Diabetes: A Primer on New Drug Options

Contrary to popular belief, advances in medical treatment rarely occur through major discoveries. Rather, improved medical care is usually the result of an incremental progression of small, collective changes. Such has been the case with diabetes: the many new agents introduced during the past 20 years have steadily improved the outlook for effective and tolerable treatment. The last decade in particular has seen tremendous progress in the pharmacotherapy of diabetes.

Although many new options for the treatment of diabetes have become available, it is vital to retain time-tested approaches that have proven track records. In this article, I review recent developments in diabetes therapy and describe how both new and old modalities can be integrated to produce the greatest benefit for patients.

A BRIEF HISTORY OF DIABETES THERAPY

From the recognition of diabetes mellitus by the ancient Greeks until the last century, the only treatment available was strict dietary modification. The pharmacotherapy of diabetes began in the 1920s with the isolation of insulin from animal pancreas. For years, insulin was the only pharmaceutical option for treating either type 1 or type 2 diabetes. Then, in the 1950s, the introduction of tolbutamide (a sulfonylurea) and phenformin (a biguanide) offered options for oral treatment of type 2 diabetes.^1,2 Sulfonylureas stimulate endogenous insulin release by closing potassium channels in the beta cell.³ The biguanides reduce hepatic glucose production and increase peripheral glucose utilization.⁴

Setback for oral antidiabetes drugs. In 1971, the publication of the University Group Diabetes Program (UGDP) data dealt a severe blow to the development of oral antidiabetes agents.⁵ This large clinical study compared vascular events and mortality in treatment groups who received tolbutamide (Box), phenformin, insulin, or placebo. The study was stopped when excess cardiovascular mortality was reported in the tolbutamide group and excess overall mortality was reported in the phenformin group. The ensuing concern led to a ban on phenformin in the United States, and sulfonylurea use was strongly discouraged in favor of diet and insulin therapy.

The UGDP results had a chilling effect on the development of new oral hypoglycemic drugs in the United States. Most of the new antidiabetic agents used today (Table 1 [Part 1, Part 2]) originate from overseas research.

Growth in use of sulfonylureas. As a result of the UGDP data, the use of sulfonylureas decreased. However, it did not stop; patients did not want to relinquish the convenience of oral therapy in favor of daily insulin injections. By 1986, the sulfonylureas had become the primary therapy for 40% of all patients with type 2 diabetes. Their use further increased in the mid-1980s with the introduction of glyburide and then glipizide, both developed outside the United States.⁶ In the mid-1990s, an additional sulfonylurea, glimepiride, was developed and came into use.⁷ This agent has a slightly better safety profile than other sulfonylureas in patients with renal disease.

Metformin. This agent was synthesized in 1958 and became a primary treatment for type 2 diabetes in Europe. Because of the oral hypoglycemic controversy in the United States, it was not introduced here until the mid-1990s.⁸ Results of a limited series of studies in the United States led to FDA approval for metformin at a maximal dose of 2500 mg/d. This is less than the 3-g maximal daily dose in Europe.

Because of the fairly minimal risk of lactic acidosis, metformin is contraindicated in patients older than 80 years and in those with elevated serum creatinine levels. Metformin is associated with a high incidence of GI complaints: problems ranging from mild heartburn to diarrhea occur in one-third of patients. However, the symptoms usually lessen with time and in most patients are not so severe that the drug has to be stopped. An extended-release formulation of metformin has a lower frequency of GI complaints.⁹ Unlike insulin and the sulfonylureas, metformin does not promote weight gain; it has therefore become the first choice for treatment of type 2 diabetes.

Disaccharidase inhibitors and thiazolidinediones. Following the successful introduction of metformin in the US market, pharmaceutical manufacturers substantially expanded diabetes drug research.

Disaccharidase inhibitors. Two agents in this class, acarbose and miglitol, were introduced in the mid-1990s.¹⁰ Disaccharidase inhibitors effectively compensate for defective early-phase insulin release in patients with type 2 diabetes by slowing the absorption of monosaccharides in the intestine. The efficacy of disaccharidase inhibitors is limited by the adverse reactions caused by a large quantity of non-absorbed disaccharides in the intestinal tract, resulting in flatulence, abdominal discomfort, and diarrhea. However, in elderly patients, many of whom have constipation, the GI effects of the disaccharidase inhibitors may actually be beneficial.

