Feature Article
|
Efficacy of New Drug Therapies for Diabetes in the Elderly Dr. Sinha is Clinical Research Fellow in the Department of Medicine, University of Birmingham, United Kingdom; and Dr. Nattrass is Consultant Diabetologist in the University Hospital Birmingham NHS Trust. Address for correspondence: Dr. Malcolm Nattrass, Diabetes Resource Center, Selly Oak Hospital, Raddlebarn Rd, Birmingham, B27 6JD, UK. E-mail: malcolm.nattrass@university-b.wmids.nhs.uk.
The treatment of diabetes in the elderly poses a challenge. If exercise and dietary measures fail, sulfonylureas may be considered as first-line therapy in the management of type 2 diabetes; however, they may be poorly tolerated in the elderly and carry a significant risk of severe hypoglycemia. Metformin (an insulin sensitizer) is quite useful in treating particularly overweight patients with type 2 diabetes, but in the elderly its use is limited by its potential to cause lactic acidosis in the presence of renal impairment. Newer drugs such as the insulin secretagogues, repaglinide and nateglinide, are as effective as sulfonylureas and have the advantage of causing less hypoglycemia. The thiazolidinediones, rosiglitazone and pioglitazone, are effective in improving glycemic control alone as well as in combination with metformin and sulfonylureas, but they may cause salt and water retention. Insulin treatment is often viewed as a last resort in the elderly, although whether this is fully justified may be debated as new approaches of combining insulin with oral agents raise hope. (Annals of Long-Term Care: Clinical Care and Aging 2001;9[6]:23-29)
Introduction
Type 2 diabetes is a common metabolic disorder that is increasing in prevalence. It is estimated that the number of people with this disorder will double worldwide by the year 2010. 1 Whereas the greatest increases will occur in the developing countries, the Western world will also see a significant rise in numbers, due partly to the increasing longevity of the population (50% of patients with type 2 diabetes are over age 60).2Appropriate management of the disease in the elderly population is a major challenge to physicians and caregivers. In recent years, the awareness of type 2 diabetes as a disease that disrupts more than glucose metabolism has grown with the realization that it forms part of a “metabolic syndrome,” which includes obesity, dyslipidemia, and hypertension. Thus, not only does the hyperglycemia of type 2 diabetes result in considerable morbidity and mortality from the specific complications of diabetes (retinopathy, nephropathy, and neuropathy), but other features from macrovascular complications of the metabolic syndrome raise them even further. Recent studies, particularly the United Kingdom Prospective Diabetes Study (UKPDS), have shown that tight metabolic control of diabetes significantly reduces microvascular complications.3 The situation with regard to macrovascular complications has been less clear. Although there was a reduction in macrovascular events (for myocardial infarction, a relative reduction of 16%), conventional levels of statistical significance were not attained (for myocardial infarction, P = .052). Physicians will interpret this result as they see fit, but the overall conclusion is inescapable: tight metabolic control is essential in the management of type 2 diabetes when there is concern over the development of microvascular, or possibly, macrovascular complications.3 The UKPDS covered much more ground than blood glucose control; however, much of it lies outside the scope of this review (eg, the effect of tight control of blood pressure). One aspect, however, deserves mention here and is particularly pertinent to the United States. Since the University Group Diabetes Programme (UGDP)4 researchers published their results, a cloud has hung over the use of sulfonylureas and biguanides (as evidenced in that study by tolbutamide and phenformin). The UKPDS dissipated this cloud. Its results were no different in outcomes for the sulfonylureas chlorpropamide and glyburide versus early insulin treatment, while its results with metformin suggested a significant improvement in outcome versus other therapies. 3 With improvements in health care and its delivery in the last two decades, many parts of the world are seeing an aging population. Consequently, physicians are treating an older cohort of patients, with a greater number experiencing diabetes. How do the findings of these recent studies, emphasizing the importance of glucose control, translate to managing this elderly population? Clearly, obtaining and maintaining good glycemic control is a primary goal, although this will always be tempered by the individual situation and the various constraints that old age may bring, whether physical (eg, coexisting disease) or social (living circumstances).
