Current Therapeutic Drugs for Type 2 Diabetes, Still Useful After 50 Years?

In 2008 it was estimated by the International Diabetes Federation that 246 million adults worldwide have diabetes mellitus (DM) and the prevalence is expected to reach 380 million by 2025.1 However, this projection is likely to be an underestimate. A recent study using a validated diabetes registry in Ontario found a steady increase in prevalence of 6.2% per year over a decade.2 This increase in DM has been attributed to a rise in new cases of Type 2 diabetes which is a consequence of obesity, lack of exercise, increased migration of susceptible patients, and an aging population. DM is a costly chronic disease and patients develop micro- and macrovascular complications that often need surgery. Improved glycemic control has been shown to delay the onset of microvascular complications (nephropathy, retinopathy, and neuropathy), whereas the beneficial effects on macrovascular complications are less clear. Increased knowledge of the pathophysiology of Type 2 diabetes, particularly insulin signaling and insulin resistance, has contributed to the development of novel treatments. In this issue of the journal Chen et al.3 have highlighted two new groups of drugs: those acting on the incretin pathway, exenatide, and sitagliptin and the synthetic amylin analog, pramlintide. In this article, we briefly review the principal treatments available for Type 2 diabetes to enable the new drugs to be placed in perspective. The primary aim of managing Type 2 diabetes is to delay, or even prevent, the complications of the disease by achieving good glycemic control. In addition to drug therapy, this often involves changes in lifestyle, such as diet and exercise. The main groups of oral drugs available are the sulfonylureas, biguanides, and thiazoldinediones (TZDs), with less common usage of the meglitinides and α-glucosidase inhibitors. Insulin is increasingly considered part of a treatment regimen in Type 2 diabetics, particularly the use of long-acting preparations to provide a constant basal insulin release. Sulfonylureas have been used since the 1950s and their efficacy is well established. They have been shown to decrease glycosylated hemoglobin concentrations by 1%–2% and fasting blood glucose concentrations by 3.3–3.9 mmol/L (59–70 mg/dL).4–6 Sulfonylureas act primarily by stimulating insulin secretion from the β cells of the pancreas. This is achieved by binding to a specific receptor, which closes an ATP-dependent potassium channel resulting in depolarization of the cell membrane, an influx of calcium ions, and the release of preformed insulin granules. All sulfonylureas can cause hypoglycemia, although this is uncommon and usually results from excessive dosage. Other important side effects include an increase in appetite and weight gain so that these drugs may not be the first choice in obese patients.7 Treatment failure may also occur. Primary failure occurs in 20%–25% of patients started on a sulfonylurea and is shown by an inadequate decrease in fasting blood glucose of <1.1 mmol/L (<20 mg/dL). In secondary failure, which occurs in 5%–10% patients per year, an initial favorable response of a decrease in fasting blood glucose >1.7 mmol/L (>30 mg/dL) is not sustained. There has been considerable controversy about the possible enhanced cardiovascular risks to patients taking these drugs. The earlier results of the University Group Diabetes Program suggested that the use of sulfonylureas was associated with an increased occurrence of cardiovascular events.8,9 Two randomized trials have addressed these concerns. The United Kingdom Prospective Diabetes Study (UKPDS) and A Diabetes Outcome Progression Trial observed a decreased cardiovascular risk, that did not reach statistical significance, and a lower incidence of cardiovascular events using a sulfonylurea, compared with rosiglitazone and metformin as monotherapy.10,11 The introduction of newer drugs for the management of Type 2 DM has lead to a decrease in the use of sulfonylureas, but these drugs are effective, inexpensive, and have a good safety profile. The biguanides, metformin, and phenformin, were also introduced in the 1950s. Phenformin was withdrawn in the 1970s because of a clear association with severe lactic acidosis. Metformin improves insulin sensitivity, particularly in skeletal muscle, decreases hepatic gluconeogenesis, and inhibits glycogenolysis. Other beneficial effects include a reduction in plasma triglycerides and low-density lipoprotein concentration. The precise mechanism of action of metformin is unknown, but in the liver it may stimulate adenosine monophosphate protein kinase to enhance fatty-acid oxidation with inhibition of lipogenesis, glucose production, and protein synthesis.12 Before the introduction of the incretin mimetics, metformin was the only drug available that was not associated with weight