Thiazolidinediones. The advent of the peroxisome proliferator-activated receptor (PPAR) agents constituted a major theoretical advance in diabetes treatment. The first of these agents to be released for marketing was troglitazone, in 1997.¹¹ Rosiglitazone and pioglitazone soon followed. All 3 agents belong to the class of PPAR agents known as thiazolidinediones (TZDs).^12,13 TZDs reduce peripheral insulin resistance, primarily through an effect on adipose tissue. There is also evidence that TZDs may preserve beta cells from ongoing deterioration.¹⁴

Troglitazone was removed from the market after it became apparent that a small percentage of patients treated with this agent had hepatic damage, which in rare cases resulted in liver failure and death. Rosiglitazone and pioglitazone do not have significant liver toxicity,¹⁵ but all the PPAR agents cause significant fluid retention, in some cases leading to congestive heart failure.¹⁶ Recent studies have suggested, although not conclusively, that rosiglitazone (but not pioglitazone) may increase the frequency of myocardial infarctions.^17,18

The use of TZDs is also limited by their tendency to stimulate the accumulation of adipose tissue. Thin patients who adhere to dietary therapy do well with these drugs, but obese patients often gain considerable weight. The association of TZDs with weight gain is a major deterrent to their use in the vast majority of patients with type 2 diabetes.

NEW ORAL AGENTS

Meglitinides. Agents in this class (repaglinide and nateglinide) stimulate endogenous insulin secretion by closing potassium channels in the beta cell, a mechanism of action similar to that of the sulfonylureas.^3,19 These agents must be taken before meals and have a much shorter duration of action than do the sulfonylureas. The short half-life of the meglitinides results in a lower incidence of hypoglycemia than is seen with the sulfonylureas, an advantage in elderly patients and those with coronary disease.

Glucagonlike peptide analogs. A new class of agents based on glucagonlike peptide 1 (GLP-1) has recently become available. This intestinal hormone has multiple effects, including stimulation of insulin secretion, suppression of glucagon levels, slowing of gastric emptying, and an early satiety effect (suggesting the possibility of weight loss).²⁰ The cumulative result of therapy with exenatide, a reptilian-derived analog of GLP-1, is a lowering of postprandial glucose levels. The degree to which exenatide lowers glycosylated hemoglobin (HbA_1c) values is modest-about 1 percentage point.

The finding of progressive weight loss in several limited studies of exenatide has led to great enthusiasm, almost approaching cult status, for the use of this drug.^21,22 However, exenatide is associated with significant adverse effects. At least 40% of patients receiving exenatide have nausea, often severe; this symptom may account for part of the observed loss of weight. Also, there is significant concern about pancreatitis in a small percentage of patients treated with exenatide. Finally, exenatide must be administered by injection, twice daily. Studies of long-acting, slow-release formulations of exenatide are under way to see whether such a formulation reduces the high incidence of adverse effects.

Dipeptidyl peptidase IV inhibitors. GLP-1 is rapidly degraded in the body by the enzyme dipeptidyl peptidase IV (DPP-IV). Several orally administered inhibitors of this enzyme have been synthesized.²⁰ The DPP-IV inhibitors slow the breakdown of GLP-1, resulting in higher circulating levels. One agent, sitagliptin, has been approved for clinical use²³; other agents will soon follow. Unlike exenatide, sitagliptin does not have prominent adverse effects, but neither does it lead to weight reduction. Sitagliptin is used primarily as an adjunct to metformin therapy; it results in less hypoglycemia than the sulfonylureas and does not cause weight gain and fluid retention such as are seen with TZDs.

Amylin analogs. Amylin is another peptide that has beneficial effects in patients with diabetes. This 37-amino acid polypeptide is secreted by the beta cell concurrently with insulin. Like GLP-1, it slows gastric emptying and inhibits postprandial glucagon secretion.²⁴ In patients with insulin-dependent diabetes, amylin concentrations-like insulin concentrations-are reduced. Injection of an amylin analog, pramlintide, has been shown to lower postprandial glucose levels in both type 1 and type 2 diabetes.^25-27 Although the reduction in HbA_1c concentration seen with pramlintide use is modest, the agent has been associated with weight loss both in patients with type 1 diabetes and in those with type 2 disease.^26,27 However, therapy with pramlintide has been limited by a number of adverse effects, including nausea and unpredictable hypoglycemic episodes.²⁸

NEW INSULIN OPTIONS

Long-term studies such as the United Kingdom Prospective Diabetes Study (UKPDS) suggest that oral therapy with a single agent is not adequate to achieve an acceptable HbA_1c. Typically, an individual oral hypoglycemic agent improves HbA_1c values by 1 to 1.5 percentage points, depending on initial glucose control. However, in the UKPDS, there was a progressive degradation of glycemic control despite the use of additional agents.²⁹ Insulin is more effective at lowering glucose levels and can produce reductions of up to 3 percentage points in patients whose levels are inadequately controlled with combination oral therapy.³⁰

Since the introduction of insulin in the 1920s, there have been significant advances in its formulation (Table 2 [Part 1, Part 2]). Semi-synthetic analogs have improved on the timing of insulin release in several ways.

