Feature Article
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Oral Agent Treatment of Diabetes Mellitus in Older Adults Dr. Cooper is Professor of Clinical and Administrative Sciences, College of Pharmacy, University of Georgia, Athens, and Assistant Clinical Professor, Department of Family Medicine, Medical College of Georgia, Augusta. Address for correspondence: James W. Cooper, PhD, College of Pharmacy, University of Georgia, Athens, GA 30602-2355.
Pharmacotherapy of diabetes mellitus in older adults, who are predominantly type 2 diabetics, has changed with newer oral agents that can either attenuate sulfonylurea or insulin weight gain, delay or prevent progression to insulin, or contribute to weight maintenance or loss and reduce insulin needs. This article differentiates alpha-glucosidase inhibitor, biguanide, troglitazone, sulfonylurea agents, and repaglinide.
(Annals of Long-Term Care 1998;6[13]:414-422)
The American Diabetes Association (ADA) has established new guidelines and terms for diabetes mellitus (DM), shown in Table I.1 Formerly called type I diabetes, or insulin-dependent diabetes mellitus (IDDM)—also referred to as juvenile-onset diabetes—this form of DM is now called type 1 diabetes and usually requires insulin. Type II diabetes, formerly known as non–insulin-dependent diabetes mellitus (NIDDM)—also known as maturity-onset or adult-onset diabetes—is now called type 2 diabetes. Type 2 diabetes usually can be managed by diet, exercise, and oral hypoglycemic agents in early stages (Figure), but it may require insulin in later stages, especially if weight gain is evident with such oral agents as the sulfonylureas.1
Fasting Plasma Glucose
New limits have been set for fasting plasma glucose (FPG).1 A normal level of FPG is now considered to be less than 110 mg/dL. An FPG 110 to 125 mg/dL is referred to as impaired glucose tolerance (IGT), which is a new ADA category. An FPG of 126 mg/dL or more in two consecutive weekly samples is now considered to be diabetes mellitus. There is a lower limit for FPG, because up to 20% of those who are not diagnosed with DM until FPG is 140 mg/dL or more have diabetic retinopathy when the diagnosis is made.2
Assessment of Diabetic Treatment Effects
Diabetic patients, once stabilized within the nursing facility, should have at least a quarterly glycosylated hemoglobin (Hb A1C) test, a monthly FPG test, and at least a weekly finger-stick glucose test at the same time of day as the FPG is measured. There is no national standard for glucose measurement that is independent of technique. Most clinical laboratories report plasma glucose levels. With the exception of the Glucometer Elite® and Sure Step® devices, other home glucose monitoring meters report glucose levels as blood glucose. Blood glucose is 10% to 15% lower than plasma glucose.1 Fasting finger-stick measurement with many devices may, therefore, be 10% to 15% lower than fasting plasma glucose taken from a concurrent venous sample that is centrifuged before the serum is assayed.
Urine sugar and acetone tests (S & As) are of little use in older patients because of variation in renal threshold. A urine acetone test benefits the person with diabetes who is prone to ketosis at any age. The older patient has an extremely variable renal threshold for blood glucose spillover into the urine. For example, a 1+ may vary between 180 and 350 mg/dL in the older patient. Table I outlines what constitutes acceptable plasma versus blood glucose control.
In the patient using a finger-stick glucose measurement device other than the Glucometer Elite or Sure Step, a preprandial level of 105 mg/dL and a one-hour postprandial blood glucose level of 160 mg/dL are suggested as reasonable goals. Because most nursing facilities use finger-stick measurement devices, both plasma and blood glycemic goals of therapy need to be considered, as well as the device that is used to measure glucose (Table II).2
Treatment of Type 1 and Type 2 Diabetes Mellitus
The treatment of people with type 1 diabetes, who constitute approximately 10% of diabetic patients, utilizes exogenous insulin to achieve glycemic control, to reduce the risk of diabetic ketoacidosis (DKA), and to sustain life. The Diabetes Control and Complications Trial (DCCT)3 has shown that tight control (ie, fasting blood glucose of 100 to 120 mg/dL) of blood glucose in type 1 diabetes patients clearly decreases the micro- and macrovascular complications of diabetes. Unfortunately, tight control (FPG < 120) also increases the frequency of hypoglycemic episodes in the type 1 diabetes patient.
