Recent advances in the treatment of type II diabetes mellitus

Recent advances in the treatment of type II diabetes mellitus – Cover Story

Bantwal Suresh Baliga

Diabetes mellitus needs to be managed early to prevent the onset and progression of complications. Diet and exercise may not be sufficient to achieve and maintain good glycemic control. Currently, no pharmacologic agent addresses all of the fundamental abnormalities in the pathogenesis of type II diabetes mellitus. However, the newer agents do not exacerbate the hyperinsulinemia that often occurs with type II diabetes, and they may help reduce the risk of cardiovascular disease that is associated with high insulin levels. Two of these agents, metformin and acarbose, have recently become available in the United States for the treatment of type II diabetes. With the availability of agents that differ in their mechanisms of action and side effect profiles, regimens can be individualized to address the variety of pathophysiologic abnormalities in type II diabetes. For this purpose, agents can be used alone or in combination.

Diabetes mellitus is associated with significant long-term morbidity and mortality. It is the leading cause of acquired blindness, renal failure and lower limb amputations.

Recently, metformin (Glucophage) and acarbose (Precose) have become available in the United States for the treatment of diabetes mellitus, particularly type II (noninsulin-dependent) diabetes. These agents can improve glycemic control without exacerbating the hyperinsulinemia and insulin resistance that are usually seen in type II diabetes. Prevention of further increases in insulin levels may help reduce the risk of atherosclerotic vascular disease associated with insulin resistance.

If type II diabetes is managed early, complications may be prevented. Frequent reevaluation of the treatment plan may be necessary to achieve therapeutic goals.

Value of Glycemic Control

The Diabetes Control and Complications Trial[1] convincingly demonstrated the relationship between hyperglycemia and the development and progression of microvascular and neuropathic complications over a nine-year period in patients with type I (insulin-dependent) diabetes mellitus. In a prospective study of Japanese patients with type II diabetes who were treated with multiple insulin injections,[2] good glycemic control was maintained over a six-year period and delayed the onset of complications and slowed their progression. The Wisconsin Epidemiological Study of Diabetic Retinopathy[3] revealed a strong relationship between elevated glycosylated hemoglobin (Hb[A.sub.1c]) and retinopathy in patients with type II diabetes.

A Veterans Affairs cooperative study[4] demonstrated the feasibility of achieving excellent glycemic control over a three-year period using intensive insulin therapy in patients with type II diabetes. A stepwise approach to insulin therapy led to about a 2 percent decline in Hb[A.sub.1c] levels (from 9.1 to 7.3 percent) without excessive weight gain or hypoglycemia.

Data were recently published from nine years of the ongoing United Kingdom Prospective Diabetes Study.[5] This study of more than 4,200 patients with type II diabetes compared the effectiveness of diet alone with the effectiveness of intensive therapy using insulin, a sulfonylurea or metformin. All three of the agents used in the intensive treatment group were found to be more effective than diet alone in reducing fasting plasma glucose and Hb[A.sub.1c] levels. Unfortunately, the goal of a near-normal fasting plasma glucose level was not achieved in any treatment group, demonstrating the difficulty of translating theoretical goals into practical, feasible and sustainable interventions. Over the nine-year period, a gradual deterioration of glycemic control occurred in all of the groups, and the incidence of diabetes-related complications was high. When the study ends (most likely in 1998), all data will be evaluated to determine whether improved glycemic control is associated with a decreased incidence of complications.

It is important to remember that macrovascular disease (i.e., coronary artery disease, cerebrovascular disease and peripheral vascular disease) is a major problem in patients with type II diabetes. Treatment strategies should be directed at reducing both macrovascular and microvascular complications.

The American Diabetes Association (ADA) has developed goals for glycemic control in patients with type II diabetes (Table 1). These goals are similar to the goals for patients with type I diabetes. In addition, the ADA consensus statement outlines the ideal drug treatment of hyperglycemia in type II diabetes and addresses several important issues relating to such treatment.[6] TABLE 1

Glycemic Goals for Patients with Type II Diabetes Mellitus Based on Recommendations from the American Diabetes Association

Biochemical index Normal value Goal value

Fasting/preprandial < 115 mg per dL < 120 mg per dL

glucose level (6.4 mmol per L) (6.7 mmol per L)

Two-hour postprandial < 140 mg per dL < 180 mg per dL

glucose level (7.8 mmol per L) (10.0 mmol per L)

Bedtime glucose level < 120 mg per dL 100 to 140 mg per dL

(6.7 mmol per L) (5.6 to 7.8 mmol per L)