Long-acting insulins. Insulin glargine provides basal insulin coverage, producing 20 to 24 hours of essentially constant insulin levels (in contrast to the peaks that occur with neutral protamine Hagedorn [NPH] or lente insulin). The use of insulin glargine as a basal insulin has been more successful than the use of NPH insulin in reducing nocturnal hypoglycemia in both type 1 and type 2 diabetes.^31,32 Insulin detemir is another long-acting analog that can provide basal insulin coverage with 1 or 2 injections a day.³³

Rapid-acting insulins. A number of semi-synthetic rapid-acting insulins have been developed by modifying a few amino acids in the insulin peptide chain to reduce the tendency of the insulin molecule to form hexamers in solution.³⁴ The insulins modified in this way are more rapidly absorbed after subcutaneous injection than regular insulin. The first of the rapid-acting semi-synthetic insulins was insulin lispro, which was followed by insulin aspart, and most recently, insulin glulisine. These insulins can be administered at the time of a meal or even after a meal and still have a rapid effect on glucose levels.³⁵ Moreover, insulin levels fall more quickly after injection than they do with regular insulin, resulting in a reduced incidence of hypoglycemia several hours after meals.³⁶

Inhaled insulin. Insulin has been unpopular because of the need for subcutaneous administration. Although injections with a small needle are almost painless, the prospect of puncturing the skin gives rise to significant psychological resistance in the majority of patients.³⁷

Inhaled insulin has become a potential alternative to rapid-acting injectable insulins. Inhaled insulin has an onset of action comparable to that of insulin lispro; however, it has a longer duration of action.³⁸ Inhaled insulin has low bioavailability (about 9% of the amount ingested) but still results in reproducible serum insulin levels. Thus, it has proved just as effective as subcutaneously administered insulin at controlling glucose levels in both type 1 and type 2 diabetes.^39,40

The availability of pulmonary administration as an option increases the willingness of patients to accept insulin therapy. In a survey of more than 700 patients with poorly controlled type 2 diabetes, 43% of those who were offered either inhalation or subcutaneous administration were amenable to insulin treatment-in contrast to only 15% of those to whom subcutaneous administration was presented as the sole option.⁴¹

Despite patient enthusiasm for inhaled insulin, there have been concerns that the long-term deposition of large amounts of protein in the lungs might lead to deterioration in pulmonary function. Studies over a 2-year period were relatively reassuring. Although reductions in both forced expiratory volume and diffusion capacity occurred, these changes did not appear to progress and disappeared after inhaled insulin was discontinued.⁴² Of course, these data do not apply to patients with underlying lung disease or to smokers, who have been excluded from the published trials of inhaled insulin.

The fact that inhaled insulin frequently has to be accompanied by an injectable basal insulin, the need to monitor pulmonary function tests periodically during therapy, and the cumbersomeness of the delivery device led to an initially slow uptake in the use of inhaled insulin. As a result of disappointing revenues from the first inhaled insulin on the market, the manufacturer unexpectedly announced on October 18, 2007 that it was discontinuing sales of the product. This decision reflected a failure in promotion and marketing rather than any perceived problem with the safety or effectiveness of inhaled insulin. At the present time, programs for the development of inhaled insulin delivered by more convenient inhalation devices are proceeding at 2 other pharmaceutical companies. It is hoped that these programs will lead to renewed clinical availability of inhaled insulin.

GLUCOSE MONITORING

Self-monitoring of blood glucose has empowered patients with diabetes to take control of their own treatment.^43,44 Glucose levels are currently measured with finger sticks at strategic times-typically before and 2 hours after meals. The advent of continuous glucose monitoring is potentially the most important change in insulin management of diabetes.

Subcutaneous glucose oxidase needle electrodes have become sufficiently accurate at low glucose levels to detect impending hypoglycemia. These electrodes furnish repetitive readings of subcutaneous fluid glucose levels at frequent small intervals; they interface with detectors that provide warnings of hypoglycemia or hyperglycemia. Two devices that use this technology have been released by the FDA for marketing.^45,46

Continuous glucose monitoring is indicated in patients treated with insulin who have wide and abrupt fluctuations in their blood glucose levels, particularly those who experience frequent episodes of hypoglycemia or significant postprandial hyperglycemia. With further advances in the technology expected, it is likely that the indications for continuous monitoring will expand in the future.