Aims of Treatment
The pathophysiology of type 2 diabetes stems from two processes: failure of the pancreas to produce enough insulin, 5 and insulin resistance in liver and peripheral tissues.6 The combined effect of these is failure to regulate hepatic glucose output and inability to promote appropriate glucose uptake into muscle and fat cells. This leads to the cardinal features of diabetes, high fasting plasma glucose levels as well as increased glucose excursions after meals. It is important that the progressive deterioration in glucose control in type 2 diabetes, with time, is mirrored by the loss of beta cell function with little or no change in insulin resistance.7 Traditionally, drugs used in the management of type 2 diabetes have tended to target high fasting plasma glucose with negligible effect upon prandial glucose excursions.8 Recently the meglitinide derivatives have been marketed under the classification of “prandial glucose regulators.” The ideal drug would target both fasting glucose and prandial glucose excursions while causing minimal side effects. Hypoglycemia is of major concern, particularly in the elderly, as are weight gain and fluid retention, especially in the presence of cardiovascular disease. In reality, goals must be set, including relieving symptoms and optimizing glycemic control to prevent complications, and thereby maintaining and/or enhancing the quality of life, while at the same time avoiding debilitating side effects of treatment.
Oral Agents for the Treatment of Type 2 Diabetes
The Table lists the categories of drugs available to treat type 2 diabetes.
Traditional Agents
Before considering the newer agents for type 2 diabetes, it is appropriate to briefly discuss the difficulties and drawbacks of the more traditional agents.
Sulfonylureas. Sulfonylureas are primarily insulin secretagogues that have proven efficacy in lowering glucose levels in type 2 diabetes. Their use is limited, particularly in an elderly population, by the potential for hypoglycemia. (It seems inappropriate to label this a “side” effect—an unwanted effect perhaps—but a direct consequence of efficacy.) The risk is considerably increased for most sulfonylureas when used in patients with impaired renal function. It has been reported that 95% of hospital admissions for hypoglycemia involved patients over the age of 60 years, and 52% of these patients had impaired renal function. 9 Sulfonylurea-induced hypoglycemia should not be taken lightly since it carries the need for hospitalization and a significant mortality. 10
Metformin. Metformin is an insulin sensitizer that, when used in sufficient dosage, also reduces caloric intake. The most commonly encountered side effect is diarrhea, although other gastrointestinal symptoms may also be troublesome. A rare side effect of metformin is lactic acidosis, and the drug is contraindicated in conditions that might impair lactate clearance (hepatic disease) or promote lactate generation (severe cardiac or respiratory disease). The majority of cases of lactic acidosis, which have been reported in the literature, have occurred in patients with renal impairment that has led to metformin accumulation. Metformin use in the elderly should therefore be contingent on pretreatment assessment of renal function and a fail-safe protocol for monitoring renal function during treatment.
Alpha-Glucosidase Inhibitors. Acarbose and vogliobose impair intestinal breakdown and hence slow absorption of disaccharides. Their effect on hemoglobin A1c (HbA1c ) is modest (approximately a 0.6% reduction),11,12 and side effects, as might be predicted, are gastrointestinal.
Recently Introduced Agents
The discussion that follows concerns the roles of new oral agents in the treatment of type 2 diabetes in the elderly.
Glimepiride. Glimepiride is a sulfonylurea preparation designed to be taken once daily. Its maximum glucose-lowering effect is seen at four hours,13 and consequently some physicians advocate its use as a twice-daily drug. It shows similar efficacy to glyburide, gliclazide, and glipizide and reduces absolute HbA 1c levels by 1-2%.14 Disturbances in insulin secretion and action are both involved in the pathophysiology of type 2 diabetes. Glimepiride has a marked insulin secretory effect, both in vitro and in vivo, increasing plasma insulin levels by as much as 50% in patients with type 2 diabetes. 14 However, it provides a less marked stimulation of insulin secretion in proportion to its effect on lowering plasma glucose, which suggests a potent extrapancrea-tic effect, mainly in adipocytes. Nevertheless, the main site of action of glimepiride is the pancreatic beta cell, where the drug initiates insulin secretion by binding to the sulfonylurea receptor (SUR). 14 Glimepiride binds predominantly to a different part of the SUR than glyburide. This may in part explain the fewer hypoglycemic episodes associated with glimepiride compared to glibenclamide.8 This makes glimepiride a suitable sulfonylurea for use in the elderly: quite efficacious and well-tolerated, with no significant effects on the cardiac or renal function.