The treatment outcomes of diabetes mellitus in the type 2 patient have been less than successful, perhaps due in large part to the very drugs used to control blood glucose, sulfonylurea oral agents and insulin. British2 and Japanese4 studies suggest that tight control of type 2 DM may prevent micro- and macrovascular complications. Exogenous or sulfonylurea-stimulated insulin is a “hunger” hormone that contributes to weight gain. Although blood glucose may appear to be controlled, the majority of patients experience primary or secondary treatment failure with the sulfonylurea oral agents and have to be placed on insulin within several years of the initiation of oral pharmacotherapy.
A significant problem in obese diabetics is related to pretreatment weight and subsequent weight gain with existing therapy. Three newer drugs may well contribute to weight control and loss: acarbose, in most patients; metformin, in younger diabetics with acceptable renal function; and troglitazone, in those with no evidence of hepatic impairment before or during therapy, which may indirectly contribute to weight loss by reducing insulin need and increasing tissue insulin sensitivity. Recent concern over troglitazone liver toxicity has recommended against use of this agent unless all other agents have failed to reduce insulin need. This drug has been removed from health care in the United Kingdom, and it has been excluded by the National Institutes of Health (NIH) from the Diabetes Prevention Program Study.5 Additionally, troglitazone has been associated with weight gain in some persons, especially those with comorbid fluid retention states, such as congestive heart failure (CHF). The contraindication of metformin in CHF patients taking medications for CHF (eg, angiotensin-converting enzyme [ACE] inhibitors or receptor antagonists, digoxin, or diuretics) must also be added to the risk factors for metformin-associated lactic acidosis.6,7
The effect of the newest oral hypoglycemic, repaglinide, on weight has not been documented to date. A much shorter-acting stimulus to a different receptor on the beta cell by repaglinide compared to the longer-acting sulfonylurea agents makes this newer agent a potentially useful therapy for type 2 diabetes patients.
Diabetes Treatment Outcomes in Nursing Facility Patients
The longest study of diabetes mellitus treatment outcomes in the nursing facility from the current literature covers three years.8 A group of 41 patients were retrospectively divided according to the treatment they received into four groups: oral sulfonylurea hypoglycemic agents and diet (five patients); insulin and diet (25 patients); diet alone (nine patients); and no dietary or drug treatment (two patients). Seven of 41 patients crossed over between groups during the three-year study period. All crossed over from the oral agent plus diet to insulin plus diet (ie, 12 patients who began the study period on oral agents and 18 who began on insulin). All patients were further classified by treatment group and by weight variance from ideal body weight (IBW), from less than 20% under their IBW to more than 20% over their IBW.8
Treatment outcomes were assessed by monthly measurements of fasting plasma glucose. Noted for all patients was the presence of hypoglycemia (FPG < 100 mg/dL), hyperglycemia (FPG > 160 mg/dL), and diabetic complications of amputation, decubitus/diabetic ulcers, stroke, high blood pressure, congestive heart failure, ischemic coronary vessel disease, and history of myocardial infarction. Diabetic complications and FPGs outside the acceptable FPG treatment range of 100 to 160 mg/dL were found predominantly in the insulin-plus-diet treatment group. Hyperglycemic episodes were more common (27 of 30 episodes) in the group of overweight patients on insulin who did not comply with the ADA diet nor lose weight. Hypoglycemic reactions were most common in the group of patients on insulin who were at IBW or underweight (17 of 24 episodes) and who had tighter (eg, FPG < 120 mg/dL) control.8
Hospitalization and death rates were compared for both DM and non-DM patients over three years. There was no statistically significant difference in the death rate (24.4% versus 25.5%) or the percentage of patients hospitalized (60.9% versus 60.1%). However, there was a significant difference in the rate of hospitalization for DM patients (2.84%) versus non-DM patients (1.82%) who required hospitalization during their length of stay or the study period. All DM patients who were hospitalized were in the insulin-plus-diet group.8
No patients in this study had a significant weight loss during the study because of general noncompliance with ADA diets on the part of the overweight group.8 All patients on oral sulfonylurea agents or insulin gained weight during their treatment. Furthermore, all patients in the insulin treatment group had failed prior oral hypoglycemic treatment and gained weight while on both sulfonylurea agents and insulin.
