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Pharmacologic Treatment Options for Non-Insulin-Dependent Diabetes Mellitus

  • Author Footnotes
    1 Current address: Chong Hua Hospital, Cebu, Philippines.
    Gerry H. Tan
    Correspondence
    Address reprint requests to Dr. R. L. Nelson, Division of Endocrinology/Metabolism, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905
    Footnotes
    1 Current address: Chong Hua Hospital, Cebu, Philippines.
    Affiliations
    Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic Rochester, Minnesota
    Search for articles by this author
  • Roger L. Nelson
    Affiliations
    Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic Rochester, Minnesota
    Search for articles by this author
  • Author Footnotes
    1 Current address: Chong Hua Hospital, Cebu, Philippines.
      Non-insulin-dependent diabetes mellitus (NIDDM) is a major health concern for clinicians who are responsible for the care of an aging population. The relationship between hyperglycemia and the chronic complications of retinopathy, nephropathy, and neuropathy has been established in patients with insulin-dependent diabetes mellitus, and it is extremely likely that such a relationship exists in patients with NIDDM as well. Diet and exercise are the cornerstone for the management of NIDDM. The assessment of glycemic control should determine which patients with NIDDM need more aggressive intervention to control hyperglycemia. Pharmacologic treatment options include oral administration of the sulfonylureas, a biguanide, and an a-glucosidase inhibitor and subcutaneous administration of insulin. Extensive education about diabetes and self-monitoring of blood glucose levels are important components in maximizing glycemic control. Additional pharmacologic treatment options are necessary when adequate individualized treatment goals are not attained. The goal of therapy is to prevent the onset or progression of long-term microvascular and macrovascular complications. In this review, we present the therapeutic options and outline our approach to the pharmacologic treatment of NIDDM. Relevant medical literature on each treatment modality is reviewed, and the cost of therapy with use of each medication is provided.
      NIDDM (non-insulin-dependent diabetes mellitus)
      Non-insulin-dependent diabetes mellitus (NIDDM) accounts for 90% of all cases of diabetes diagnosed in the United States. The increasing prevalence of obesity, an aging population, and decreased physical activity have led to the increase in the number of patients diagnosed with this condition. In the United States alone, the estimated financial cost of treating NIDDM probably exceeds $30 billion.
      • Huse DM
      • Oster G
      • Killen AR
      • Lacey MJ
      • Colditz GA
      The economic costs of non-insulin-dependent diabetes mellitus.
      The The common misconception that NIDDM is “mild diabetes” has led to less aggressive intervention. The major aim of medical practitioners in managing diabetes should be to prevent the onset or the progression of both macrovascular and microvascular complications. The recent Diabetes Control and Complications Trial of patients with insulin-dependent diabetes mellitus convincingly demonstrated that intensive management of hyperglycemia can decrease these complications.
      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-dependentdiabetes mellitus.
      The pathologic similarity between microvascular complications in insulin-dependent diabetes mellitus and NIDDM suggests that the decreased risk of microvascular complications associated with good glycemic control, as shown in that recent study.
      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-dependentdiabetes mellitus.
      should apply to patients with NIDDM. This assumption was recently supported by a randomized, prospective study of Japanese patients with NIDDM who were followed up for 6 years while they were receiving an intensive insulin regimen.
      • Ohkubo Y
      • Kishikawa H
      • Araki E
      • Miyata T
      • Isami S
      • Motoyoshi S
      • et al.
      Intensive insulin therapy prevents the progressionof diabetic microvascularcomplicationsin Japanese patientswith non-insulin-dependent diabetesmellitus: a randomized prospective 6-year study.
      In this group of patients, good glycemic control delayed the onset and decreased the progression of nephropathy, retinopathy, and neuropathy. Several risk factors of macrovascular disease (lipid profile and platelet adhesiveness) have also been shown to decrease with good glycemic control.
      • Zimmerman BR
      Improvementsin diabetes treatment [editorial].
      Therefore, the purpose of this review is to outline a therapeutic approach to help patients with NIDDM achieve better glycemic control (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Algorithm for treating patients with non-insulin-dependent diabetes mellitus. FPG = fasting plasma glucose; GHgb = glycosylated hemoglobin; LFF = liver function test.
      NIDDM is considered a heterogeneous disorder, characterized by the overproduction and underutilization of glucose due to the impairment of both insulin secretion and insulin action.
      • DeFronzo RA
      The triumvirate: β-cell, muscle, liver; a collusion responsible for NIDDM.
      Diet and exercise remain the cornerstone of the management of NIDDM, with the aim of maintaining ideal body weight and reversing potentially damaging metabolic consequences of the disease.
      • Henry RR
      • Wallace P
      • Olefsky JM
      Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus.
      When these measures fail, pharmacologic therapy is indicated.
      American Diabetes Association
      The pharmacological treatment of hyperglycemia in NIDDM [consensus statement].
      The current treatment options available for NIDDM include the sulfonylureas, a biguanide, an a-glucosidase inhibitor (Table 1), and insulin, either alone or in combination with these orally administered agents. This review deals with our approach in the use of these drugs.
      Table 1Oral Therapy for Non-Insulin-Dependent Diabetes Mellitus
      Side effects
      DrugDose per day (mg)CommonRare
      SulfonylureasHypoglycemiaGastrointestinal, skin rash, liver abnormalities
       Glipizide (Glucotrol)2.5–40
       Glipizide XL (Glucotrol XL)5–20
       Glyburide (Micronase, DiaBeta)1.25–20
       Glyburide (micronized) (Glynase)1.5–12
       Glimepride (Amaryl)1–8
      BiguanideAnorexia, nausea, abdominal discomfort, diarrheaLactic acidosis, pernicious anemia
       Metformin (Glucophage)500–2,500
      α-Glucosidase inkibitorFlatulence, diarrhea, abdominal cramps
       Acarbosc (Precosc)75–300

