acting insulins before breakfast. You can add fast- acting insulins before breakfast and lunch. Or give her a second dose of the premixed analog. Do you think you should add some exenatide before breakfast? Of course, it is a huge peak. Choose one of these answers. Let’s see what you do. Remember, the pattern dictates your choice of therapy, as well as types of insulins you put together.
95 So most people would add the premix before breakfast, and that is obviously the way you should go. After all, you can see the distinct peak after breakfast, and it will also spill over the rest of the day. Besides, you are using the same insulin. You get this patient, you have a pen with 70/30 and another pen with the analog, and you are going to get a phone call that says, “I took my analog at bedtime, and I took the premix in the morning.” Now what do you do? You get a call at midnight, and you say, “Eat all the ice cream you want.” So she does this, and you can expect this sort of response. This is very typical in a patient with type 2 diabetes. Let’s move on.
96 SMBG Results: Pre-dinner and Pre- breakfast Premix
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 122 150 122 160 135 160
Tue 140 132 143 140 135
Wed 100 156 150 Thu 152 141 130 147 Fri 112 121 150 133 Sat 131 130 178 123 Sun 96 143 128 134 166
These patterns are important. Most of my patients will not do these many tests all the time. Once they get on to insulin they certainly will need to do 4 tests a day with one postprandial, 2 hours, either after breakfast, lunch, or dinner. Often they will do that for you.
97 SMBG Results: Pre-breakfast and Pre-dinner Premix Patient returns a few months later with these SMBG results
Breakfast Lunch Supper Bed Nite
Pre Post Pre Post Pre Post Mon 122 150 122 160 135 110
Tue 284 132 143 140 135
Wed 100 156 150 Thu 152 141 130 147 98 Fri 256 121 150 133 Sat 131 130 178 123 Sun 96 143 128 134 166
Every couple of months, I put them up to this intensive thing. Do a week of as many tests as you can, so I can look at where things are going.
98 SMBG Results: Pre-breakfast and Pre-dinner Premix Patient returns a few months later with these SMBG results
Breakfast Lunch Supper Bed Nite
Pre Post Pre Post Pre Post Mon 122 150 122 160 135 110
Tue 284 132 143 140 135
Wed 100 156 150 Thu 152 141 130 147 98 Fri 256 121 150 133 Sat 131 130 178 123 Sun 96 143 128 134 166
So she arrives, we are all very happy a few months later, and you see this pattern. Does anybody recognize anything special here? Remember, we are looking down. Is there anything that stands out here? Yes. You can see there is a low here. She is doing fairly well, but she has got these 2 spikes. So we need to ask, did she snack all night? Was there a party or something? So this is what we see.
99 What should you do? ?
1. Add hs snack
2. Reduce the pm insulin dose
3. Have patient check blood sugar at 3–4 am
What do we do? You have 3 choices here. You see this pattern in front of you. Do you want to add a snack to this patient? Do you want to reduce the pm insulin dose if you haven’t? Or would you have the patient check on early hours of the morning blood glucose? You have 1 of 3 choices, so vote on this one.
100 The correct answer is 3. Good, most people want to check the 3 am blood sugar, and that is exactly right.
101 SMBG Results: Pre-breakfast and Pre-dinner Premix
Breakfast Lunch Supper Bed Nite Pre Post Pre Post Pre Post Mon 122 150 122 160 135 110 72
Tue 284 132 143 140 135
Wed 100 156 150 Thu 152 141 130 147 98 54 Fri 256 121 150 133 Sat 131 130 178 123 Sun 96 143 128 134 166
This patient has wonderful fasting sugars, and yet we have these 2 markedly elevated blood glucose levels. What would we expect? This is what you see—a nocturnal drop, even with the analogs if you do not take the necessary precautions. What are those? You can see that these things do not correspond to this. When you see this pattern, you are not always as lucky to see a drop like this. Sometimes all you see are just these highs in the early hours of the morning. Remember, patients with type 2 diabetes can still do this. It is not something that only exists in the patient with type 1 diabetes.
102 Dosing and Titration - Resolving Potential Problems - Problems 1. As control improves, risk for hypoglycemia increases 2. Occasional high FBG with lower hs sugars 3. Rule out nocturnal hypoglycemia Response 1. Test BG at 3–4 am 2. If low, reduce pm dose 3. Make sure hs snack is eaten 4. Regular follow-up; review of SMBG at every visit
So the problems are, as control improves, the risk for hypoglycemia increases. This was shown in the DCCT. It can happen as we insulinize our patients to the optimal dosages. When you see this high fasting with an occasional lower sugar in the evening, rule out nocturnal hypoglycemia. Test that 3 or 4 am blood sugar. The critical element is, when you add a second dose to an evening dose of insulin, reduce that evening dose appropriately, because now you are going to get a carryover. Make sure that the patient has this. Regular follow-up is going to be extremely important in this patient. We need to review the self-monitoring blood glucoses at every visit. She may do well for the next 3–6 months, a year, 2 years.
103 Mission Accomplished!
As Dr. Tibaldi mentioned, the time may arrive in many of these patients where you will have to move from this fixed-dose approach to a more intensified approach, which is now moving into basal bolus. This is the most physiological approach, because your patient will have to learn carbohydrate counting, insulin sensitivity factors, and make adjustments based on glucose monitoring. You would be surprised—patients will do this once they understand the need and the fact that they are in charge. It gives them a great deal of flexibility. If we adopt this approach to diabetes, we need to look at the patient, understand the pathophysiology, and look at those blood glucose patterns. They are the key to day-to-day management. They are the key to your decision making. If you do this in conjunction with the patient, you will engage them and empower them to participate in the treatment of diabetes. Finally, we may truly say, mission accomplished. Thank you.
104