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A 52-year-old Caucasian man was diagnosed with type 2 diabetes (T2DM) eight years ago and has been under your care for the past three years. His current treatment regimen includes glargine (50 units daily), metformin (1,000 mg b.i.d.), and glimepiride (2 mg daily), as well as lisinoprol (20 mg daily), and atorvastatin (20 mg daily).
Recent blood tests came back normal for lipid levels as well as renal and liver function, but showed an HbA1c level of 8.0%.
In his most recent physical, you found this patient to have mild retinopathy but normal blood pressure (110/80 mmHg) and no symptoms of gastroparesis. You found no signs of cardiovascular disease despite a family history of both athlerosclerosis and myocardial infarction. You also noted that the patient has gained an average of two pounds a year since he first came to your office, and currently weighs 210 pounds (giving him a BMI of 32 kg/m2). The patient reports making efforts to exercise by jogging about four times a week but finds it difficult to control food intake. He says he understands that weight loss might help control his blood sugar but finds himself uncontrollably hungry, particularly at night, and is unable to resist the high-calorie foods brought into the house by his teenage children.
Although self-employed, this patient currently has health insurance that includes prescription drug coverage. He seeks advice about whether a change in medications might help him reach his glycemic goal (HbA1c of 7.0%) and prevent potential neurologic and cardiovascular complications.
Treatment Options
Which one of the following treatment options do you think would be most appropriate for this patient?
- Add mealtime insulin
- Add pre-mixed insulin twice a day
- Add a GLP-1
Continue to Management Options
Mealtime insulin
Kevin A. Peterson, MD, MPH
University of Minnesota Medical School
Minneapolis, MN
This man is already showing early signs of microvascular disease. At 52 he will need better control to prevent progressive damage to his eyes over the next 30+ years he can expect to live. He is already on glargine and metformin. Great! Certainly insulin provides the surest guarantee for lowering his A1c to safer levels.
Information gathering
I would start by taking him off the sulfonylurea (SU). With wide variability in action over the course of the day, the SU will present the greatest risk of hypoglycemia as work to get his blood sugar down to a safer range proceeds.
Then we need some more information. We know this patient is failing to achieve good control, but we don’t really know the cause of the problem. I expect that he has already pushed the glargine up as high as he can tolerate. This will be limited either by intermittent hypoglycemia in the late afternoon as the glimiperide kicks in on days that he has not been able to have a regularly scheduled lunch, or by morning hypoglycemia from the glargine. Stopping the SU should help prevent any late afternoon hypoglycemia, and might enable us to increase the glargine with a subsequent drop in the A1c—one less drug, and better control. On the other hand, if the glargine is already maximized, then we need to find out when the hyperglycemia is occurring. That will be helped by an evaluation of his dietary habits, and by asking for some pre- and postprandial blood sugars.
It sounds like he is doing pretty well until getting home. Checking before eating in the evening and adding a four-hour postprandial measure before bed will be educational by identifying better food options, and by seeing if higher sugars are present at that time. If his blood sugar is going up over supper, then it is time to begin to consider adding some prandial insulin. Of course, better food choice is essential. No amount of short-acting insulin will allow him to continue to eat badly, and weight control will need to be addressed with behavioral and perhaps family interventions. But preprandial and postprandial blood sugars will show both of us the effect of his meal choices, and will prepare for introduction of short-acting insulin.
A stepwise approach to short-acting insulin
When I initiate short-acting insulin in a person like this with type 2 diabetes, I generally start with one meal at a time, rather than introducing the challenge of prandial insulin at each meal. I start with the biggest meal of the day and then recheck. It may be that one shot at supper will result in much better control, and will be better accepted and easier to manage than three shots per day. If control isn’t achieved, then I look for the next largest meal. Many people don’t eat three meals a day, so I start off by tailoring insulin to real eating habits.
Although adding short-term insulin may triple rates of hypoglycemia, there is no more certain way of lowering A1c. And this patient’s overall safety and the preservation of his vision demand a lower A1c. Education is essential, and will go a long way in preventing problems. As he begins to get better control, he will need to learn more about eating, exercise, sick days, precautions while driving, and how to use insulin. He should get started with learning more right away.
Then there is the weight control. This is a great time to bring the family in to help. The kids need to know what Dad is going through, and to see what they can do to change the environment. Behavioral change is a family affair.