      Pharmacologic Treatment

      Sulfonylureas

      The sulfonylureas have been used since 1955. Their mechanism of action is complex, but they mainly act by stimulating insulin secretion.
      • Lebovitz HE
      Sulfonylureadrugs.
      Extrapancreatic effects of these drugs include their ability to increase the number of insulin receptors and insulin sensitivity.
      • Gerich L
      Oral hypoglycemicagents.
      In our practice setting, the most commonly used sulfonylureas are glipizide (Glucotrol) and glyburide (Micronase and DiaBeta). These second-generation sulfonylureas are well tolerated and have generally supplanted the first-generation agents; however, no consistent evidence shows that diabetic control is better with use of these second-generation sulfonylureas. The duration of action of glipizide and glyburide is 16 to 24 hours and 18 to 24 hours, respectively.
      • Lebovitz HE
      Sulfonylureadrugs.
      A long-acting preparation for glipizide (Glucotrol XL) and a more potent variant of glyburide (Glynase) are available. A third sulfonylurea, glimepride (Am aryl) recently has recently become available. Patients with liver and renal dysfunction have an increased risk of hypoglycemia, especially when their capacity to counterregulate is impaired. Although we usually have no preference regarding the choice of agents, distinct differences exist between the two drugs. Glyburide has a longer half-life and can be taken with meals, whereas glipizide (excluding Glucotrol XL) has a shorter half-life and ideally should be taken 30 minutes before meals. Unlike glyburide, glipizide is metabolized to inactive components and is therefore preferable for patients with mild renal impairment.
      Obtaining detailed information about the other medications that the patient is taking is extremely important. Drug interactions with trimethoprim, cimetidine, alcohol, and anticoagulants may increase the risk of hypoglycemia, especially with first-generation agents. Sulfonylurea drugs are a major cause of drug-induced hypoglycemia. For mild reactions, adjusting the dose is the only strategy that is necessary. Severe hypoglycemic reactions necessitating hospitalization should be managed by immediate administration of a bolus of 50% glucose, followed by continuous infusion of 10% or 20% dextrose. Hypoglycemia can be avoided by teaching patients to monitor their blood glucose levels periodically, as subsequently outlined. Elderly patients are especially prone to hypoglycemia.
      • Brodows RG
      Benefitsand risks with glyburideand glipizide in elderly NIDDM patients.
      Adverse effects such as skin rash or gastrointestinal discomfort are minimal. Although the University Group Diabetes Program study suggested increased mortality from cardiovascular disease,
      • Meinert CL
      • Knatterud GL
      • Prout TE
      • Klimt CR
      (for the University Group Diabetes Program)
      A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results.
      subsequent subsequent studies have failed to confirm this association.
      • Ohneda A
      • Maruhama Y
      • Itabashi H
      • Oikawa SI
      • Kobayashi T
      • Horigome K
      • et al.
      Vascular complications and long-term administration of oral hypoglycemic agents in patients with diabetes mellitus.
      Once the decision has been made to initiate pharmacologic treatment, we usually begin with the lowest dose (glyburide, 1.25 mg; glipizide, 2.5 mg) and gradually titrate the dose upward by the same increment and no more often than weekly. Patients are instructed to check their blood glucose levels before breakfast and supper until stable glycemic control is reached, at which time, monitoring twice a week before those two meals is sufficient. We instruct patients to aim for a preprandial goal range of blood glucose between 80 and 120 mg/dL or 100 and 140 mg/dL depending on certain factors (Table 2) and a glycosylated hemoglobin value of less than 8% or less than 9% (normal, 4 to 7%), in accordance with the recommendations of the American Diabetes Association (hemoglobin Ale normal, 4 to 6%).
      American Diabetes Association
      The pharmacological treatment of hyperglycemia in NIDDM [consensus statement].
      Twice-a-day dosing with the sulfonylureas is generally used when the dose exceeds 10 mg with glyburide or 20 rug with glipizide. Because studies of the sulfonylureas have shown that the relationship between the drug dose and its biologic effect is not linear, further titration of the dose is by increments higher than these doses. Nevertheless, the greatest effects on glucose control are achieved with a dosage up to 10 mg daily with both glyburide and glipizide.
      • Groop LC
      Sulfonylureas in NIDDM.
      Table 2Prepraitdial Goal Ranges for Patients With Non-Insulin-Dependent Diabetes Mellitus
      • Blood glucose level 80 to 120 mg/dL and glycosylated hemoglobin <8%
        • 1.
          Young age
        • 2.
          Hypoglycemia awareness
        • 3.
          No comorbid factors
      • Blood glucose level 100 to 140 mg/dL and glycosylated hemoglobin <9%
        • 1.
          Advancing age
        • 2.
          Hypoglycemia unawarencss
        • 3.
          Comorbid factors