Glycosylated hemoglobin < 6% < 7%

(Hb[A.sub.1c])

concentration

Value at which therapeutic

intervention is suggested

Fasting/preprandial < 80 mg per dL (4.5 mmol

glucose level per L) or > 140 mg per

dL (7.8 mmol per L)

Two-hour postprandial > 180 mg per dL

glucose level (10.0 mmol per L)

Bedtime glucose level < 100 mg per dL (5.6 mmol

per L) or > 160 mg per

dL (8.9 mmol per L)

Glycosylated hemoglobin > 8%

(Hb[A.sub.1c])

concentration

SULFONYLUREA FAILURE

A small number of patients fail to respond to initial treatment with sulfonylureas. These patients usually are not obese, and they may have a slow-onset form of type I diabetes. In patients who do respond initially to sulfonylureas, glycemic control tends to deteriorate over a number of years, possibly due to progressive deterioration of beta cell function (i.e., secondary sulfonylurea failure).

In the past, most patients with secondary sulfonylurea failure were treated with insulin. However, due to the reluctance of patients to use insulin, plasma glucose levels remain poorly controlled in many of these patients. Patients with secondary sulfonylurea failure may benefit from the addition of metformin or acarbose to their sulfonylurea regimen.

Metformin

Metformin, a member of the biguanide drug class, was approved by the U.S. Food and Drug Administration (FDA) in 1995. This drug is a helpful addition to the armamentarium of pharmacologic agents for type II diabetes.

Metformin has no effect on insulin secretion; it works by enhancing peripheral and hepatic sensitivity to insulin. This agent acts primarily by inhibiting hepatic gluconeogenesis, thereby decreasing hepatic glucose output.[8] In addition, metformin decreases appetite, induces weight loss and has a beneficial effect on plasma lipid levels. By itself, metformin does not cause hypoglycemia.

In one multicenter study,[9] metformin lowered both fasting blood glucose levels and Hb[A.sub.1c] concentrations in moderately obese patients with type II diabetes that was inadequately controlled by diet therapy. When patients who had poor glycemic control with monotherapy using the sulfonylurea glyburide were switched to metformin, their plasma glucose levels did not improve. However, when metformin was added to the glyburide regimen, fasting plasma glucose and Hb[A.sub.1c] concentrations decreased significantly (Hb[A.sub.1c] dropped from 8.8 percent to 7.1 percent).[9]

The nine-year data from the United Kingdom study[5] indicate that metformin is as effective as insulin or glyburide in decreasing both fasting plasma glucose levels and Hb[A.sub.1c] concentrations, without causing weight gain, hypoglycemia or hyperinsulinemia. The last finding may be important, because hyperinsulinemia is a risk factor for cardiovascular disease.[10]

PRECAUTIONS AND SIDE EFFECTS

Phenformin, another biguanide, was withdrawn from use in 1975 because in rare instances it caused potentially fatal lactic acidosis. The experience with phenformin has raised concern about the risk of lactic acidosis with metformin. However, the effects of metformin on lactate metabolism differ from those of phenformin, which inhibits mitochondrial oxidation of lactate.[9,11] Unlike phenformin, metformin does not elevate plasma lactic acid concentrations beyond the normal range.[12] Furthermore, unless a patient has hepatic or renal disease, metformin does not increase lactic acid turnover or lactate production from the skeletal muscle.[12]

Based on 30 years of experience with metformin in other countries, the estimated risk of lactic acidosis for patients receiving this drug is three cases per 100,000 patient-years, compared with 64 cases per 100,000 patient-years for phenformin. In fact, the risk of lactic acidosis is extremely small when metformin is avoided in patients with contraindications to its use (Table 3). Such contraindications include the presence of renal impairment, as determined by a plasma creatinine concentration of greater than 1.5 mg per dL (120 ,[micro] mol per L) in men and 1.4 mg per dL (110 ,[micro] mol per L) in women. TABLE 3

Contraindications and Precautions for Metformin Therapy in Patients with Type II Diabetes Mellitus

Contraindications

Renal disease or dysfunction (as suggested by, for example,

abnormal creatinine clearance or serum creatinine levels

greater than 1.5 mg per dL [120 [micro] mol per L] in men and 1.4

mg per dL [110 [micro] mol per L] in women), which may also result

from conditions such as cardiovascular collapse

(shock), acute myocardial infarction and septicemia

Known hypersensitivity to metformin

Acute or chronic metabolic acidosis, including diabetic

ketoacidosis, with or without coma (diabetic ketoacidosis

should be treated with insulin)

Precaution

Temporarily withhold metformin in patients undergoing radiologic

studies involving the parenteral administration of iodinated

contrast media, because the use of such products may result

in the acute alteration of renal function

The success of acarbose therapy depends on the presence of digestible complex carbohydrates in the small intestine. Therefore, patients should take the drug along with foods that contain carbohydrates.

