CLINICAL DIABETES
VOL. 18 NO. 2 Spring 2000


FEATURE ARTICLE


Factors Influencing Patient Acceptability of Diabetes Treatment Regimens


Jayant Dey, MD, Lawrence Blonde, MD, and Richard Guthrie, Jr., MD


IN BRIEF

Helping patients adhere to often complex treatment regimens and achieve tight blood glucose control can be a challenge. With the appearance during the past few years of several new antidiabetic agents, the task of choosing the most appropriate therapy for patients has become more complex. Various aspects of medication regimens can influence diabetic patients long-term adherence to treatment programs. These include side effects, hypoglycemia, and frequency of administration. This paper attempts to assess oral antidiabetic agents with respect to features that can directly or indirectly affect therapy adherence.

Editor's note: This article includes a discussion of the thiazolidinedione troglitazone (Rezulin). Rezulin was withdrawn from the U.S. market as this issue was going to press.

The linkage between hyperglycemia and complications of diabetes has firmly established the need for maintenance of blood glucose within a recommended range in individuals with diabetes. Helping patients adhere to often complex treatment regimens and achieve tight blood glucose control is a challenge that must be addressed during all phases of diabetes treatment.1

Complications of diabetes, including diabetic eye disease, nephropathy, neuropathy, and peripheral vascular disease, are common in patients with type 2 diabetes. Moreover, type 2 diabetes is a major risk factor for cardiovascular disease. Two landmark studies, the Diabetes Control and Complications Trial2 and the United Kingdom Prospective Diabetes Study (UKPDS),3 have clearly established that tight blood glucose control in both type 1 and type 2 diabetes can decrease the risk of developing secondary microvascular complications. In other studies, lower fasting blood glucose levels have also been associated with reduced mortality4 and reduced incidence of complications5 in type 2 diabetic patients.

Diagnostic guidelines issued by the American Diabetes Association (ADA) in July 1997 have stressed the importance of early and effective treatment of the disease by primary care providers, diabetologists, and patients.6 Treatment goals developed by the ADA emphasize the importance of tight glycemic control for type 2 diabetic patients. ADA Clinical Practice Recommendations (which can be viewed at the ADA Website, www.diabetes.org) include goals of 80120 mg/dl for fasting glucose measurements; 100140 mg/dl for bedtime glucose measurements; and HbA1c <7%.7

One recent model demonstrated that treating type 2 diabetic patients with the goal of achieving normoglycemia can be estimated to cost approximately $16,000 per quality-adjusted life year gained, which is well within acceptable cost-effectiveness ranges established by health policy experts.8 Furthermore, recent studies have shown that improved blood glucose control in patients with diabetes mellitus is associated directly with improvement in several quality-of-life measures.9 Short-term benefits have been demonstrated in patients' mood, affect, sense of well-being, and alertness.10

It is, therefore, important to examine various strategies for improving glycemic control in patients with type 2 diabetes. With the appearance during the past few years of several new antidiabetic agents, the task of choosing the most appropriate therapy for patients has become more complex. Efficacy, patient acceptability, side effects, and cost are important issues to be considered in developing therapeutic regimens.

The vast majority of diabetic outpatients self-administer their own treatment plans developed with their physician and other health care providers. Thus, patient attitudes and beliefs can strongly influence the effectiveness of interventions. Patients' perceptions of the importance of glycemic control and their self-care ability have been identified as key areas for intervention in modifying behavior of type 2 diabetic patients with high HbA1c measurements.11 The difficulty of dietary adherence, complexity of some medication regimens, fear of taking insulin injections, and fear of hypoglycemia and weight gain are all factors that can adversely influence patients' ability to adhere to treatment.12

Patients' ability to adhere to their treatment regimen is crucial for successful management of type 2 diabetes. However, several studies have shown difficulty maintaining optimal adherence with all aspects of therapy. For example, many diabetic patients in the United States have never monitored their own blood glucose levels, and only a minority monitor their blood glucose at least once a day.13 Ensuring that patients take oral medications as prescribed is among the most common problems encountered by primary care physicians treating patients with type 2 diabetes.14 Commonly cited reasons for nonadherence to oral medication regimens include forgetfulness and spontaneous activities.15 Furthermore, patient adherence to diet and exercise regimens is often suboptimal. In one random survey, 85% of primary care providers identified following diet regimens as a problem for people with type 2 diabetes.14

Various aspects of medication regimens can influence diabetic patients' long-term adherence to treatment programs. These include side effects, hypoglycemia, and frequency of administration. Adherence to medication regimens appears to decrease with an increasing number of doses per day.16 Complex regimens may also interfere with adherence and ultimately the success of therapy.17 The relative convenience of drug regimens can be an important determinant of patients' willingness and ability to adhere to effective therapy and therefore affect ultimate efficacy.18

Drugs that are indistinguishable in terms of conventional measures of safety and efficacy may have significantly different effects on quality of life, general perceived health, vitality, health status, sleep, and emotional control.19 Each of these dimensions of drug effect may affect patient adherence, particularly if patients do not fully recognize the seriousness of their health problems, as may sometimes be the case for those with type 2 diabetes.

