Can't open the PDF? Click here for help.

A checklist approach to selecting the optimal treatment regimen for a patient with type 2 diabetes

Professor of Medicine, Department of Internal Medicine, Des Moines University, Des Moines, Iowa

The Management of Patients with type 2 diabetes mellitus (T2DM) requires thoughtful consideration of the available treatment options, which must then be tailored to the individual patient in order to achieve and maintain therapeutic goals. This process, which begins at the time of diagnosis and continues for the remainder of the patient’s life, can be aided through the use of a treatment checklist, along with the 2009 treatment consensus algorithm jointly developed by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD).¹

A checklist of attributes or key features of the ideal treatment regimen, along with goals for each patient with T2DM who requires add-on therapy to lifestyle management and metformin, must be developed with a clear objective and monitoring plan in mind. Although the primary focus of this checklist is antihyperglycemic medications and glycemic control, treatment goals for blood pressure and lipids should also be established and treated to goals.

According to the ADA/EASD consensus panel,¹ an overarching treatment principle is to quickly attain glycemic control without causing hypoglycemia or weight gain, and then maintain glycemic control over the patient’s life span. Implicit in this treat-to-success approach is the need to modify treatment based on glycemic measures and to match disease progression over the continuum of diabetes care while minimizing potential harm and individualizing treatment. This approach most often requires combination therapy. Also included is the need to manage diabetes in the context of the whole patient and minimize the risk of development or progression of comorbidities such as cardiovascular disease, retinopathy, neuropathy, and nephropathy. This is a challenging set of objectives, but with careful consideration and an individualized approach, it is increasingly possible to achieve these objectives with the greater array of treatment options available.

In this article, I review the treatment checklist, discussing the factors to consider in selecting the ideal diabetes treatment regimen—either monotherapy or combination therapy—for a specific theoretical patient over the continuum of diabetes care. We then apply this checklist in the next 2 articles in this supplement. Undoubtedly, you already consider many of the factors in the checklist as you manage your patients with T2DM, making it a useful means to confirm and enhance your practice patterns. Because the checklist embraces a team approach to patient management, it also provides an opportunity to consider the potential roles for office staff and other health care professionals.

  The treatment checklist

Many factors must be considered in developing a treatment plan for patients with T2DM (TABLE). In addition to being useful at the time of diagnosis, the treatment checklist can also be helpful when the treatment plan must be modified to ensure that it is optimally effective. Involving nursing staff, certified diabetes educators, and other health care professionals can be especially helpful in this process.

The following sections focus on the selection and use of antihyperglycemic treatment to manage hyperglycemia. Good nutrition and physical activity should be encouraged, along with monitoring of not only glycemic factors but also blood pressure and lipids, as well as any other risk factors or comorbid conditions. Although some antihyperglycemic agents may have extraglycemic benefits, many patients will be using other agents for comorbid conditions such as hypertension and dyslipidemia. These medications should also be adjusted when blood pressure or lipid goals are not being met.

Factors to consider in selecting an antihyperglycemic treatment for a patient with type 2 diabetes

	Effective in lowering blood glucose Baseline glycosylated hemoglobin (A1C) Fasting plasma glucose Postprandial glucose
	Time to lower blood glucose
	Long-term ability to maintain glycemic control
	Effect on the pathogenesis of type 2 diabetes mellitus Insulin resistance Pancreatic β-cell dysfunction Altered glucagon secretion
	Extraglycemic effects Body weight Blood pressure Lipids Other
	Safety and tolerability Hypoglycemia Weight gain Other
	Ease of use Route of administration Simple dosing regimen Self-monitoring of blood glucose Likely adherence
	Cost Insurance and formulary coverage Copayments

EFFECTIVE IN LOWERING BLOOD GLUCOSE

The ability of a treatment regimen to effectively lower blood glucose and sustain glycemic control is of major importance, as demonstrated in both the Diabetes Control and Complications Trial² and the United Kingdom Prospective Diabetes Study (UKPDS),³ which found a strong, direct correlation between reductions in mean glycosylated hemoglobin (A1C) over time and reductions in the progression of retinopathy and nephropathy. These results provide compelling evidence of the need for treatment efficacy to reach an A1C <7% in most patients; however, these and other available data are insufficient to determine whether any particular treatment is superior to another regarding effects on chronic complications.¹

All agents approved by the US Food and Drug Administration as either monotherapy or combination therapy for the treatment of patients with T2DM reduce blood glucose levels, albeit to varying degrees. Insulin reduces blood glucose in a dose-dependent manner, limited only by hypoglycemia. Metformin, sulfonylureas, thiazolidinediones, glinides, and glucagon-like peptide-1 (GLP-1) receptor agonists significantly reduce blood glucose levels.⁴ Combination therapy using agents with complementary mechanisms of action is often needed to achieve glycemic targets [www.jfponline.com/supplements.asp?id=6690].