In a study contrasting Colorado nursing home and ambulatory diabetic patients, the nursing home diabetics had consistently higher proportions of hospitalizations for diabetic ketoacidosis, coma, insulin reactions, and amputations than diabetics aged 65 and older not residing in nursing homes.9
Up to three-fourths of diabetes in older patients may be glucose intolerant secondary to obesity, especially when patients are more than 20% over their ideal body weight. If overweight people decrease their weight to within 20% or less than their IBW, it is then possible to determine whether they are diabetic or glucose intolerant. If obese type 2 diabetes patients could be leaned down to less than 20% over their ideal body weight, perhaps no more than 10% to 20% would be found to require insulin therapy.1-4
Whereas up to 75% or more of type 2 diabetes patients are obese, and weight reduction alone normalizes FPG, very few patients can actually lose weight, primarily due to the predominant antidiabetic drugs used, sulfonylurea agents and insulin. Both sulfonylurea agents and insulin stimulate appetite and produce weight gain in many type 2 diabetes patients. Therefore, it is difficult or impossible for them to lose weight or approach their ideal body weight without an oral agent that may lower their insulin need.1-4
Newer Oral Hypoglycemics
Newer oral hypoglycemics may help minimize exogenous insulin or sulfonylurea usage and allow weight control. The recently revised ADA guidelines for treatment of type 2 diabetes patients suggest that all oral agents and combinations of oral agents should be tried before resorting to insulin, as long as relative contraindications to use do not exist.1 Acarbose, repaglinide, and metformin present a nonsystemic (acarbose) and two systemic (repaglinide and metformin) approaches to treat the person with type 2 diabetes. Troglitazone may be a last resort before insulin and may be added to other oral agents before resorting to insulin in patients with acceptable liver function, both before and during therapy.
Table III illustrates the ways in which all current oral agents exert their effect in the treatment of diabetes.1,2,10-12 In early stages of type 2 diabetes treatment, a logical addition to the dietary approach would be to add the following to a sulfonylurea agent or repaglinide: metformin, if renal function is adequate; troglitazone, if poor renal but good hepatic function is seen; or acarbose, in order to attenuate gut carbohydrate absorption and to aid in weight control. Table IV depicts the biochemical effects of the oral agents on plasma glucose and lipids.1,2,10-12
Step-Care Treatment of Type 2 Diabetes Patients
In the nonobese type 2 diabetes patient, a sulfonylurea, acarbose (an alpha-glucosidase inhibitor), repaglinide (a sulfonylurea agent), or metformin (if renal function is appropriate and no CHF is evident) may be indicated as the first drug, after diet and exercise.
Acarbose
The primary clinical effect of acarbose is to reduce the postprandial glucose level and subsequent insulin release by producing a reversible, delayed absorption of dietary complex carbohydrates (CHO) from the upper to the lower bowel. This effect shifts the CHO load to the lower gut, where bacterial fermentation produces gas and an increased stool volume that can lead to increased stool softening and frequency, prokinetic effect, hyperdefecation, and, if not carefully titrated, diarrhea. The intake of simple sugars appears to contribute more to flatulence than complex CHOs. The laxative effect is similar to that of 70% sorbitol, the most rational laxative available for use in the long-term care resident who is predominantly renally impaired and incontinence dehydrated.13
Because chronic constipation exists in more than 50% of long-term care residents, this beneficial side effect of acarbose may decrease the use of laxatives.13 Acarbose also has been demonstrated to lower insulin requirements. In addition, acarbose has been investigated in weight-reduction trials with some success, but neither this use nor its use for lipid lowering has been thoroughly evaluated nor approved by the Food and Drug Administration. Acarbose should not be used in persons with a serum creatinine clearance of 2 mg/dL or greater or those with a creatinine clearance of less than 25 ml per minute.14
The starting dose of acarbose is 25 mg daily with the first bite of a meal for two weeks, then 25 mg twice daily with meals for two weeks, then 25 mg three times daily. The dose may be similarly increased to 50 mg, and up to 100 mg three times daily at biweekly intervals, as tolerated and needed. Most nursing facility patients use 100 to 150 mg per day. The maximal reduction in postprandial blood glucose level will be from 20 to 40 mg/dL. The maximal reduction in levels of hemoglobin A1C is about 1 g% to 1.5 g%, with ranges from 0.5% to 6% in the most obese patients.