A major barrier to achieving optimal blood glucose control in patients with type 2 diabetes is the association of improved glycemic control with weight gain. Further, fear of weight gain has also been linked to reduced treatment adherence in both patients with type 1 diabetes and those with type 2 diabetes.

Whereas hypoglycemia is less common among patients with type 2 compared to those with type 1 diabetes, hypoglycemia does occur in type 2 diabetic patients, and its consequences may be even more serious because of the increased prevalence of cardiovascular and cerebrovascular disease. Furthermore, the fear of hypoglycemic episodes may inhibit both physicians and patients from optimizing care.20

Oral hypoglycemic medications vary considerably in their dose regimens, efficacy, and side effects. Each of these parameters may have an impact on the overall likelihood of patient adherence and treatment success. We, therefore, attempted to describe features of oral antidiabetic agents that might be likely to directly or indirectly affect therapy adherence, including the number of daily doses, risk of hypoglycemia, and potential for causing weight gain (Tables 1 and 2).3,9,21-26

Table 1. Characteristics of Specific Insulin Secretagogues*

 

Glipizide

Glipizide GITS

Glyburide

Repaglinide

Glimepiride

Approved daily dosage range (mg)

2.5-40

2.5-20

1.25-20

1-16

1-8

Near mazimum effective dosage (mg)

10 bid

10qd

5 bid

4 bid

4 qd

Excretion

Kidney 80%

Kidney 80%
Bile 20%

Kidney 50%
Bile 50%

Kidney 10%
Bile 90%

Kidney 60%
Bile 40%

Weight Gain

Yes

Minimal Yes Yes Minimal
Frequency of hypoglycemia 19% <4% 20% 16% 1-2%
GI side effects 1-5% 4-7% 1-2% 5% 1-8%
Recommended laboratory monitoring HbA1c HbA1c HbA1c HbA1c HbA1c

*The package insert and/or Physician's Drug Reference should be carefully reviewed for indications, contraindications, and precautions before prescribing any of these medications.
Data in table compiled from the following sources:
Medical Management of Type 2 Diabetes (4th edition); Kelley DB, Ed. Alexandria, Va., American Diabetes Association, 1998.
Physician's Drug Reference 2000.

Glyburide and micronized glyburide (DiaBeta, Glynase, Micronase) are usually taken once daily. Glyburide has a relatively long half-life and also has been associated with significant hypoglycemia.21 Weight gain is also a common accompaniment of treatment with glyburide.

Glimepiride (Amaryl) is usually taken once daily. In a study of single and split daily doses of glimepiride, no patients met the criteria for laboratory-documented hypoglycemia, although two patients experienced mild hypoglycemic symptoms and four patients left the study because of hypoglycemia-like symptoms.22

Glipizide (Glucotrol) is a sulfonylurea that has a duration of action of 1224 h and should be taken 30 min before meals, once or twice daily. The frequency of hypoglycemia and weight gain reported in the registration trials is similar to that of other sulfonylurea agents of its vintage, such as glyburide.

Table 2. Characteristics of Non-Insulin Secretagogue Antidiabetic Agents
  Metformin Troglitazone Rosiglitazone Pioglitazone Miglitol Acarbose
Approved daily dosage range (mg) 5002,550 200600 48  1545 25300 25300
Usual maximum effective dosage (mg) 1,000 bid 600 qd 4 bid 45 qd 100 tid 50 tid

Clearance 

Renal Hepatic Hepatic Hepatic Not absorbed Not absorbed
Weight change None/Modest weight loss Weight gain Weight gain Weight gain None None
GI side effects 1030% 56% 23% Rare Up to 50% Up to 75%
Abnormal liver function tests

Rare, but potentially serious

Rare; not greater than placebo in registration trials

Rare; not greater than placebo in registration trials

Rare

Lactic acidosis Rare, but potentially serious

Recommended laboratory monitoring Creatinine;
HbA1c

LFTs;
HbA1c

LFTs;
HbA1c
LFTs;
HbA1c
HbA1c LFTs;
HbA1c
*The package insert and/or Physician's Drug Reference should be carefully reviewed for indications, contraindications, and precautions before prescribing any of these medications.
LFTs, liver function tests; HbA1c, hemoglobin A1c.
Data in table compiled from the following sources:
1Medical Management of Type 2 Diabetes (4th edition). Kelley DB, Ed. Alexandria, Va., American Diabetes Association, 1998
2Physician's Drug Reference 2000.