It is often said that the basal/prandial split should be 50/50, but this patient’s being on metformin and glargine will alter this. I would avoid adding correctional doses, and would not vary the dose by carbohydrate load, at least not until he had more education. Instead, I’d start with a specific dose, and adjust if the patient continued to have significantly higher readings four hours later. Much more can be done, but this is simple and safe. If he skips the meal, skip the insulin.
Conclusion
There is no doubt that we can lower this patient’s A1c below 7 using a basal bolus approach and adding prandial insulin. Although I can’t be sure if lowering his A1c from 8.0 to less than 7.0 will prevent cardiovascular disease, it will certainly will help prevent microvascular disease, and is the best way to help him keep his eyesight.
References
n/a
Pre-mixed insulin
Doron Schneider, MD
Abington Memorial Hospital
Abington, PA
Intensification. In medicine it means more aggressive treatment. It usually involves increasing doses or medication strength, or adding more medication. Our patient requires intensification of his diabetes regimen given that oral therapy and once daily basal insulin has not helped him get to goal A1C (<7). In light of this patient’s preexisting retinopathy, some degree of urgency is required.
Intensification options for this patient include stopping premeal bolus insulin injections or stopping basal insulin and adding a premixed insulin. While adding a GLP1 agonist is an evolving, attractive option, it remains FDA-unapproved and will not be covered here. Adding another oral antidiabetic drug probably won’t bring this patient to goal and is thus not considered a good option either.
A patient-centered approach
Given that our patient has an A1C of 8mg/dl and is already on 50 units of glargine, attention must be paid to postprandial sugars. As one attempts to move closer towards A1C goal of 7.0 mg/dl, post-prandial sugars become more important contributors to A1C elevation than the fasting sugars. Increasing glargine further probably won’t work. In this scenario I attempt to take a patient-centered approach to the decision of how to intensify. Patients who actively participate in the decision may be more adherent down the line, an important factor given adherence rates as low as 60% with new insulin starts. For our patient the discussion of the premixed option should include the following:
- Simplicity and flexibility: I usually start at one or two injections daily, using an analog 70/30 mix with the largest meal of the day (usually dinner). There is a good chance that goal A1C will be reached due to better postdinner control of glucose excursions. Additional doses can be added as necessary as demonstrated in the 1-2-3 trial described below
- Eating patterns: Any premixed insulin regimen should be considered only with a stable meal pattern. Unlike basal therapy administered before bed, premixed insulin cannot be administered without a meal and thus may not be suitable for individuals with erratic meal habits (whether in content or timing). For example, they cannot be scheduled before breakfast if the patient never has breakfast!
- Number of injections: Relative to the basal bolus option (BBT), premixed insulin minimizes injections by combining prandial and basal insulins into a single injection that can address both basal and post-prandial requirements
- Insurance coverage: The analog premixed insulins available in pen devices are well covered by insurance. However, patients lose insurance or reach the “donut hole,” switching to human vial and syringe, a less expensive option for individuals needing to pay out of pocket, is relatively simple.
- Copays: BBT requires two copays versus only one needed with premixed insulin—material to patients on tight budgets.
- Self-Monitoring: Relative to BBT, a premixed option may require less daily self-monitoring of blood glucose.Discontinuing oral agents: To minimize complexity, cost, and risk of hypoglycemia and weight gain, oral sulfonylureas should be stopped whether intensifying with premixed or BBT.
Safety and efficacy considerations
Excellent data show the efficacy of intensifying with a premixed option. The 1-2-3 study[1] took patients uncontrolled with multiple oral antidiabetic drugs (OADs), or at least one OAD and a basal insulin, randomizing the group to a 70/30 BiAsp premix at dinner or single injection of basal insulin. 70/30 BiAsp was titrated to a fasting blood glucose of 80-110. If at week 16 A1C was over 6.5, a second injection of BiAsp 70/30 was added at breakfast with a goal to titrate to pre-dinner 80-110 range. If by week 32 the A1C was not under 6.5 a third (prelunch) injection was added. Using this approach investigators brought 41%, 70% and 77% of patients to goal using daily, BID, and TID injection respectively, with low hypoglycemia incidence.
Other studies have demonstrated the ability to, if needed, safely schedule 70/30 insulin three times a day.[2] Many clinicians underappreciate the flexibility of adding a prelunch dose.