      Biguanide

      Although metformin (Glucophage) has been used extensively in other parts of the world, it was only recently approved by the Food and Drug Administration for the treatment of NIDDM in the United States. In comparison with the sulfonylureas, this class of drug does not cause hypoglycemia or weight gain. The exact mechanism of action is not entirely known. Investigators have shown that it decreases intestinal absorption of glucose, decreases hepatic production of glucose, and increases glucose uptake by peripheral tissues.
      • Jackson RA
      • Hawa MI
      • Jaspan JB
      • Sim BM
      • Disilvio L
      • Featherbe D
      • et al.
      Mechanism of metformin action in non-insulin-dependent diabetes.
      Investigators estimate that up to 30% of patients will complain of gastrointestinal adverse effects including anorexia, nausea, diarrhea, and abdominal discomfort.
      • Bailey CJ
      Biguanides and NIDDM.
      Malabsorption of vitamin B12 occurs in about 30% of patients, but pernicious anemia is rare.
      • Tomkin GH
      Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin.
      The The most serious adverse effect is lactic acidosis, but the incidence is low and is estimated to be between 0.01 and 0.067 cases per 1,000 patient-years.
      • Campbell IW
      Metformin and the sulfonylureas: the comparative risk.
      Lactic acidosis is rare if the drug is used appropriately-that is, not in patients who have renal impairment (creatinine level, greater than 1.5 mg/dL) or liver dysfunction.
      We use metformin as monotherapy for selected patients, especially obese patients. In the recent United Kingdom Prospective Diabetes Study, metformin was used in obese patients and was shown to be as effective as glyburide and insulin in achieving glycemic control with no change in mean body weight.
      United Kingdom Prospective Diabetes Study Group
      United Kingdom Prospective Diabetes Study (UKPDS) 13: relative efficacy of randomly allocated diet, sulfonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.
      Metformin Metformin also significantly decreased mean fasting plasma insulin concentrations.
      United Kingdom Prospective Diabetes Study Group
      United Kingdom Prospective Diabetes Study (UKPDS) 13: relative efficacy of randomly allocated diet, sulfonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.
      It should be considered when a second drug is needed for patients who are responding poorly to maximal doses of sulfonylureas (glipizide, 40 mg; glyburide, 20 mg) and who are hesitant to initiate insulin therapy. We usually begin with a low dosage of 500 mg once daily to avoid gastrointestinal adverse effects. The dose is increased at weekly intervals until glycemic control is achieved. A maximal dose of 2.5 g administered in divided doses can be tolerated by most patients. The frequency of home blood glucose monitoring is similar to that outlined for the sulfonlyureas-that is, before breakfast and supper two times a week.