Repaglinide. Repaglinide is a member of the meglitinide family of benzoic acid derivatives, developed from the nonsulfonylurea moiety of glyburide.15 Working partly through the SUR on pancreatic beta cells, it has a potent insulin-releasing effect. It is absorbed quickly, with fast elimination (plasma half-life less than one hour), through the liver into the bile.16 It is taken, therefore, immediately before each meal to provide the advantage of increased insulin levels at mealtimes. Hence, it is particularly useful in elderly patients who are dependent on an outside source for their meals; they can now miss one meal and avoid the consequence of hypoglycemia simply by omitting the tablet. Metabolized through the liver, repaglinide is suitable for use in the elderly, most of whom have some degree of renal impairment. Trials indicate that repaglinide (0.5 mg to 4 mg with each meal) elicits its primary effect upon postprandial glucose excursions, and that the reduction in prandial glucose excursion, in turn, leads to lower fasting plasma glucose and HbA1c. Compared to placebo, in patients not controlled by diet, two-hour postprandial glucose was lowered by 110 mg/dL, fasting glucose by 70 mg/dL, and HbA1c by 2.1%. 17 Its efficacy in lowering glucose is similar to that of glyburide, but with almost a 50% reduction in severe hypoglycemia for a similar improvement in HbA1c.17 It is well-tolerated, and its short duration of action connotes less hypoglycemia—a serious advantage in the management of diabetes in the elderly. It is also particularly valuable for patients with irregular mealtimes. Repaglinide is effective in combination with metformin. 18 To date, the only study of a combination with a thiazolidinedione was with troglitazone, which also demonstrated efficacy in combination. 19
Nateglinide. Nateglinide is similar to repaglinide in that it is a short-acting insulin secretagogue. Glycemic control is improved by the enhancement of early insulin response to meals. It is effective in combination with metformin; as monotherapy it produces similar reductions in HbA1c to metformin alone. 20 The current trend in the management of both type 1 and type 2 diabetes is to match modern rapid-acting agents (repaglinide or nateglinide/rapid-acting insulin analogues) to physiologic mealtime insulin requirements. There are two main reasons for trying to tailor therapy to mealtimes: one is pathophysiologic and the other is behavioral. The pathophysiologic reason is to restore the early insulin response to meals and hence mealtime levels of insulin to physiologic (or near physiologic) levels to ensure tight glycemic control. The behavioral rationale is derived from the observation that persons with type 2 diabetes are usually overweight and interested in reducing their caloric intake, but because of the risk of hypoglycemia they are unable to vary their day-to-day caloric intake. The particular benefit of repaglinide and nateglinide is the fact that each allows omitting both the tablet and the meal, which results in improved glycemic control without weight gain. Clearly, to omit lunch after taking a long-acting sulfonylurea in the morning is an act of folly with potentially disastrous consequences. This, of course, brings forth the problems associated with using oral agents for diabetes in the elderly. There is abundant clinical information that illustrates the difficulty of persuading patients to take a drug three times a day, particularly those who may be exhibiting increasing forgetfulness. However, does using drugs of considerable potency and with long half-lives, at the risk of disaster in any deviation from the routine, present a viable solution?
