Overview of new and developing pharmacological treatments
School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
* Corresponding author. E-mail address: c.j.bailey{at}aston.ac.uk
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The need for new therapies |
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There are several reasons why new pharmacological treatments are needed for type 2 diabetes and metabolic syndrome. First, the global prevalence of type 2 diabetes continues to grow despite the efforts to improve prevention. Existing treatments do not halt the progression of the disease. Single or multiple oral therapies are often unable to achieve or maintain glycaemic control, and vascular complications remain rife.1 Another important factor is the cost of managing type 2 diabetes. It has been estimated that diabetes consumes 9–14% of total healthcare budgets in Europe and North America.2
Treatment of type 2 diabetes and the metabolic syndrome is complicated by many factors (Figure 1). Disease progression presents a moving target for treatment. In most cases, insulin action has deteriorated to the point of insulin resistance long before type 2 diabetes is diagnosed. Insulin resistance may initially be compensated for by a period of hyperinsulinaemia in some individuals, but insulin secretion will typically have deteriorated to at least 50% below normal capacity by the time diagnosis is made. It is believed that insulin resistance underlies the metabolic syndrome, and risk factors for coronary heart disease and type 2 diabetes are components of this syndrome.
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Metabolic syndrome occurs on average in 20% of adults in the western societies and in >40% of those who are in older age groups.3 Importantly, the condition is not static but progressive. Thus, by analogy with the treatment of type 2 diabetes, it is necessary to modify the treatment of various manifestations of metabolic syndrome as the condition progresses (Figure 1).
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Type 2 diabetes: current treatment options |
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In the current armamentarium for type 2 diabetes, there are treatments to reduce basal and post-prandial glycaemia by the modification of insulin secretion, insulin action, and rate of carbohydrate digestion. Sulphonylureas and meglitinides increase insulin secretion, metformin and thiazolidinediones improve insulin action (through different cellular mechanisms), and acarbose slows carbohydrate digestion.4 For the more severely hyperglycaemic patients with insulinopenia, there is the availability of insulin replacement treatments (Table 1).
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Owing to disease progression, the effectiveness of treatments essentially reduces with time and dosages need to be increased or combinations of agents used. For example, United Kingdom Prospective Diabetes Study (UKPDS) shows that there is a progressive deterioration of glycaemic control in type 2 diabetes whichever treatment is used (Figure 2).5
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The general approach to treatment of type 2 diabetes is initially diet, exercise, weight control, and health education. If this does not achieve the desired glycaemic target, then drug therapy usually starts with one agent. A combination of two differently acting agents may be used at the initial stage when hyperglycaemia is marked, and combination therapy is the inevitable recourse if monotherapy is unable to achieve or maintain control. In the UKPDS, <50% of patients were adequately controlled with one agent for 3 years. By 9 years, <25% were controlled to a target of 7% HbA1c with any one of the agents, resulting in 75% needing at least two different approaches to achieve glycaemic control (Figure 2).
Thus, no single agent will, as yet, fit all the requirements for treating type 2 diabetes, because this disease has multiple heterogeneous presentations with considerable diversity of progression and comorbidity. To date, metformin has shown perhaps the widest therapeutic benefits. The UKPDS found that independent of its capability to reduce glucose levels, metformin is also able to reduce cardiovascular outcomes and increase life expectancy in type 2 diabetes. Metformin has been shown to have multiple effects on the different components of the metabolic syndrome. For example, it can reduce insulin resistance and reduce hyperinsulinaemia without weight gain, and exerts various potentially anti-atherogenic and anti-thrombotic effects.6 Metformin has also been shown to reduce the progression from impaired glucose tolerance to type 2 diabetes.7
Thiazolidinediones
The latest therapies to emerge are the peroxisome proliferator activated receptor-gamma (PPAR-
) agonists. These agents are lipophilic molecules that are able to easily enter cells and activate PPAR- which is attached to the retinoid-X receptor in the cell nucleus. When PPAR- is activated, it promotes the transcription of a number of genes, resulting in improved insulin sensitivity. PPAR- is most strongly expressed in the adipose tissue. In particular, there is adipogenic activity, especially in subcutaneous fat where newly differentiated small, insulin sensitive adipocytes show increased uptake of fatty acids and glucose. This reduces fatty acids in the circulation, re-balancing the glucose–fatty acid cycle, resulting in increased utilization of glucose primarily by muscle and a decreased availability of energy (as fatty acids) to the liver, thereby decreasing gluconeogenesis (Figure 3).