      α-Glucosidase Inhibitor

      Acarbose (Precose) was recently approved by the Food and Drug Administration for the treatment of hyperglycemia in patients with NIDDM. It is an intestinal a-glucosidase inhibitor that has been shown to decrease postprandial hyperglycemia by inhibiting carbohydrate digestion and absorption.
      • Bressler R
      • Johnson D
      New pharmacological approaches to therapy of NIDDM.
      In a recent multicenter trial, acarbose was shown to improve glycemic control in patients with NIDDM by causing a significant decrease in mean postprandial glucose levels with a further decrease in hemoglobin Ale levels of 0.4% in the insulin-treated group and 0.9% in the diet-treated group in comparison with pla cebo.
      • Chiasson 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.
      The recommended dosage is 50 mg three times daily to be taken at the beginning of each meal; if the response is inadequate after 6 weeks, the dose is titrated up to 100 mg three times a day. No hematologic or other systemic toxic adverse effects occurred with dosages as high as 200 mg three times daily.
      • Chiasson 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.
      The only major adverse events noted were gastrointestinal symptoms including flatulence, diarrhea, and abdominal cramps. Such symptoms tend to dimin ish with time and be minimized if therapy is initiated with a low dose. Our experience with this drug is limited. It may have a role as a second drug for patients in whom sulfonylureas or metformin fail or as primary therapy for obese patients with reasonable preprandial glucose levels but disproportionately increased glycosylated hemoglobin values.

      Insulin

      Patients with newly diagnosed NIDDM who have severe hyperglycemia (glucose, greater than 350 mg/dL) suggestive of substantial insulin deficiency may not achieve good glycemic control with the orally administered agents. To prevent further effects of glucose toxicity, we usually initiate insulin therapy to control blood glucose levels as quickly as possible. Once glycemic control is achieved in some patients with low insulin requirementsthat is, less than 20 U/day-sulfonylurea therapy may be initiated, and use of insulin therapy may be discontinued; blood glucose levels should be closely monitored.
      Insulin therapy is also indicated for patients in whom the sulfonylurea drugs have failed and who are unable to tolerate the addition of metformin or for those with either significant renal (creatinine level, greater than 2.0 mg/dL) or liver dysfunction. For our patients with NIDDM, we generally initiate intermediate-acting human insulin as a single dose. In our experience, some patients achieve good glycemic control with this approach. This strategy makes the regimen less complicated and more acceptable. We provide extensive education to these patients relative to the frequency of blood glucose testing and insulin dose adjustments, which are usually titrated up by 10% every 3 days. We prefer to initiate insulin treatment in the morning. Certainly more complex regimens can be used (see subsequent discussion) if single injection therapy is inadequate.
      Once the patient's daily insulin requirements reach 60 to 80 U, the total dose of insulin is divided; two-thirds of the dose is given in the morning, and a third of the dose is given before the evening meal. We usually suggest that patients adjust their insulin doses in a “staggered” manner. Instructions are given to adjust the morning insulin dose first to achieve a presupper blood glucose level within the goal range. Once this occurs, the afternoon insulin dose is adjusted to achieve a fasting blood glucose within the goal range. If the glycosylated hemoglobin value is not within the acceptable goal range (less than 8%, or less than 9% in some circumstances, see Table 2), patients may need to add shortacting insulin to the regimen. The need for regular insulin is based on the determination of blood glucose levels before lunch and at bedtime. Premixed insulin (NPH [isophane insulin suspension] and regular insulin) is used only occasionally; dose titration with regular insulin is not possible. Occasionally, for motivated patients, the multiple daily insulin regimen is initiated at our specialized Diabetes Unit.
      • Zimmerman BR
      Practical aspects of intensive insulin therapy.
      This program consists of three injections of regular insulin given before each meal, with an injection of Ultralente (extended insulin zinc suspension) before the evening meal. We rarely recommend insulin pump therapy for these patients.