Further evidence that 70/30 premix is a reasonable option for intensification after basal insulin comes from the DURABLE trail. In a sub-study,[3] 475 patients unable to achieve A1C goal of <7mg/dl on glargine insulin and OAD therapy were randomized to intensification with premixed insulin (LisproMix, LM, 75/25) vs BBT)with glargine and premeal lispro. Mean A1C was 8%. and mean age 57 years. 199 were randomized to BBT and 200 to LM 75/25 twice daily. After six months study groups showed no significant difference in total daily insulin dose, weight gain, incidence or rate of hypoglycemia, or incidence of serious adverse events. While the study is potentially limited by lack of aggressive dose titration (fewer than 20% of patients in each group achieved A1C goals) it does provide perspective on the potential noninferiority and relative simplicity of the premixed approach.
Like all insulin regimens a 70/30 premix approach requires careful glucose monitoring and adjustments. Patients will fail to get to goal without effective dose titration. Relative simplicity of titration is another reason I advocate a premixed insulin for our patient. While studies show patients can get to goal with once daily injections, many physicians prefer commencing with BID dosin –especially with quite elevated A1C. In that scenario most clinicians will give half the basal dose prebreakfast and the other half predinner. This proportion can be modified for patients with a large imbalance of calories/carbohydrates between breakfast and dinner (a larger breakfast may require greater percentage of the daily insulin, for example). Patients injecting predinner insulin can adjust this dose based on morning sugars (prebreakfast fasting). Patients injecting prebreakfast premixed can adjust this dose based on predinner sugars. Table 1 suggests such a titration schedule.
Premixed options
There are several premix options on the market. Each delivers both intermediate and rapid acting insulin. Differences include 1) human versus analog and 2) various intermediate:short acting ratios.
Analog insulins have the advantage of a more physiologic action profile. They are available in both vials and pen format and are more expensive than human insulins, although insured individuals may have similar copays. Selection of a particular agent should be made based on patient preference, dexterity (individuals with arthritis or neuropathy for example may not be able to administer vial and syringe), cost, lifestyle, and overall comfort. Patients who experience hypoglycemic episodes may benefit by switching from human to analoginsulin.
Table 2. Available Premix Insulins
Potential limitations
Despite the many advantages of a premixed approach, several important limitations should be considered.
- Need for consistent carbohydrates in each meal, which may be difficult for some patients to regulate
- Inability to manage “high sugars” with supplemental injections. Theintermediate acting component will leave untreated the high sugarsnormally addressed by additional rapid acting units of insulin in a supplemental or correctional manner.
- Intermediate acting insulin may not act quickly enough to cover the dawn phenomena,resulting in high morning sugars.
- Patients transitioned to NPO status or admitted to the hospital will not be able to continue their 70/30 regimen.
- This approach’s fixed ratios may keep patients with elevated post-prandial sugars but low or controlled fasting (or predinner) sugars from achieving post-prandial control. When control of postprandial sugars occurs before fasting control or vice versa, the savvy clinician must consider switching premixed ratios—for example from 70:30 to 75:25 or, in some scenarios, 50:50.
Summary
One thing is clear: this patient needs to have his regimen intensified. Too often clinicians (and patients) maintain the status quo through inertia. Premixed insulin provides a proven, simple, flexible, and efficacious option for this patient. Benefits must be weighed against the limitations outlined above and together, with the patient, the decision should be made.
References
1. Garber AJ et a. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes Obes Metab 2006;8(1):58-66
2. Ushakova O et al. Comparison of biphasic insulin aspart 30 given three times daily or twice daily in combination with metformin versus oral antidiabetic drugs alone in patients with poorly controlled type 2 diabetes: a 16-week, randomized, open-label, parallel-group trial conducted in Russia. Clin Ther. 2007;29(11):2374-2384.
3. Miser WR et al. Randomized, open-label, parallel-group evaluations of basal-bolus therapy versus insulin lispro premixed therapy in patients with type 2 diabetes mellitus failing to achieve control with starter insulin treatment and continuing oral antihyperglycemic drugs: a noninferiority intensification substudy of the DURABLE trial. Clin Ther 2010;32(5): 896-908.
4. Adapted from Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260-265 and Mooradian AD, Bernbaum M, Albert SG. Narrative review: a rational approach to starting insulin therapy. Ann Intern Med 2006;145:125-134.