Thiazolidinediones. Thiazolidinediones, or “glitazones,” are a new class of oral hypoglycemic agents that selectively or partially mimic certain actions of insulin by activating the peroxisome proliferator-activated receptor-gamma (PPAR-g). PPAR-g is a nuclear receptor that is mainly expressed in adipose tissue and minimally in skeletal muscle and the liver.21 It increases the transcription of several insulin-sensitive genes. Accordingly, thiazolidinediones increase glucose and fatty acid uptake by adipocytes, promoting lipogenesis and adipogenesis.20 They also increase glucose uptake, glycogenesis, and glucose utilization by muscle tissue, and reduce glucose production by the liver.22,23 They are well-tolerated by the elderly. Troglitazone was the first among this group of drugs and was marketed in 1996. It was, however, rapidly withdrawn after multiple case reports of raised aminotransferases (AST/ALT) and fatal liver failure. These reactions occurred so disparately that it was impossible to predict who or which group of patients was most likely to suffer these consequences. 24 In 1999-2000, newer and apparently safer generations of glitazones or PPAR-g agonists, namely rosiglitazone and pioglitazone, were marketed. Randomized, double-blind, placebo-controlled studies have shown that rosiglitazone (4-12 mg once daily) significantly reduces fasting plasma glucose and HbA1c levels in persons with type 2 diabetes over an eight-week period.25 Its combination with metformin has been reported to be a more potent option than that of metformin alone. 26 In combination with sulfonylureas as well, rosiglitazone has also been found to be effective and well-tolerated.27 In all these clinical trials, the main side effects reported were salt and water retention, hemodilution, and mild anemia.25-27 In combination with insulin, these side effects were much more serious and frequent. Some case reports have recently suggested that rosiglitazone may be associated with hepatic damage, early on in the course of treatment. 28 Therefore, frequent and early monitoring of liver function in patients receiving this group of drugs is recommended. Studies with pioglitazone have yielded similar results. Therefore it appears that thiazolidinediones are a useful adjunct to other oral hypoglycemics in the management of diabetes in the elderly. They lower HbA1c by approximately 1% and offer additional advantages: they do not cause hypoglycemia and come in a convenient once-daily dosage. On the other hand, these drugs cause fluid retention, and in elderly persons with diabetes, who are more than likely to have associated cardiac compromise and impaired renal function, this may be a major disadvantage.
Insulin Use in the Elderly
The use of insulin in elderly patients can pose major questions. On the one hand, the elderly person may live alone, may be dependent upon outside agencies for support and, particularly, for meals, and may have a considerable coexisting disease whose symptoms may include forgetfulness. In addition, symptoms of poorly controlled diabetes can be easily mistaken for signs of the aging process: tiredness may be overlooked, as may more specific symptoms such as changes in the genitourinary system. On the other hand, however, there are benefits that can accrue in a well-controlled patient with diabetes irrespective of age, and perhaps to a greater extent in patients at the highest risk of degenerative arterial, nerve, and kidney disease. One further point deserves mention: the attending physician is invariably younger than the elderly patients and tends to underestimate (sometimes grossly) the life expectancy of the elderly patient. Thus the possible result is an elderly patient with diabetes, poorly controlled on oral agents, with 10-15 years of life ahead. In a situation such as this, it is difficult to justify prescribing a regimen for the patient that will provide poor control of diabetes for that length of time. As for insulin therapy regimens in the elderly, marked differences can be found in physicians’ recommendations, ranging from a once-daily isophane, through twice-daily isophane or premixed insulins, to occasional use of more intensive treatments. Recent years have been marked by a growing tendency to combine the use of insulin with oral agents in the treatment of younger persons with type 2 diabetes. Regimens that combine a single (usually nightly) injection of an isophane insulin with metformin, a sulfonylurea, a thiazolidinedione, or repaglinide have been developed. The use of any of these oral agents in combination with insulin would be subject to the strictures discussed above, but the possibilities raised by such combinations are the improvement of control with the minimization of side effects—particularly, lessening the risk of hypoglycemia.
Conclusion
Multiple pathologies are common in the elderly, with diabetes being a major complicating factor. Patients afflicted with diabetes in their late 60s may live long enough to develop microvascular complications from the disease. The goals, therefore, in the management of diabetes in the elderly include avoidance of symptomatic hyperglycemia and prevention of long-term complications, while taking care to prevent hypoglycemia and minimize other side effects. Treatment needs to be tailored to each individual’s needs and should be reviewed regularly. If dietary measures fail, insulin secretagogues (especially the newer ones) and insulin sensitizers, alone and in combination, should be used as first-line therapy. The choice of a secretagogue should take into consideration side effects, particularly the propensity of an agent to cause hypoglycemia. The choice of a sensitizer will also reflect coexisting disease and the likelihood of interaction, with resulting side effects. In conclusion, the treatment of diabetes in the elderly remains a therapeutic challenge.