Glipizide gastrointestinal therapeutic system (GITS) (Glucotrol XL) allows the same short-acting glipizide to become a once-a-day agent by incorporating the GITS to provide a controlled steady release of glipizide resulting in maintenance of effective plasma glipizide concentrations throughout the 24-h dosing interval. Glipizide GITS has been associated with a very low incidence of hypoglycemia, even when used in elderly patients. In a controlled trial in which 567 men and women with type 2 diabetes were randomized to placebo or glipizide GITS for 12 weeks, the reported hypoglycemic symptoms were not statistically significantly different between the two treatment groups, and there were no documented episodes of hypoglycemia.24 Glipizide GITS-treated patients in this study also experienced no significant weight gain despite significantly improved glycemia.

Furthermore, a recently reported study demonstrated that improved glycemic control of type 2 diabetes was associated with substantial short-term symptomatic, quality-of-life, and health economic benefits. In this study, treatment with glipizide GITS for 12 weeks resulted in a 1.8-percentage-point reduction in HbA1c compared to placebo. Quality-of-life differences for symptom distress, general perceived health, cognitive functioning, and overall visual analog quality-of-life scales were more favorable for the glipizide GITS-treated patients. The glipizide GITS-treated patients had higher retained employment, greater productive capacity, less absenteeism, fewer bed-days, and fewer restricted-activity days than did subjects treated with placebo.9

Repaglinide (Prandin) is a newly approved agent that is a benzoic acid derivative. Like sulfonylureas, it stimulates endogenous insulin secretion from b-cells. It has a very short half-life and must be taken 030 min before each meal.23 In the registration trials, the average weight gain in patients treated with repaglinide and not previously treated with sulfonylurea drugs was 3.3%.

Acarbose (Precose) and miglitol (Glyset) are alphasmll.gif (897 bytes)-glucosidase inhibitors (AGIs) that primarily diminish postprandial hyperglycemia by delaying the digestion of complex carbohydrates to simpler sugars that can be absorbed by the intestine. They are not associated with either weight gain or hypoglycemia when used as monotherapy.26 However, they must be taken before each meal and are frequently associated with gastrointestinal (GI) side effects, especially flatus and diarrhea, which can adversely affect treatment adherence.

Metformin (Glucophage) is taken two or three times daily and is also associated with GI side effects, especially diarrhea. However, its side effects are less frequent than those occurring with AGIs and tend to be self-limiting, diminishing over time.27 Metformin has not been associated with weight gain or significant hypoglycemia when used as monotherapy.28 Metformin therapy in overweight patients in the UKPDS also decreased the incidence of diabetes-related death and myocardial infarctions.29

Troglitazone (Rezulin) is taken once daily and has relatively few side effects but can be associated with edema and weight gain. Troglitazone should be taken with meals in order to optimize absorption. It also requires frequent (monthly for the first year and at least quarterly thereafter) assessment of liver function status because of the potential for rare but serious hepatotoxicity. Troglitazone is no longer indicated as initial therapy in patients with type 2 diabetes. Hypoglycemia is unlikely unless troglitazone is used in combination with insulin or an insulin secretagogue.

Rosiglitazone (Avandia) and pioglitazone (Actos) are the newest thiazolidinediones to become available. Rosiglitazone may be taken once or twice daily with or without food. Rosiglitazone has relatively few side effects but can be associated with edema and weight gain. In clinical studies in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient-years of exposure, there was no evidence of drug-induced hepatotoxicity or elevated ALT levels. The manufacturer recommends "that patients treated with rosiglitazone undergo periodic monitoring of liver enzymes . . . before the initiation of therapy with rosiglitazone . . . and every two months for the first twelve months, and periodically thereafter."30

Pioglitazone can be used as monotherapy or in combination with sulfonylureas, metformin, and insulin. Pioglitazone has relatively few side effects but can be associated with edema and weight gain. It requires once-a-day dosing and carries similar precautionary monitoring guidelines as rosiglitazone with regards to liver enzyme abnormalities. All the thiozolidinediones may take several weeks for onset of action and several months for "peak" action. When used as monotherapy, thiozolidinediones carry little risk of hypoglycemia.

In summary, the approval of several new medications increases the available treatment options for patients with type 2 diabetes and provides the opportunity to combine two or more agents with complementary mechanisms of action when monotherapy fails to achieve desired glycemic targets. Physicians should consider efficacy, side effects, dosing frequency, monitoring requirements, quality-of-life implications, and cost in selecting therapeutic agents. They should also seek to accomplish blood glucose control with agents that intrude as little as possible on lifestyle, cultural issues, personal and professional activities, and individual preferences.


REFERENCES

1Lutfey KE, Wishner WJ: Beyond "compliance" is "adherence." Improving the prospect of diabetes care. Diabetes Care 22:635-39, 1999.