Glucagon-like peptide-1 (GLP-1)
Irl B. Hirsch, MD
University of Washington Med Ctr-Roosevelt
Seattle, WA
Seattle, WA
This is a typical patient for both specialists and primary care physicians. He is relatively young with hopefully many years of life ahead of him, but because he developed his diabetes in his 40s his beta cell exhaustion has resulted in inability to reach glycemic goals. He is also obese with no evidence that he will lose weight (let alone stay weight neutral), and his description of finding himself “uncontrollably hungry” is a comment we all hear. While his A1C of 8.0% is not ideal but at the same time not horrendous, his young age and early retinopathy would suggest he needs more aggressive therapy, ideally one which will result in both an improvement of glucose control and weight reduction. While traditionally prandial insulin would be suggested for this patient, there is a tremendous resistance by both patients and providers to initiate this therapy for this degree of glycemia.[1] Furthermore, insulin for this patient would only contribute to further weight gain, especially as overall glycemia approaches the normal range.[2]
Since the introduction of exenatide in 2005, many of us have been intrigued about the possibility of combining a GLP-1 analog such as exenatide with basal insulin. From a theoretical point of view, this combination therapy seems logical: basal insulin to mostly reduce hepatic glucose production and fasting hyperglycemia with exenatide to improve postprandial glucose excursions. Anecdotally, many of us have found this combination to work well as we see both glycemia reduction and weight loss—a combination not seen with the addition of mealtime insulin therapy. In fact, in a database of 20,000 clinicians (65% primary care) and 540,000 people with type 2 diabetes, it was shown that 25% of patients who used exenatide did so in combination with insulin therapy.[3]
While this is all interesting, it has been anecdotal. Until now. Recently several reports have documented the benefits of basal insulin therapy in combination with exenatide.[4] While none of these trials have had the appropriate prandial insulin comparator, we know that compared to basal insulin, exenatide will result in weight loss and a reduction of hypoglycemia.[5] Adding mealtime insulin to basal insulin, on the other hand, consistently results in weight gain and dramatically increases hypoglycemia risk. Furthermore, the addition of a GLP-1 analog is fundamentally simpler than the addition of prandial insulin. Dosing is easier (only two doses for exenatide, three for liraglutide) and the number of injections is reduced (twice daily for exenatide, once daily for liraglutide).
In late December 2010, Eli Lilly and Amylin Pharmaceuticals filed a supplemental New Drug Application to the U.S. Food and Drug Administration for use of exenatide as an add-on therapy with or without metformin and/or pioglitazone in combination with basal insulin for patients not achieving adequate glycemic control.[6] Essentially, when this is approved and added to the exenatide label, it will only provide official acknowledgement to what many of us are already doing.
But is this enough? The answer is a strong “no!” We still do need appropriate randomized trials with the appropriate comparator: mealtime rapid-acting analog insulin. What is the real differences (if any) in A1C, hypoglycemia, and, maybe more important than previously given credit for in the past, quality of life, both for the patient and the provider? Let’s face it: mealtime insulin adjustments are much more difficult for the clinician than basal insulin therapy, whether patients count carbohydrates or use some other system for insulin dosing. The need to see pre-meal, occasional post-meal glucose values, and insulin doses, on top of all of the many issues involved with the timing of the insulin, makes prandial insulin complex, especially when compared to the simplicity of using a GLP-1 analog.
The drawbacks of GLP-1 analog therapy have been well-documented, the most common being gastrointestinal side effects and certainly cost. Neither of these should be trivialized as both can result in individual patients not receiving this therapy.
Still, for this patient the addition of exenatide seems to me to be the best choice, and it is my hunch that within the next five years GLP-1 analog and basal insulin combination will be the standard of care for patients with type 2 diabetes.
References
1. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes, Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28:2673-2679.
2. Henry RR, Gumbiner B, Ditzler T, et al. Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-month outpatient trial. Diabetes Care 1993;16:21-31.
3. Hirsch I, Silberman C, Calingaert B. Patient factors associated with GLP-1 analog use with and without insulin in type 2 diabetes: results from a large cohort analysis. Diabetes 2010;59(1):A164.
4. Buse JB, Berganstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized controlled trial. Ann Intern Med e-pub December 7, 2010; Riddle M, Ahmann A, Basu A et al: Metformin+exenatide+basal insulin vs metformin+placebo+basal insulin: reaching A1C < 6.5% without weight gain or serious hypoglycemia. American Diabetes Association Late Breaking Abstract 18, 2010. Last accessed January 9, 2011; Blevens TC, Arakaki RF, Lilenquest DR et al. Once daily basal insulin added to oral antihyperglycemic medications and exenatide improves glycemic control in patients with type 2 diabetes. American Diabetes Association Late Breaking Abstract 19, 2010. Last accessed January 9, 2011.
5. Heine RJ, Van Gal LF, John D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Intern Med 2005;143:559-569.
6. Amylin and Lilly seek expanded use of BYETTA® along with basal insulin. Last accessed January 9, 2011.
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