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PPAR-
is expressed in pancreatic ß-cells and there is evidence that PPAR- agonists can preserve ß-cell function in animal models of impaired glucose tolerance and type 2 diabetes. Thus, there is much interest in the durability of the glucose-lowering effect of PPAR- agonists. Preliminary data indicate that in patients who respond to PPAR- agonists, anti-hyperglycaemic efficacy is maintained for at least 3 years and longer data are awaited.
PPAR- agonists have beneficial effects on the metabolic syndrome. They reduce insulin resistance, hyperinsulinaemia, and the extent of hyperglycaemia. They have variable effects on triglycerides, depending on how much PPAR-
activity they have. Typically, they decrease the free fatty acids and increase the proportion of larger buoyant less atherogenic LDL particles usually associated with a small increase in HDL.
PPAR- agonists have been reported to reduce blood pressure in impaired glucose tolerance (IGT) subjects. Several studies have recorded small but significant reductions of systolic blood pressure and diastolic blood pressure in type 2 diabetic patients, despite the retention of fluid and the usual small reduction in haemoglobin that customarily accompany use of these agents. PPAR- agonists have been shown to improve several factors and markers of endothelial function, inflammation, and haemostasis and have been reported to improve measures of vascular reactivity and reduce various indicators of atherogenesis. PPAR- agonists generally do not tend to have any significant effect on visceral obesity but they do cause weight gain via increased subcutaneous adipose deposition.
There are many trials with PPAR- agonists that will complete in the next 2–4 years (Figure 4). Hopefully, these trials will provide evidence about the effects of thiazolidinediones on clinically relevant diabetes and cardiovascular outcomes.
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New and developing treatments |
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Combinations and polypills
There has been considerable interest in multiple combinations or ‘polypills’ because of the large pill burden for individuals with type 2 diabetes. Compliance is a recognized problem with chronic multiple therapies; therefore, if two, three, or more agents can be combined, then compliance should increase. Currently available combinations include glucovance (metformin plus glibenclamide), metaglip (metformin plus glipizide), and avandamet (metformin plus rosiglitazone). Combinations in development include avandaryl (rosiglitazone plus glimepiride) and fortamet (metformin plus pioglitazone). In addition, there are a number of other combinations in development in which metformin is used as the base together with another agent. The concept of fixed-dose combination therapies in other areas relevant to metabolic syndrome (e.g. combination of a statin and an anti-hypertensive agent) is also gaining acceptance.
Dual agonists of PPAR- and PPAR-
Dual PPAR-/ agonists act on both PPAR- and PPAR- receptors, resulting in the improvement of insulin resistance and benefits to both lipid (from PPAR- action) and glucose (from PPAR- action) disorders (Figure 5). By acting on the PPAR- receptor, there is transcription of genes that stimulate ß-oxidation of fatty acids, which will reduce hypertriglyceridaemia. Therefore, a single agent that acts as an agonist of both PPAR- and PPAR- receptors can offer both glucose-lowering and lipid-modulating effects (decrease in triglycerides and increase in HDL-C).
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There are two dual PPAR-
/ agonists advanced in development: tesaglitazar and muraglitazar. Tesaglitazar has been studied in insulin resistant, obese, hyperglycaemic rats and mice. Short-term studies in ob/ob mice found a reduction in glucose, hyperinsulinaemia, and hypertriglyceridaemia without weight gain and the insulin activity was notably improved. In the Zucker fatty rat, which has impaired glucose tolerance but a fairly normal basal glucose, tesaglitazar reduced hyperinsulinaemia, triglycerides, and free fatty acids. Glucose clamp studies showed that insulin sensitivity was near normalized by the treatment with tesaglitazar.8 Muraglitazar is another dual PPAR-/ agonist in development. No full papers have been published yet on muraglitazar.
Increase ß-cell function and mass
Since ß-cell function is decreased by 
50% by the time diagnosis of type 2 diabetes is made and continues to decline irrespective of treatment, agents are being developed to stimulate ß-cell function and increase ß-cell mass.9 These include glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors.