The efficacy of a treatment in lowering blood glucose is dependent on several factors, including the duration of T2DM as a consequence of declining pancreatic β-cell function, as well as baseline blood glucose and A1C levels. Because fasting plasma glucose (FPG) is a greater contributor to A1C when it is ≥8.4%, treatments that target FPG reduction may initially be preferred.⁵ However, as the A1C level drops to <8.4% with therapy, the use of treatments that also lower postprandial glucose (PPG) is essential for achieving the target A1C level of <7.0%.⁵ Additional factors include body weight, because of the greater likelihood of insulin resistance with increasing body weight, and previous therapy.

TIME TO LOWER BLOOD GLUCOSE

Medications with a greater and more rapid ability to lower blood glucose are preferable when the A1C level is high or when symptoms of severe or persistent hyperglycemia are present.¹ When the A1C is >8.5%, initiating and carefully titrating basal insulin therapy may be necessary.¹ However, the addition of other glucose-lowering medications should also be considered after 2 to 3 months of treatment with inadequate response or whenever the A1C level is not being achieved.¹ However, the risk of hypoglycemia should be carefully considered, particularly when using aggressive therapy. Before initiating intense regimens, age and other factors should be considered and may be cause for consultation with an endocrinologist.

LONG-TERM ABILITY TO MAINTAIN GLYCEMIC CONTROL

Because T2DM is a progressive disease associated with worsening hyperglycemia and the development of micro-and macrovascular complications, the use of medications that provide long-term glycemic control would be optimal. However, no single medication or combination of medications has been shown to maintain the A1C level at <7.0% over the course of the disease. Therefore, for the vast majority of patients with T2DM, treatment must be intensified or changed over the course of the disease based on blood glucose levels and symptoms. This can involve adding agents or replacing certain agents with those that have greater glucose-lowering efficacy. Because of the need to frequently modify treatment over time, it is essential that the patient take an active role in self-management.^1,6,7

EFFECT ON THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS

The effect of a treatment on one or more underlying pathogenic causes of T2DM is becoming an increasingly substantial consideration. In general, hepatic and peripheral insulin resistance and progressive insulin deficiency caused by β-cell failure are the hallmarks of T2DM. More recently, defects in the incretin response and altered glucagon secretion have also been identified.⁸

When adding a second agent to the initial treatment of lifestyle management and metformin, a medication with a mechanism of action that does not involve increasing hepatic insulin sensitivity, as with metformin, should be chosen. The reduction in the blood glucose level is usually greater when medications that act on different causes of T2DM are used together.¹ With the development of incretin-based therapies, it now appears possible to correct some of the underlying causes of T2DM that are not addressed by most conventional agents, such as β-cell dysfunction^9-12 and altered glucagon secretion.^13,14 If confirmed in large clinical trials, the ability to address these pathogenic causes has significant implications for the treatment of patients with T2DM.

EXTRAGLYCEMIC EFFECTS

Similarly, in selecting an antihyperglycemic agent, its effects on parameters and risk factors other than blood glucose level are important considerations. Because obesity is a major risk factor for T2DM, and its prevalence worldwide is increasing dramatically, the effect of treatment on body weight must be considered. This is a particular concern because many of the medications used to treat T2DM promote weight gain. Indeed, the actual and perceived weight gain associated with the use of many antihyperglycemic medications, including insulin, can be a substantial barrier to treatment.¹⁵ Conversely, weight loss in patients with T2DM is associated with improved control of blood glucose, blood pressure, and blood lipids.¹⁶

T2DM carries substantial risk for cardiovascular disease, with numerous studies showing that treatment of T2DM lowers certain markers of cardiovascular risk.^2,3,17 Using a variety of antihypertensive medications, the UKPDS demonstrated that for each 10 mm Hg decrease in systolic blood pressure, the average reduction in diabetes-related mortality was 15%, the reduction in microvascular complications was 13%, and the reduction in myocardial infarction was 11%.¹⁸ Although not appropriate as primary therapy for cardiovascular disease, it is a significant factor that diabetes treatments can act synergistically with other treatments to lower cardiovascular risk. For example, the ability of insulin, thiazolidinediones, and GLP-1 receptor agonists to improve the lipid profile may be especially valuable for patients with T2DM and hyperlipidemia. Most patients will be using antihypertensive and lipid-lowering agents to achieve blood pressure and lipid goals. The potential for drug-drug interactions should be checked when changing therapy.