References
1. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: Estimates and projections to the year 2010. Diabet Med 1997;14(suppl 5):1-85.
2. Morley JE. The elderly diabetic patient: Special considerations. Diabet Med 1998;(suppl 4):41-46.
3. UK Prospective Diabetes (UKPDS) Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131):837-853.
4. University Group Diabetes Program (UGDP). A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1975;24(suppl 1):65-184.
5. Temple RC, Carrington CA, Luzio SD, et al. Insulin deficiency in non-insulin-dependent diabetes. Lancet 1989;1(8633):293-295.
6. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995;75(3):473-486.
7. UK Prospective Diabetes Study Group (UKPDS16). Overview of 6 years’ therapy of type 2 diabetes: A progressive disease. Diabetes 1995;44(11):1249-1258.
8. Nattrass M, Bailey CJ. New agents for type 2 diabetes. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13(2):309-329.
9. Chan TYK, Chan JCN, Tomlinson B, Critchley JA. Adverse reactions to drugs as a cause of admissions to a teaching hospital in Hong Kong. Drug Saf 1992;7(3):235-240.
10. Nattrass M, Lauritzen T. Review of prandial glucose regulation with repaglinide: A solution to the problem of hypoglycemia in the treatment of type 2 diabetes? Int J Obes Relat Metab Disord 2000;24(suppl 3):S21-S31.
11. Lebovitz H. Alpha-glucosidase inhibitors as agents in treatment of diabetes. DiabeticReviews 1998;6:132-145.
12. Goke B, Fuder H, Wieckhorst G, et al. Vogliobose (AO-128) is an efficient alpha-glucosidase inhibitor and mobilizes the endogenous GLP-1 reserve. Digestion 1995; 56(16):493-501.
13. Dills DG, Schneider J. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 1996;28(9):426-429.
14. Langtry HD, Balfour JA. Glimepiride: A review of its use in management of type 2 diabetes mellitus. Drugs 1998;55(4):563-584.
15. Graul A, Castaner J. Repaglinide. Drugs of the Future 1996;39: 1083-1090.
16. Mallaisse WJ. Stimulation of insulin release by non-sulphonylurea hypoglycaemics: The meglitinide family. Horm Metab Res 1995:27:263-266.
17. Wolffenbuttel BH, Nijst L, Sels JP, et al. Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol 1993;45(2):113-116.
18. Moses R, Slobodniuk R, Boyages S, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 1999;22(1):119-124.
19. Raskin P, Jovanovic L, Berger S, et al. Repaglinide/troglitazone combination therapy: Improved control in type 2 diabetes. Diabetes Care 2000; 23(11):979-983.
20. Horton ES, Clinkingbeard C, Gatlin M, et al. Nateglinide alone and in combination with metformin improves glycaemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 2000;23(11):1660-1665.
21. Spiegelman BM. PPAR-g: Adipogenic regulator and thiazolidinedione receptor. Diabetes 1998;47(4):507-514.
22. Day C. Thiazolidinediones: A new class of antidiabetic drugs. Diabet Med 1999;16(3):179-192.
23. Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone on monotherapy in type 2 diabetes mellitus. Ann Intern Med 1998;128(3):176-185.
24. Watkins PB,Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998;338(13):916-917.
25. Nolan JJ, Jones NP, Patwardhan R, Deacon LF. Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabet Med 2000;17(14):287-294.
26. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in type 2 diabetes mellitus: A randomised controlled trial. JAMA 2000;283(13):1695-1702.
27. Wolffenbuttel BH, Gomis R, Squatrito S, et al. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabet Med 2000;17(1):40-47.
28. Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a patient receiving rosiglitazone: A case report. Ann Intern Med 2000;132(2):121-124. Annals of Long-Term Care - ISSN: 1524-7929 - Volume 9 - Issue 06 - June 2001 |