Glucagon-like peptide-1 (GLP-1)
GLP-1 is a peptide produced by L-cells located mainly in the mucosa of the ileum. Food in the lumen stimulates the release of GLP-1, which travels to the islets and increases glucose-induced insulin secretion. There is also an increase in proinsulin biosynthesis and evidence that GLP-1 could increase the ß-cell mass by decreased apoptosis, increased proliferation, and neogenesis of ß-cells.10
GLP-1 acts on a specific receptor on the ß-cell, which is linked to adenylate cyclase, increasing cyclic AMP. In this way, there is a potentiation of the release of insulin after stimulation by nutrients absorbed during a meal and little likelihood of interprandial hypoglycaemia. GLP-1 also suppresses glucagon release and may have a modest satiety effect. Because GLP-1 is a peptide with a very short half-life, it has been difficult to develop it into a pharmaceutical entity. The analogues that are currently being considered show an increased duration of action when compared with the native peptide.11
Several GLP-1 analogues, notably exenatide and liraglutide, each administered as subcutaneous injections, have shown encouraging results in clinical trials.11
Dipeptidyl peptidase-4
Another approach to stimulate ß-cell function is inhibition of DPP-4—a circulating and cell surface peptidase enzyme which degrades peptides (including GLP-1) by deleting two N-terminal residues if the second residue is alanine or proline. Oral drugs have been developed that inhibit DPP-4, thereby elevating levels of endogenous GLP-1 without the need to administer the peptide itself.12
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Future treatments |
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Certain trace elements have been reported to improve glycaemic control. In some diabetic patients, particularly in areas of the world where diet is poor, there is a deficiency of elements such as chromium, magnesium, and zinc. A magnesium supplement, for example, can improve glycaemic control in magnesium-deficient patients, probably because it is an ATP cofactor necessary for kinase reactions. Other areas where there may be future developments include early insulin signal enhancers (e.g. inhibitors of protein tyrosine phosphatase-1B) and other signal enhancers such as lipoic acid. Patients who have received lipoic acid for the treatment of neuropathy showed improved insulin sensitivity.
Currently, there is much interest in adiponectin, which is produced and secreted by the adipose tissue. The less adipose tissue a patient has, the more the adiponectin produced. Adiponectin reduces insulin resistance, enhances glucose utlilization, reduces glucose production, and exerts beneficial effects on vascular function.
As the number of people affected by the metabolic syndrome, insulin resistance, and type 2 diabetes continues to grow, research will need to explore new therapeutic avenues that will help to prevent the development, progression, and vascular consequences of these conditions.
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References |
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TopThe need for new...Type 2 diabetes: current...New and developing treatmentsFuture treatmentsReferences |
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- Zimmet P, Alberti KGMM, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782–787.[CrossRef][Medline]
- Jönsson B, Board CA. Revealing the cost of Type 2 diabetes in Europe. Diabetologia 2002;45:S5–S12.[CrossRef][Web of Science][Medline]
- Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults—findings from the Third National Health and Nutrition Examination Survey. JAMA 2002;287:356–359.
[Abstract/Free Full Text] - Bailey CJ. Day C. Antidiabetic drugs. Br J Cardiol 2003;10:128–136.
- Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999;281:2005–2012.
[Abstract/Free Full Text] - Bailey CJ and Turner RC. Metformin. N Engl J Med 1996;334:574–579.
[Free Full Text] - Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.
[Abstract/Free Full Text] - Ljung B, Bamberg K, Dahllöf B, et al. AZ242, a novel PPAR / agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. J Lipid Res 2002;43:1855–1863.
[Abstract/Free Full Text] - UKPDS Study Group 16. Overview of six years' therapy of type 2 diabetes—a progressive disease. Diabetes 1995;44:1249–1258.[Abstract]
- Vilsboll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357–366.[CrossRef][Web of Science][Medline]
- Deacon CF. Therapeutic strategies based on glucagons-like peptide 1. Diabetes 2004;54:2181–2189.
- Drucker DJ. Therapeutic potential dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs 2003;12:87–100.[CrossRef][Web of Science][Medline]
- Bailey CJ, Day C. Avandamet: combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes. Int J Clin Pract 2004;58:867–876.[Medline]
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