DIETARY MANAGEMENT AND WEIGHT LOSS

The degree of postprandial glucose elevation depends primarily on the carbohydrate content of the meal.^47,48 Reduction of carbohydrate ingestion can successfully reduce postprandial glucose levels and HbA_1c.⁴⁸ Carbohydrate counting consists of flexible adjustment of the mealtime insulin dose based on an estimate of the number of grams of carbohydrate consumed. This approach has been very effective in patients whose insulin therapy is intensively managed, including those using insulin pumps.⁴⁹

Regrettably, the successes in insulin management achieved with carbohydrate counting have not been accompanied by parallel achievements in the battle against obesity, the primary contributing factor in type 2 diabetes. Caloric regulation and physical activity are very effective at preventing diabetes,^50,51 but counseling has been generally unsuccessful in changing lifestyles.⁵² There are no truly effective agents for the treatment of obesity. The agents available, which include anorexiants and orlistat, can achieve a 6% to 10% initial reduction in weight, but this reduction is typically maintained for a relatively short period.^53,54

The most successful current treatment for obesity is bariatric surgery. Rates of substantial weight loss and remission of diabetes with surgical treatment approach 60% in some series.⁵⁵ However, bariatric surgery can have significant complications and should be reserved for morbidly obese patients.⁵⁶

The current popularity of exenatide stems from the hope that it will facilitate long-term, progressive weight loss without intolerable adverse effects. However, this goal is achieved in only a minority of patients.⁵⁷

MAKING BEST USE OF OLD AND NEW TREATMENTS

In the face of ongoing scientific progress, it is important not to lose sight of the proven treatments of the past. There is a disquieting tendency to simply add new agents to current therapy without maximizing the benefits of the options already available. The prospect of patients receiving 3 or more oral hypoglycemic agents in an effort to suppress hyperglycemia is troublesome, particularly when little effort has been made to address obesity, which is the main cause of type 2 diabetes in so many patients. Furthermore, the ever-expanding armamentarium of new pharmaceutical agents increases the cost of treatment and the likelihood of drug-related side effects.

The basis of the treatment of type 2 diabetes remains dietary control. The preferred oral agent is still metformin, which is available in generic form everywhere in the world, costs little, and does not promote weight gain. I favor maximizing the tolerated dose of metformin before adding additional agents. The sulfonylureas are now all available as generics and are appropriate add-on therapy when metformin alone at maximum dosage is insufficient.

Monotherapy with a meglitinide has advantages in certain patients, such as elderly persons, in whom hypoglycemia poses a significant risk. Monotherapy with a disaccharidase inhibitor can also be particularly beneficial in older patients. I do not use TZDs very often because of the numerous associated adverse effects, including weight gain, potential cardiac damage, and fluid retention that can lead to congestive heart failure. The DPP-IV inhibitors are appealing because of their good safety profiles, but they are quite expensive and yield relatively small improvements in HbA_1c values.

Insulin is very effective at controlling hyperglycemia but has been underutilized in patients with type 2 diabetes because of the unpopularity of injections. As a result, many patients have received multiple oral hypoglycemic agents without achieving acceptable glucose levels. If inhaled insulin is shown in trials with longer follow-up to have no detrimental effects on the lungs, inhalation may become the predominant route of administration of mealtime insulin in patients with type 1 diabetes and in those with type 2 disease.

CLINICAL HIGHLIGHTS

• Unlike insulin and the sulfonylureas, metformin does not promote weight gain; it has therefore become first-line therapy for type 2 diabetes.

• Thiazolidinediones (TZDs) tend to stimulate the accumulation of adipose tissue and cause fluid retention. Thin patients who adhere to dietary therapy do well with these drugs, but obese patients often gain considerable weight. There is also an increased risk of congestive heart failure with TZD therapy.

• The usefulness of disaccharidase inhibitors is limited by the adverse reactions caused by a large quantity of non-absorbed disaccharides in the intestinal tract, resulting in flatulence, abdominal discomfort, and diarrhea. However, elderly patients who suffer from constipation may do well with these agents.

• Meglitinides have the same mechanism of action as sulfonylureas, but because they have a shorter duration of action, they are less likely to cause hypoglycemia.

• Some of the weight loss seen with use of the glucagonlike peptide 1 (GLP-1) analog exenatide may result from associated nausea, which occurs in about 40% of patients.

• Dipeptidyl peptidase IV (DPP-IV) inhibitors work by inhibiting the breakdown of GLP-1, resulting in higher circulating levels of this hormone and, as a consequence, greater stimulation of insulin secretion. Unlike GLP-1 analogs, DPP-IV inhibitors do not have prominent adverse effects; however, neither are they associated with weight loss.

• The amylin analog pramlintide lowers postprandial glucose levels in both type 1 and type 2 diabetes. Although the reduction in glycosylated hemoglobin concentration seen with pramlintide is modest, the agent has been associated with weight loss. However, its use has been limited by nausea and unpredictable hypoglycemic episodes.

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