Diet and Acarbose. It is important for the patient and the dietitian in the nursing facility to realize that patients should be given CHOs (eg, starches, cereals, pasta, and bread) rather than such simple sugars as sucrose and fructose with each meal. The amount of gas that they have will be increased with intake of increased proportions of simple sugars, or “sweets.” Beer and legumes, such as peanuts and peas, will also increase flatulence when acarbose is started. Fifty percent to 60% of the diet should be composed of complex carbohydrates in order for acarbose to be beneficial. Patients on high-protein diets will derive little benefit from acarbose.
Acarbose and Excessive Gas. Despite a gradual titration schedule as suggested for acarbose, excessive gas may be a problem. Antiflatulents that contain simethicone may be effective. Preparations made of alpha-D-galactosidase enzyme, which is inhibited by acarbose, would not be expected to reduce gas when used with acarbose. If the patient has chronic constipation, a reduced laxative dose should be administered as needed and will be necessary to decrease the chance of diarrhea when acarbose therapy is started.
Acarbose and Pancreatic Insufficiency. The digestive enzymes that are given to patients with pancreatic insufficiency, such as pancrelipase and pancreatin, are also inhibited by acarbose. The only carbohydrate digestive enzyme that is not inhibited by acarbose is lactase. Therefore, skim milk may be used for the treatment of low blood sugar and dairy products may be used for the prevention of osteoporosis. Unfortunately, lactase deficiency may be prevalent in as many as 60% of elderly patients, especially females. This deficiency necessitates the use of glucose tablets or solutions for the treatment of low blood sugar when acarbose has been used in the previous 24 to 48 hours.
Hypoglycemia Treatment During Acarbose Therapy. Hypoglycemia is not a side effect of acarbose. Hypoglycemia is caused by the sulfonylurea agents, repaglinide, metformin, troglitazone, and insulin, but not by acarbose. The treatment of low blood sugar may be the problem when acarbose is added to other antidiabetic agents. Because acarbose inhibits the breakdown of such oral disaccharides as sucrose to the usable sugar glucose, the patient or caregivers must have glucose tablets or solution available—or skim milk, if the patient has tolerated milk in the past—in order to treat hypoglycemic episodes due to sulfonylurea agents or insulins. Whereas acarbose itself is not absorbed appreciably from the normal gut, the breakdown products may be absorbed up to 30%. In higher doses above 300 mg per day, transient elevations of serum transaminases have been noted in up to 3.8% of patients.15
Possible Benefits of Acarbose. Gastroesophageal reflux disease (GERD) is common in more than 60% of nursing facility residents, and diabetic gastroparesis may be a complication of diabetes mellitus. Because acarbose increases the osmotic carbohydrate load in the lower small bowel, it increases peristalsis that can aid in gastroparesis “from the bottom up.” The prokinetic agents—metoclopramide and cisapride—work “from the top down” in the gut and tighten the lower esophageal sphincter, as well as promoting peristalsis. It may, therefore, be necessary to decrease the dose of both laxatives and prokinetic agents or to discontinue the use of both agents when starting acarbose to lessen the chance of hyperdefecation or diarrhea.
Pharmacoeconomics of Acarbose in Nursing Home Patients. Acarbose addition to the drug regimen of a patient with chronic constipation or GERD may save drug costs for laxatives and other gastrointestinal drugs. For example, the daily use of laxatives and such gastrointestinal (GI) agents as cisapride for GERD may be decreased when acarbose is added to the patient’s drug regimen. The following case illustrates this point.