SAFETY AND TOLERABILITY

The safety and tolerability of medications can be substantial barriers to treatment. They are especially significant considerations in the care of patients with T2DM because of the generally silent nature of T2DM until late in the disease. Safety, or protection from severe or life-threatening harm, is a central treatment goal. Selection and modification of therapies should be based on concomitant medications and the patient’s underlying comorbid conditions. Although safety and efficacy of medications are the primary focus of clinical trials, physicians are encouraged to monitor and report concerns if they arise during postmarketing use. The practice of monitoring how patients take their medications helps to minimize potential contraindications and drug interactions. Tolerability relates to the degree to which a patient is willing to accept the adverse effects of a drug. Adverse effects are a common reason cited by patients for not adhering to prescribed diabetes medications.¹⁹ Hypoglycemia is a common fear among patients with diabetes, especially those treated with insulin¹⁵ or long-acting sulfonylureas.^20,21 Similarly, the potential for treatment-related weight gain can be a substantial barrier for these patients. Some drugs may be associated with transient nausea or other tolerance issues among patients.

EASE OF USE

When selecting treatment options, ease of use is not often at the forefront but should be considered, given the polypharmacy often required by patients who are managing their T2DM and other conditions. Adding 1, 2, or more diabetes medications to what may already be a long list of medications for comorbid conditions may be overwhelming for the patient. The same can be said of lifestyle management, with recommended changes that often challenge lifelong dietary and exercise habits. In the latter case, the involvement of a skilled clinician, such as a diabetes educator, who is experienced in providing care to patients with T2DM, can be helpful in developing a plan that patients may be more likely to follow.

A simplified treatment option, provided that glycemic control is not compromised, improves adherence. Selecting medications that match the patient’s lifestyle, are administered on the same schedule as concomitant medications, or involve a similar level of self-monitoring of blood glucose (SMBG) are possible approaches. Insulin is well recognized as a diabetes treatment with numerous barriers to its use.^15,22 The perceived complexity associated with insulin, including the use of needles, multiple daily dosing, and the need to adjust the dose based on SMBG, can be mitigated in many ways. For example, while the patient is in your office, having him or her self-inject a saline solution using an insulin pen usually demonstrates the simplicity and lack of discomfort. The predictability of long- and short-acting analog insulin simplifies initiation of insulin therapy. Once-daily insulin dosing is widely accepted by physicians and patients because it is relatively simple to use and is associated with a low risk of hypoglycemia.

The same principle applies to SMBG. Although there is no consensus regarding the role and frequency of SMBG,²³ patients may be instructed to self-monitor their blood glucose level at the same time that they take other medications or with a recurring daily event. SMBG should be part of an educational process to enhance the patient’s understanding of diabetes and can be instrumental in empowering the patient to take an active role in self-management.

It is essential to discuss the complex issues that are priorities to the patient, such as difficulty opening the medication bottle or not wanting to take a medication at work. Based on this discussion, the most appropriate treatment regimen can be chosen. The key points to remember are (1) to keep the treatment as simple as possible to achieve the treatment goals, and (2) to frequently discuss with the patient any concerns or difficulties in using the treatment(s).

COST

Given the current trend toward reduced health care benefits and increased copayments and other out-of-pocket expenses, the medication cost to a patient has never been a more prominent treatment consideration. This cost can vary widely based on insurance coverage, formulary availability, and copayments. Similarly, differences in the cost of a medication among pharmacies can be substantial. Consequently, the cost of medications should be discussed with the patient frequently, especially when a change to his or her health plan is being contemplated. In addition, office staff should be instructed to alert the physician when a patient does change his or her health plan so that concerns about medication costs or availability can be addressed and resolved quickly.

  Summary

T2DM is a multifaceted disease that requires careful selection of treatment, which must be frequently modified over the continuum of care to attain successful long-term management. A checklist of factors to be considered can be helpful in individualizing treatment for optimal effectiveness based on each patient’s needs, concerns, and capabilities.

References

1. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203.
2. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995;44:968–983.
3. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–412.
4. Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):3–68.
5. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003;26:881–885.
6. Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005–2012.
7. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443.
8. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199–E206.
9. Zinman B, Hoogwerf BJ, Duran GS, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146:477–485.
10. Bunck MC, Diamant M, Corner A, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients. Diabetes Care. 2009;32:762–768.
11. Matthews D, Marre M, Le-Thi TD, et al. Liraglutide, a once-daily human GLP-1 analog, significantly improves beta-cell function in subjects with type 2 diabetes. Presented at: American Diabetes Association 68th Scientific Session; June 6-10, 2008; San Francisco, CA.
12. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39–47.
13. Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27:1335–1342.
14. Vilsboll T, Zdravkovic M, Le Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30:1608–1610.
15. 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.
16. Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 2007;30:1374–1383.
17. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–117.
18. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412–419.
19. Grant RW, Devita NG, Singer DE, et al. Polypharmacy and medication adherence in patients with type 2 diabetes. Diabetes Care. 2003;26:1408–1412.
20. Gangji AS, Cukierman T, Gerstein HC, et al. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389–394.
21. Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev. 2001;17:467–473.
22. Rubin RR. Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med. 2005;118(suppl 5A):27S–34S.
23. American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care. 2009;32 (suppl 1):S13–S61.

The Journal of Family Practice ©2009 Quadrant HealthCom Inc.