2The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-86, 1993.

3U.K. Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 352:837-53, 1998.

4Andersson DKG, Svardsudd K: Long-term glycemic control relates to mortality in type II diabetes. Diabetes Care 18:1534-43, 1995.

5Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: 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 28:103-17, 1995.

6Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183-97, 1997.

7American Diabetes Association: Clinical Practice Recommendations 2000. Diabetes Care 23 (Suppl 1):S1-116, 2000.

8Eastman RC, Javitt JC, Herman WH, Dasbach EJ, Copley-Merriman C, Maier W, Dong F, Manninen D, Zbrozek AS, Kotsanos J, Garfield SA, Harris M: Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 20:735-44, 1997.

9Testa MA, Simonson DC: Quality of life and health economic benefits of improved glycemic control in patients with non-insulin dependent diabetes mellitus. JAMA 280:1490-96, 1998.

10Reichard P, Pihl M, Rosenqvist U, Sule J: Complications in NIDDM are caused by elevated blood glucose level: the Stockholm Diabetes Intervention Study (SDIS) at 10-year follow up. Diabetologia 39:1483-88, 1996.

11Blaum CS, Velez L, Hiss RG, Halter JB: Characteristics related to poor glycemic control in NIDDM patients in community practice. Diabetes Care 20:7-11, 1997.

12Thompson CJ, Cummings JF, Chalmers J, Gould C, Newton RW: How have patients reacted to the implications of the DCCT? Diabetes Care 19:876-79, 1996.

13Harris MI, Cowie CC, Howie LJ: Self-monitoring of blood glucose by adults with diabetes in the United States population. Diabetes Care 16:1116-23, 1993.

14Jacques CHM, Jones RL: Problems encountered by primary care physicians in the care of patients with diabetes. Arch Fam Med 2:739-41, 1993.

15Ary DV, Toobert D, Wilson W, Glasgow RE: Patient perspective on factors contributing to nonadherence to diabetes regimen. Diabetes Care 9:168-72, 1986.

16Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR: The effect of prescribed daily dose frequency on patient medication compliance. Arch Int Med 150:1881-84, 1990.

17Shinn M, Caplan RD, Robinson EA, French JR Jr, Caldwell JR: Advances in adherence: social support and patient education. Urban Health 6(4):20-21, 57-59, 1977.

18Musey VC, Lee JK, Crawford R, Klatka MA, McAdams D, Phillips LS: Diabetes in urban African-Americans. I. Cessation of insulin therapy is the major precipitating cause of diabetic ketoacidosis. Diabetes Care 18:483-89, 1995.

19Testa MA, Anderson RB, Nackley JF, Hollenberg NK: Quality of life and antihypertensive therapy in men: a comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. N Engl J Med 328:907-13, 1993.

20Korzon-Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, Amiel S: Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care 21:283-90, 1998.

21Gerich JE: Oral hypoglycemic agents. N Engl J Med 321:1231-45, 1989.

22Rosenstock J, Samols E, Muchmore DB, Schneider J: Glimepiride, a new once-daily sulfonylurea: a double-blind placebo-controlled study of NIDDM patients: Glimepiride Study Group. Diabetes Care 19:1194-99, 1996.

23Balfour JA, Faulds D: Repaglinide. Drugs Aging 13:173-80, 1998.

24Blonde L, Guthrie R, Tive L, Fischette C, the Glipizide GITS Efficacy and Safety Trial Study Group: Glipizide GITS therapy improved glycemic control without increasing body weight or adversely affecting plasma lipids in a large double-blind, placebo-controlled efficacy and safety trial [Abstract]. Diabetes 46 (Suppl 2):158A, 1997.

25Simonson DC, Kourides IA, Feinglos M, Shamoon H, Fischette CT: Efficacy, safety and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM: results of two multicenter, randomized, placebo-controlled clinical trials. Diabetes Care 20:597-606, 1997.

26Wolever TM, Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH: Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes. Int J Obes Relat Metab Disord 21:756-63, 1997.

27DeFronzo RA, Goodman AM, the Multicenter Metformin Study Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541-49, 1995.

28U.K. Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-65, 1998.

29U.K. Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-65, 1998.

30Avandia package insert. SmithKline Beecham Pharmaceuticals, Philadelphia, Pa., 2000.


Jayant Dey, MD, is a fellow in Endocrinology, Diabetes, and Metabolic Diseases at the Alton Ochsner Medical Foundation; Lawrence Blonde, MD, is vice chair of the Department of Medicine; and Richard Guthrie, Jr., MD, is medical director in the Section on Endocrinology, Diabetes, and Metabolic Diseases in the Department of Internal Medicine at the Ochsner Clinic and Alton Ochsner Medical Foundation in New Orleans, La.


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