An 81-year-old male had type 2 diabetes that had been poorly controlled with the maximum dosage of 40 mg of glipizide daily (FPG = 170-192, HbA1C = 9.1). Despite compliance with the drug, he had gained 17 pounds over the past four years of glipizide therapy. He was also taking 60 ml per day of 70% sorbitol and 10 mg of cisapride three times per day for GERD and suspected diabetic gastroparesis. The addition of acarbose resulted within a six-month period in a discontinuance of sorbitol and a decrease of cisapride to 5 mg twice a day, as well as a decrease in glipizide to one-half the maximum dose. The net cost savings of this change was the 1996 Drug Topics Redbook cost of acarbose at $41.05 a month, minus the cost of decreased doses of cisapride ($39.64 a month), discontinued sorbitol ($19.63 a month), and decreased doses of glipizide ($36.00 a month), or a savings of $96.62 per month. The patient also lost 9 lbs and had a range of FPG of 124 to 144 and an HbA1C of 7.4 after six months of acarbose and glipizide therapy. The patient did not require antiflatulence therapy.
Acarbose Added to Other Antidiabetics. A recent double-blind, placebo-controlled study of the one-year efficacy of acarbose addition to other antidiabetic agents has shown that acarbose lowered the postprandial glucose and HbA1C levels in all treatment groups in the following descending order: diet alone (0.9% drop in HbA1C); sulfonylurea agent (0.9%); metformin (0.8%); and insulin (0.4%). The only caveat beyond those for flatulence and GI function is that because metformin has GI effects, especially in the first several weeks of therapy, neither acarbose nor metformin should be added to the other until GI effects are minimal with the first agent.14 There was no additional effect on serum C peptide or lipids when acarbose therapy was added to other drugs.
Combinations of Oral Agents
When considering an alternate agent, it is essential to add a second agent and not discontinue the first oral agent, unless there is unacceptable toxicity or complete lack of efficacy with the first agent.
Metformin Therapy of Type 2 Diabetes Patients
The biguanide phenformin was taken off the market due to lactic acidosis problems. To date, metformin has not been linked with frequent acidosis problems in younger patients with normal renal function or CHF after extensive usage in Europe and Canada. This difference may be due to the fact that metformin is not extensively metabolized in the liver and is excreted via the renal route. Unfortunately, if the renal route is compromised—even on a functional loss basis—the likelihood of lactic acidosis is increased.
The main use of metformin should be as the systemic oral drug of choice in the obese younger (up to age 55) type 2 diabetes patient with good renal function (ie, creatinine clearance [CrCl] > 60 ml/min)16 who has not responded to diet plus sulfonylurea or acarbose therapy. The package labeling for metformin states that metformin should not be used in males with a serum creatinine (SCr) level of 1.5 mg/dL or more, or in females with an SCr level of 1.4 or greater, or an abnormal creatinine clearance. A recent review has suggested that metformin not be used in patients with an actual or estimated CrCl of less than 60 ml/min.16 Because the average CrCl of nursing facility residents is 40 ml/min17—and virtually all residents have a moderate renal impairment on a functional loss basis—metformin is not considered to be a safe agent for use in nursing home residents with type 2 diabetes. The CrCl is a more reliable indicator of renal function than SCr in older adults. The Cockcroft-Gault method is a simple and reliable method of estimating CrCl.18 The Cockcroft-Gault equation for CrCl estimation is as follows:
CrCl for males = 140 - age x current body weight (kg)/
serum creatinine x 72
(Multiply by 0.85 for females. Always round up Scr if less than 1.0 to 1.0 to avoid overestimating CrCl.)
The following case illustrates an important point regarding the less than rational use of metformin in nursing facility residents: metformin does cause low blood glucose when used as monotherapy.
An 80-year-old female weighing 50 kg with a serum creatinine level of 1.0 mg/dL was started on 500 mg of metformin twice daily for type 2 DM. Her calculated CrCl was as follows: 140 - 80 x 50 x 0.85/ 1.0 x 72 = 35.4 ml per min. After two weeks of therapy, she was found stuporous with an FPG of 42 mg/dL. The metformin was discontinued, and the patient recovered.