gain and was particularly appropriate in obese patients. Metformin may improve cardiovascular risk factors; the UKPDS studies showed that metformin monotherapy decreased the occurrence of myocardial infarction (MI) and all-cause mortality.13 Indeed, the 10-yr follow-up of UKPDS again emphasized the benefits of long-term glycaemic control on death from any cause and micro- and macrovascular complications.14 Metformin has a mostly favorable side effect profile. Because it does not affect insulin secretion, hypoglycemia is rare when metformin is used as monotherapy, but is more of a risk when used in combination with a sulfonylurea or insulin. Gastrointestinal side effects, such as metallic taste, nausea, abdominal pain, and diarrhea, are present in 30% of patients. Most are transient and occur when the drug is started or the dose increased rapidly. There are still concerns about the occurrence of severe lactic acidosis in patients taking metformin. The evidence for metformin-induced lactic acidosis is based on about 300 case reports, and it has been suggested that it has an estimated incidence of three cases per 100,000 patient years.15,16 Underlying medical conditions, such as MI and chronic renal disease, are well-established risk factors for lactic acidosis and in many instances attributing the acidosis to metformin rather than the underlying pathology is unverifiable. Nevertheless, metformin is not recommended in patients with renal disease (creatinine clearance <60 mL/min, serum creatinine >120 μmol/L in women or >130 μmol/L in men), hepatic disease, cardiac disease (New York Heart Association class III or IV), chronic pulmonary disease, severe infection, alcohol abuse, history of lactic acidosis, pregnancy, or use of radiographic contrast. Despite these concerns, metformin remains one of the cornerstones of diabetic management. Holstein and Stumvoll17 highlighted the lack of good evidence to support these contraindications to metformin and suggested that the drug can be safely used in elderly patients, those with stable heart failure, moderate renal impairment (with a reduced dose), and mild liver impairment. TZDs, like metformin, are insulin sensitizers. Although metformin acts mainly on the hepatocyte and muscle, the TZDs act predominantly on adipocytes and muscle. These agents enhance insulin sensitivity by increasing the efficiency of glucose transporters, decreasing glycosylated hemoglobin by 1%–2% and decreasing both fasting and postprandial glucose concentrations.18 They do not cause hypoglycemia when used as a single drug but can do so in combination with other drugs. TZDs activate peroxisone proliferator-activated γ nuclear receptors in adipose tissue, altering gene transcription in adipocytes with resultant changes in lipid metabolism and distribution.19,20 Circulating free fatty acid concentrations decrease by 20%–40%, and this is postulated to enhance insulin-receptor signaling peripherally. A further benefit may be a reduction in exposure of the β cells of the pancreas to lipotoxicity, which is thought to contribute to β-cell death.19,21 This improvement in β-cell function may account for the lower risk of monotherapy failure after 5 yr (rosiglitazone compared with metformin and glyburide [glibenclamide]).11 TZDs can cause edema and weight gain and are contraindicated in patients with liver disease and cardiac failure (New York Heart Association class III or IV).9 They should be used with caution in patients with class II disease. Although these drugs are associated with an overall expansion of adipocyte mass, activation of peroxisone proliferator-activated γ-nuclear receptors stimulates differentiation into smaller insulin-sensitive adipocytes.22 Furthermore, fat is redistributed from visceral to subcutaneous deposits, a pattern which is associated with a lower risk of cardiovascular disease.23 Both rosiglitazone and pioglitazone have favorable effects on high-density lipoproteins, and pioglitazone also decreases circulating triglyceride concentrations.24 Other benefits of the TZDs include antiinflammatory effects, improved peripheral and coronary vascular endothelial function, and a modest improvement in hypertension.25–29 TZDs have been associated with an increased incidence of MI. A meta-analysis evaluated the cardiovascular effects of rosiglitazone versus placebo or active controls from 42 trials and concluded that rosiglitazone was associated with significant 42% relative increased odds for MI and a trend toward a 64% increased relative odds for cardiovascular death.30 However, none of the studies were designed to examine cardiovascular effects, and the event rates were very low. The results of the systematic review were in contrast to the findings of the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events), which showed a nonstatistically significant 10% decrease in the hazard ratio and a reduction in all-cause