The recommended starting dosage for acarbose is 25 mg three times daily, with a dose taken at the beginning of each meal. The dosage should be titrated upward every four to eight weeks. The goal is a maintenance dosage of 50 to 100 mg three times daily (150 to 300 mg per day), depending on individual therapeutic needs and drug tolerance.

Insulin Treatment for Type II Diabetes

Over the long natural history of type II diabetes, many patients ultimately fail to respond to oral agents and require insulin for glycemic control. The decision to start insulin therapy is based on a host of considerations beyond overall glycemic control. Other important factors include the patient’s age, complications, symptoms, concomitant diseases and overall life expectancy. The use of insulin in type II diabetes has been comprehensively reviewed.[17]

Increased hepatic output of glucose, especially at night, is the main determinant of fasting hyperglycemia in patients with type II diabetes. Hence, the bedtime administration of an intermediate-acting insulin (such as NPH) can be very effective in enhancing glycemic control. Studies have established the efficacy of the combination of oral hypoglycemic agents during the day and NPH insulin given at night, the so-called BIDS regimen (bedtime insulin, daytime sulfonylurea).[18] Such a combination may permit the patient to improve glycemic control with only one injection a day. The typical starting dose for nighttime NPH insulin is 0.1 to 0.2 units per kg of ideal body weight, and the dose is then titrated upward until morning hyperglycemia resolves.

Combination Therapy

In its consensus statement, the ADA reviewed the use of combination therapy for type II diabetes.[6] The availability of various drugs that act by different mechanisms and have different side effects permits physicians to design individualized regimens that address the heterogeneity of the pathophysiology of type II diabetes. Cost, duration of action and convenience of administration are also important considerations that may influence the design of a medication regimen (Table 4).

TABLE 4

Comparison of Oral Antidiabetic Agents

Agent Dosage

SULFONYLUREAS

Tolbutamide (Orinase) 1,500 to 2,000 mg per day in divided

doses

Tolazamide (Tolinase) 100 to 500 mg per day, given as a

single dose or in divided doses

Acetohexamide 250 to 1,500 mg per day, given as a

(Dymelor) single dose or in divided doses

Chlorpropamide 100 to 500 mg per day, given as a

(Diabinese) single dose or in divided doses

Glyburide (DiaBeta, 2.5 to 20.0 mg per day for DiaBeta

Glynase, Micronase, and Micronase; 0.75 to 12 mg per

etc.) day for Glynase; 5 to 20 mg per

day for generic

Glipizide (Glucotrol, 2.5 to 40.0 mg per day

Glucotrol XL)

Glimepiride (Amaryl) 1 to 4 mg per day (maximum dosage:

8 mg per day)

BIGUANIDES

Metformin 1.0 to 2.5 g per day in divided doses

(Glucophage)

ALPHA-GLUCOSIDASE

INHIBITORS

Acarbose (Precose) Initially, 25 mg three times daily,

with gradual increase up to

100 mg three times daily, taken

with meals

Duration

of action Cost for one month

Agent (hours) at maximum dosage(*)

SULFONYLUREAS

Tolbutamide (Orinase) 6 to 12 $35.00 (generic: 10.50 to

13.50)

Tolazamide (Tolinase) 12 to 24 36.50 (generic: 12.00 to

15.00)

Acetohexamide 12 to 24 42.00 (generic: 29.00 to

(Dymelor) 34.00)

Chlorpropamide Up to 60 46.50 (generic: 5.00 to

(Diabinese) 8.50)

Glyburide (DiaBeta, 10 to 24 71.50 to 75.50 for DiaBeta

Glynase, Micronase, and Micronase; 53.00

etc.) for Glynase (generic:

61.00 to 62.00)

Glipizide (Glucotrol, 10 to 16 85.00 for Glucotrol; 37.50

Glucotrol XL) for Glucotrol XL

Glimepiride (Amaryl) 24 41.50

BIGUANIDES

Metformin 10 to 12 71.00

(Glucophage)

ALPHA-GLUCOSIDASE

INHIBITORS

Acarbose (Precose) 63.00

(*)–Estimated cost to the pharmacist based on average wholesale prices, rounded to the nearest half-dollar, in Red book. Montvale, N.J.: Medical Economics Data. 1996. Cost to the patient will be higher, depending on prescription filling fee.

The goal of metabolic control may not be attainable with a single agent, either initially or after several years of successful treatment using only one agent. Clinical trials of combination therapy for type II diabetes have been conducted in patients late in the course of their disease, usually after sulfonylurea failure.[15] In the past, most patients who failed to respond to sulfonylureas were treated with insulin alone. This approach resulted in weight gain and very often did not adequately treat the hyperglycemia. Clinical trials of sulfonylureas given with either metformin or acarbose have demonstrated success with this approach.[9,15] If lower doses of individual agents are used, it is possible that the incidence of side effects may be reduced. The use of combination therapy may delay the need for insulin therapy.