It bears reiteration that the recent addition of congestive heart failure to the list of contraindications to the use of metformin should be followed. Any patient receiving preferred CHF treatment of ACE inhibitors or receptor antagonists, digoxin, and/or diuretics should be followed closely and considered a candidate for alternative oral hypoglycemic agent or insulin therapy.6,7
Hypoglycemia Caused by Metformin Monotherapy
A three-patient case series has recently been reported (J.W.C., unpublished data, 1998). All of the patients were elderly diabetics with moderate renal impairment (ie, CrCl = 10 to 50 ml/min) via the Bennett-Singer method of classification of renal impairment.19 Three other patients using metformin monotherapy within the same nursing facility, but with higher CrCl levels, did not exhibit low blood glucose. The sulfonylurea agents are the most likely agents to cause hypoglycemia, especially the longer-acting forms (Table IV1,2,10-12 and Table V20).
Acarbose With Metformin Therapy
The aforementioned benefit of adding acarbose to metformin has been shown.14 However, there is limited experience when metformin is added to acarbose therapy. The likelihood of significant GI effects (ie, gas and laxative effect) bears reiteration, because the predominant side effects of metformin are nausea, emesis, and diarrhea.
Metformin With Sulfonylurea Agents
A study of metformin efficacy found that both metformin monotherapy and combined therapy with glyburide improved glycemic control and lipid concentrations. Whereas metformin alone is not likely to produce significant hypoglycemia, the combined use of metformin with glyburide produced hypoglycemia in nearly one of five patients. This result may necessitate a 25% to 33% reduction in sulfonylurea dose when metformin is added or titrated, if the patient is at maximal sulfonylurea dose.19 The mean reduction in FPG was 77 mg/dL and the level of HbA1C was 1.9% with both the sulfonylurea agent and metformin.
Metformin and Iodinated Contrast Materials
Metformin should be withheld for two to four days before patients receive iodinated contrast materials because of the acute alteration in renal function caused by iodinated contrast. It is essential that renal function be checked at weekly intervals after use of iodinated contrast materials. If SCr is more than 1.4 in either sex or if CrCl is less than 50 to 80 ml per minute via the estimated method above,18,21 metformin should not be restarted.
Special caution should be followed when acute dehydration problems occur in otherwise healthy persons. Acute or chronic acidosis is also a contraindication. There is a boxed warning in the package insert about lactic acidosis, and the University Group Diabetes Program (UGDP)22,23 study results have been repeated in package information, even though the UGDP involved phenformin and tolbutamide, not metformin. Liver impairment is also a contraindication to metformin usage.
The usual starting dose of metformin monotherapy in patients with a CrCl of more than 60 ml/min is 500 mg given twice a day with the morning and evening meals. This dose may be titrated upward weekly by changing from 500 mg to 850 mg with the morning meal and with similar increases with the evening meal. Most patients should reach acceptable FPG and HbA1C levels with four to six weeks of metformin therapy.
The therapeutic effect of metformin in younger patients with acceptable renal function may not be seen until the dose is 1000 mg to 1700 mg per day or more. Dosage increments of 500 mg or 850 mg may be made weekly, up to a maximum dosage of 1700 mg to 2000 mg per day. If patients have not responded after four weeks of maximal metformin dosage, a sulfonylurea agent may be added cautiously; however, only glyburide has been studied with metformin. Studies have been done of metformin use with chlorpropamide (which should be avoided due to a variable and long half-life), tolbutamide, and glipizide. Acetohexamide (which should also be avoided due to a prolonged half-life) and tolazamide have not been studied with metformin.
Weight loss may be common in obese type 2 diabetes patients who respond to metformin therapy and is regarded as a beneficial effect. It would be prudent to decrease the dose of metformin or a sulfonylurea agent if combined therapy is employed, in order to prevent hypoglycemic reactions.
Metformin and Insulin
There are studies that show the benefit of sulfonylurea agents in lowering the insulin dose needed in some people with type 1 and type 2 diabetes. Although it remains an attractive possibility that metformin may well be shown to have a similar or greater effect than the sulfonylurea agent, there is no current FDA-approved or labeled indication for this use. There are, however, anecdotal reports of patients who have both reduced their insulin doses and completely converted to metformin therapy from their insulin. The loss of weight with metformin therapy appears to be the best indicator of reduced insulin need. Perhaps this result may bear out the impression that if, indeed, up to three-fourths of people with type 2 diabetes are glucose intolerant seconoary to obesity to some extent, weight loss can produce euglycemia in a substantial portion of this population.