mortality, nonfatal MI, and stroke in high-risk patients with Type 2 diabetes treated with pioglitazone compared with placebo.31 This may reflect important differences between the two drugs. In an observational study of almost 30,000 patients with a 1–2 yr follow-up, pioglitazone was associated with a 22% lower incidence of MI compared with rosiglitazone and a 15% lower incidence of MI and coronary revascularization.32 In January 2008 both the American Diabetes Association and the European Association for the Study of Diabetes recommended TZDs as a second-line treatment for Type 2 diabetes after lifestyle interventions and metformin. However, the action to control cardiovascular risk in diabetes trial was terminated early when it was shown that patients in the intensive treatment area, 91% of whom received rosiglitazone, were at significantly increased risk of cardiovascular death.33 Full analysis of the data showed that the use of intensive therapy to achieve normal glycosylated hemoglobin values for 3.5 yr increased mortality, attributed mostly to hypoglycemia, and did not significantly reduce major cardiovascular events. There was no evidence to show that a specific drug was directly responsible.34 Both the American Diabetes Association and European Association for the Study of Diabetes issued guidelines advising explicitly against the use of rosiglitazone for the treatment of Type 2 diabetes, with pioglitazone relegated to third-line treatment.35 However, Woo has emphasized the differences in clinical practice guidelines between Canada, America, and Europe and the lack of evidence from long-term studies examining the association between rosiglitazone and MI.36 The results of the RECORD study, which is designed to prospectively assess the cardiac outcomes of rosiglitazone, are awaited with interest.37 In the early stages of treatment of Type 2 DM, the emphasis is on managing insulin resistance but, as the disease progresses, β-cell failure becomes more prominent and insulin may be required. Treatment with insulin is no longer seen as a therapeutic “last resort” after long-term oral drugs have failed, but rather as a means for the earlier achievement of glycemic targets. Starting insulin therapy in low doses in combination with oral hypoglycemics is effective in maintaining glycosylated hemoglobin values and achieving glycemic targets and may improve insulin resistance.38 From this brief review, it can be seen that the two mainstays of the treatment of Type 2 diabetes are the sulfonylureas and the biguanide-metformin, both of which have been in use for about 50 yr. Therefore, the new drugs described by Chen et al.3 are a welcome addition to the therapeutic armamentarium, particularly in view of the recent disappointments over the safety of the TZDs. The incretin mimetics and the amylin analog offer potential advantages over existing treatments as they target different aspects of glucose homeostasis. The recent demonstration that a sustained release formulation of exenatide given once weekly was as effective as the usual twice daily regimen in obtaining glycemic control with no increased risk of hypoglycemia and similar decreases in body weight is a further incentive to use this drug.39 However, in view of the problems associated with rosiglitazone, it would be wise to heed the advice that continuing evaluation and long-term studies are necessary to determine the clinical role of incretin therapy.40 Sitagliptin, a DPP-IV inhibitor, needs particularly careful evaluation as the peptidase is found in many cell types and there are many potential substrates for this enzyme. The new drugs have only just been introduced into clinical practice and there is no anesthetic literature to suggest clinical problems specific to these drugs. Chen et al.3 discuss the possible adverse effects of nausea, delayed gastric emptying, and hypoglycemia. The risk of hypoglycemia is greatest with the use of exenatide, particularly if combined with a sulfonylurea or insulin. The authors recommend that the GLP-1 analogs (exenatide), DPP-IV inhibitors (sitagliptin), and the amylin analog (pramlintide) are withheld on the day of surgery but can probably be taken the day before surgery, without the risk of hypoglycemia when fasting. This is in keeping with current recommendations that other hypoglycemic drugs, with the exception of insulin, are omitted on the day of surgery in Type 2 diabetic patients. There remains great potential for new drugs in the treatment of DM. As the molecular pathogenesis of diabetes is better understood, novel compounds will be available for evaluation. For example, phosphotyrosine phosphatase 1B (PTP 1B) is a negative regulator of insulin signaling, and inhibition of its activity with specific agents, or a decrease of its protein concentrations with antisense oligonucleotides, has been found to enhance insulin activity in preclinical testing.41