An algorithm for the pharmacologic treatment of type II diabetes, as recommended by the ADA, is presented in Figure 1. Some combination therapies have been well studied and are used frequently. Others are less well studied but are likely to be used occasionally. It is possible that the gastrointestinal side effects of metformin and acarbose may occur with increased frequency when these two drugs are used together. However, one study[19] found that the addition of acarbose to metformin did not lead to increased side effects and that the Hb[A.sub.1c] concentration fell by 0.8 percent with this combination therapy. Figure 1. Algorithm for the suggested pharmacologic therapy of type II diabetes mellitus.

[Figure 1 ILLUSTRATION OMITTED]

New Drugs in Development

With a greater understanding of the abnormalities in insulin secretion and insulin resistance, physicians will be able to target pharmacologic therapy. The agents currently undergoing clinical trials for the treatment of type II diabetes include thiazolidinediones such as troglitazone. Thiazolidinediones have been described as “insulin sensitizers,” because they have been shown both to enhance glycemic control and to lower insulin levels. There is hope that these drugs will correct the fundamental abnormalities of the “insulin resistance syndrome.”[9] Not only has troglitazone been shown to improve glycemic control but also it may reduce the hypertension and improve the dyslipidemia that are associated with insulin resistance.[20]

The authors thank Charles W. Smith, M.D., for his suggestions and his critique of the manuscript.

Figure 1 adapted from American Diabetes Association. Consensus statement. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care 1995;18:1510-8. Used with permission.

REFERENCES

[1.] Diabetes Control and Complications Trial 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 1993;329:977-86.

[2.] Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, 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;28:103-17.

[3.] Klein R, Klein BE, Moss SE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. The relationship of C-peptide to the incidence and progression of diabetic retinopathy. Diabetes 1995; 44:796-801.

[4.] Abraira C, Colwell JA, Nuttall FQ, Sawin CT, Nagel NJ, Comstock JP, et al. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM). Results of the feasibility trial. Diabetes Care 1995;18:1113-23.

[5.] Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med 1996;124(1 Pt 2):136-45.

[6.] American Diabetes Association. Consensus statement. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care 1995;18:1510-8.

[7.] American Diabetes Association Task Force on Financing Quality Health Care for Persons with Diabetes. Diabetes outpatient education: the evidence of cost savings. Workshop on approaches to third-party reimbursement for diabetes outpatient education. Alexandria, Va.: American Diabetes Association, 1986.

[8.] Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in noninsulin-dependent diabetes mellitus. N Engl J Med 1995;333:550-4.

[9.] DeFronzo RA, Goodman AM. Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1995;333:541-9.

[10.] DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-94.

[11.] Crofford OB. Metformin [Editorial]. N Engl J Med 1995;333:588-9.

[12.] Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 1994;11:223-41.

[13.] Dandona P, Fonseca V, Mier A, Beckett AG. Diarrhea and metformin in a diabetic clinic. Diabetes Care 1983;6:472-4.

[14.] Hollander R Safety profile of acarbose, an alpha-glucosidase inhibitor. Drugs 1992;44(Suppl 3):47-53.

[15.] Coniff RF, Shapiro JA, Seaton TB, Bray GA. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 1995; 98:443-51.

[16.] Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M, Schollberg K, et al. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732-7.

[17.] Yki-Jarvinen H, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1992;327:1426-33.

[18.] Genuth S. Insulin use in NIDDM. Diabetes Care 1990;13:1240-64.

[19.] Chaisson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus: a multicenter controlled clinical trial. Ann Intern Med 1994;121:928-35.

[20.] Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effects of troglitazone. A new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996;19:151-6.

The Authors

BANTWAL SURESH BALIGA, M.D. is a fellow in the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences and the John L. McClellan Memorial Veterans Hospital, Little Rock. Dr. Baliga received his medical degree from Kasturba Medical College, India, and completed a residency at Royal Liverpool University Hospital in England.

VIVIAN A. FONSECA, M.D. is associate professor of medicine and director of the diabetes program in the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences and the John L. McClellan Memorial Veterans Hospital. Dr. Fonseca attended medical school in India and completed a residency and a fellowship at the Royal Free Hospital in London.

Address correspondence to Vivian A. Fonseca, M.D., Division of Endocrinology/Metabolism, University of Arkansas for Medical Sciences, Mail Slot 587, 4391 W Markham St., Little Rock, AR 72205-7199.

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