Pharmacoeconomics of Metformin Therapy
If metformin therapy is used in an older adult with type 2 diabetes, despite the above caveats about functional renal loss and CHF, the cost of renal function monitoring (RFM) should be taken into account. RFM may cost from $50 to $150 per month, depending on the renal function test(s) ordered.
Troglitazone as Monotherapy and Combined With Sulfonylurea or Insulin
Troglitazone is an insulin sensitizer that acts similarly to metformin but is almost exclusively hepatically transformed. Troglitazone is indicated for first-step therapy or for addition to patients on insulin therapy whose HbA1C is more than 8.5%. It is important to watch for hepatic impairment, expansion of overall fluid volume (high blood pressure, CHF), and weight gain. Troglitazone may increase low-density lipoproteins and total cholesterol and decrease triglyceride levels. Troglitazone should be carefully added to the regimen of patients with fluid retention states, such as NYHA [New York Heart Association classification] heart failure at stages higher than II or chronic renal failure. It may be wise to weigh patients daily for the first month of therapy. Because troglitazone has been taken off the market in the United Kingdom and removed by the NIH Diabetes Prevention Program Study due to liver toxicity, need for liver transplants, and deaths, it would be prudent to conduct monthly liver function tests (LFTs) for the first six months, then every other month for six months. Quarterly LFTs should be conducted when troglitazone is added to the diabetic’s regimen. Because LFTs can run some $60 to $130 per month, cost should be borne in mind when adding troglitazone therapy to nursing facility residents’ diabetes treatment.
Sulfonylurea Agents in Type 2 Diabetes Patients
The sulfonylurea agents were the sole oral agents available for type 2 DM after the removal of phenformin from the market until the introduction of acarbose, repaglinide, troglitazone, and metformin. The sulfonylurea agents remain the first-step agents used by many clinicians. The newer agents are preferred (eg, glipizide, glyburide, and glimepiride) over the older agents because of a lower prevalence of adverse effects, such as the effect of disulfiram that occurs when alcohol is used.
Glimepiride is the newest sulfonylurea agent and the only one approved for use with insulin. Other sulfonylurea agents that have been used off label with insulin in the type 2 diabetes patient are glyburide and glipizide. Glimepiride may improve peripheral glucose utilization more than the other sulfonylurea agents; it may stimulate beta cell production of insulin as much as the other sulfonylurea agents. However, glimepiride does not work without beta cell function and has, thus, been referred to as a third-generation sulfonylurea agent.
A Sulfonylurea-like Agent: Repaglinide
Repaglinide is a sulfonylurea-like oral hypoglycemic that acts on a different receptor in the beta cell but produces the same net effect as the sulfonylurea agents. Repaglinide is short-acting, meant to be taken with each meal (as 0.5-mg, 1-mg, and 2-mg tablets) with a dosage range of 0.5 mg to 4 mg and a daily maximum dose of 16 mg. Repaglinide may allow the pancreas relief from the continual stimulation of the long-acting sulfonylurea agents, which is referred to as “beta cell burnout.” This burnout typically occurs after as long as five to seven years of sulfonylurea therapy and is considered a secondary treatment failure. Repaglinide reduces PPG (-104 mg/dL) as well as FPG (-61mg/dL) as monotherapy.24 There have been several other recent reviews of oral antidiabetic agents in the elderly.25,26
Summary
This article has discussed both older and newer agents for the treatment of type 2 diabetes mellitus. Table VI is a summary of recommended oral agents.
Acknowledgments
ýhe author has received grant support and/or served on speakers bureaus or advisory boards of Bayer Pharmaceuticals, Bristol-Myers Squibb Company, Pfizer-Roerig, Pharmacia & Upjohn, Warner Chilcott/ Parke-Davis, Hoechst Marion Merrell Dow, and Glaxo Wellcome.
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