      Combination Oral Medication and Insulin Therapy

      Although many centers have advocated the combined use of insulin and a sulfonylurea,
      • Peters AL
      • Davidson MB
      Insulin plus a sulfonylurea agent for treating type 2 diabetes.
      this regimen has not been used routinely at our institution. It is more expensive and complex than treatment with insulin alone, and studies have not consistently shown it to be more efficacious than optimized insulin therapy.
      • Pugh JA
      • Wagner ML
      • Sawyer J
      • Ramirez G
      • Tuley M
      • Friedberg SJ
      Is combination sulfonylurea and insulin therapy useful in NIDDM patients?. A metaanalysis.
      The concern that hyperinsulinemia associated with insulin treatment will accelerate atherosclerosis remains controversial.
      American Diabetes Association
      The pharmacological treatment of hyperglycemia in NIDDM [consensus statement].
      • Stem MP
      Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents?.
      We occasionally use the combined regimen for patients whose NIDDM is not controlled with more than 100 U of insulin. We combine the maximal dose of glyburide, 10 mg twice daily, or glipizide, 20 mg twice daily, with insulin and discontinue use of the sulfonylurea after 1 month if no substantial effect is noted. Limited studies have indicated a beneficial effect with metformin in addition to insulin therapy for obese patients with diabetes.
      • Giugliano D
      • Quatraro A
      • Consoli G
      • Minei A
      • Ceriello A
      • De Rosa N
      • et al.
      Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors.

      Goals of Therapy and Frequency of Monitoring

      The preprandial target blood glucose goal range (Table 2) is between 80 and 120 mg/dL for otherwise healthy, relatively young patients with NIDDM. For elderly patients and those with serious medical conditions (for example, coronary artery disease), a blood glucose goal range between 100 and 140 mg/dL is used. The goals for glycosylated hemoglobin levels are less than 8% and less than 9%, respectively. Initially, blood glucose levels in patients taking oral agents or insulin should be monitored twice daily every day until glycemic control is achieved and then twice daily every 2 to 3 days. For patients in whom the multiple daily insulin program is used, extensive education is provided for 5 days, and patients are required to monitor their blood glucose four times a day before meals and at bedtime.

      Cost

      Cost of therapy must be considered for patients with NIDDM. Specific pharmacy charges based in Rochester, Minnesota, are detailed in Table 3. Note that incurred daily expenses total about $35 a week with the combination therapy (glyburide, 10 mg twice daily, and metformin, 2.5 g daily) in comparison with a total of about $7 a week with 40 U of intermediate-acting insulin alone. The cost for home glucose monitoring is generally $0.70 per test; thus, testing twice a day two times a week would cost approximately $3 per week.
      Table 3Patient's Cost per Dose or per Day for Treatment of Non-Insulin-Dependent Diabetes Mellitus
      MedicationDose (mg)Cost per dose
      Sulfonylureas
       Glyburide
        Micronase2.5$ 0.37
      50.60
        DiaBeta2.50.36
      100.65
        Generic2.50.34
      50.53
        Glynase30.55
      60.97
       Glipizide
        Glucotrol50.39
      100.65
        Generic50.35
      100.58
        Glucotrol XL50.31
      100.67
       Glimepride
        Amaryl20.45
      40.80
      Biguamde
       Metform in
        Glucophage5000.48
      8500.87
      α-Glucosidase inhibitor
       Acarbose
        Precose1000.69
      Insulin
       NPH (isophane insulin suspension)1,000 U (bottle)18.03
      Insulin versus combination therapyDoseCost per day
      NPH insulin40 U$0.72
      Syringe0.25
       Total0.97
      Glyburide10 mg b.i.d.
      b.i.d. = twice daily.
      2.40
      and
      Metformin2.5 g/day2.50
       Total4.90
      * b.i.d. = twice daily.

      Conclusion

      The management of NIDDM is challenging to both the patient and the physician. Of importance, each person with diabetes must be aware of the known relationship between hyperglycemia and chronic complications of the disease. Most patients tend to neglect to follow instructions on home glucose monitoring partly because they have not been taught how to adjust the dose of oral medication or insulin based on their glucose readings. Monitoring of glycemic status should be a cornerstone of diabetes management.
      • Goldstein DE
      • Little RR
      • Lorenz RA
      • Malone LL
      • Nathan D
      • Peterson CM
      Tests of glycemia in diabetes.
      Herein we outlined our approach to the treatment of hyperglycemia in patients with NIDDM. Newer, probably more efficacious agents are now in various stages of pharmaceutical development.
      • Bressler R
      • Johnson D
      New pharmacological approaches to therapy of NIDDM.
      Whatever Whatever approach is used, each physician's goal should be to prevent long-term complications associated with hyperglycemia.

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        Tests of glycemia in diabetes.
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