RECENT DEVELOPMENTS IN THE TREATMENT OF DIABETES TYPE 2
3. CLINICAL MANAGEMENT OF T2DM AND ITS COMPLICATIONS
Clinical management of T2DM includes lifestyle intervention by means of advisories about exercise and diet, as well as the use of oral or injected hypoglycemic agents. The responsiveness of T2DM patients to pharmacologic therapy varies between individuals due to variability in the clinical course of the disease.
Depending on the symptoms and the severity of T2DM in a given patient, insulin and adjunctive therapies may be conferred to treat various consequences of T2DM progression (Table1).
A review of the pharmacological interventions to date to delay or prevent the onset of T2DM was presented byPadwal et al.,2005. Ten studies of oral hypoglycemic agents and 15 studies of non-oral hypoglycemic agents were analyzed. Studies involving metformin, acarbose, troglitazone and orlistat (see below) showed a decrease in the incidence of T2DM compared with placebo. Genuine diabetes
Table 1. Present therapies in the treatment of T2DM
• Oral hypoglycemic agents
• Biguanides: Metformin
• Sulphonylureas
• Nateglinide (D-Phenylalanine)
• Meglitinide family
• -glucosidase inhibitors
• GLP-1, imidazolines, morpholinoguanidines, etc.
• Thiazolidinediones
• Insulin
• Adjunctive therapies
• Anti-hypertensive agents
• ACE inhibitors
• Calcium channel blockers
• - and-blockers
• Angiotensin II receptor antagonists
• Thiazide diuretics
• Lipid lowering agents
• Hydroxymethyl glutaryl CoA-reductase inhibitors (statins)
• Fibrates
• Anti-obesity drugs
• Lipase inhibitors
• Serotonin and norepinephrine re-uptake inhibitors
• Phertermine, other noradrenergic drugs, etc.
Adapted from English and Williams, 2001; Kahn et al., 2005.
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prevention studies are being sought and no single agent can be recommended at present for diabetes prevention (Anderson,2005;Padwal et al.,2005).
A summary of T2DM prevention studies were reviewed by Laakso (2005) and Stumvoll et al., 2005. Therapeutic approaches to T2DM have recently been addressed (Stumvoll et al.,2005; Kahn et al., 2005). Drastic changes in lifestyle seem at the moment the most efficient strategy to tackle the T2DM epidemic.
Lifestyle intervention in patients with impaired glucose tolerance results in an impressive reduction in the conversion to overt diabetes, which is greater than the effect of early intervention with drugs such as metformin or acarbose (Hauner, 2004).There are clear benefits between exercise, consumption of a diet rich in fruits and vegetables and the risk of getting T2DM. Daily exercise and a low-glycemic- index nutritional plan have been suggested as palliatives (Anderson, 2006). The progression of T2DM disease stages is preventable through a complete change in dietary habits, replacing refined carbohydrates and sweets, consuming less alcohol, avoiding a sedentary behavior and smoking, and observing proper weight control (Schulze and Hu,2005). Nutrition therapy guidelines can be found inKahn et al., 2005andShils et al.,2006. A number of general T2DM treatment guidelines can also be found inLebovitz,2005and inKahn et al.,2005.
Below, potential treatments for individual symptoms are presented such as obesity, hyperglicemia, hyperlipidemia, hypertension and lack of insulin. As with all medications, there might be side effects, and interactions with other drugs taken simultaneously could be harmful. Therefore, the use of T2DM drugs must be prescribed by a physician. Further information about these and other drugs can be found at www.nlm.nih.gov/medlineplus/druginformation.html, www.rxlist.com/, www.drugs.com/, www.drugdigest.org, at the manufacturer’s homepages, Kahn et al.,2005, etc.
The thiazolidinediones in the treatment of T2DM will be reviewed separately in section4.
3.1 Anti-Obesity Agents
Obesity is a state of increased body weight, specifically adipose tissue that can lead to health problems. Obesity develops only if energy intake (feeding) chronically exceeds total body expenditure (Spiegelman and Flier,2001). Obesity is currently defined using BMI; its etiology and management is described in Hill et al., 2005 and in other chapters inKahn et al.,2005and inShils et al.,2006.
Obesity is the most important modifiable risk factor for T2DM and most patients with diabetes are overweight or obese. It is well known that excess bodyweight induces or aggravates insulin resistance, which is a characteristic feature of T2DM. Thus, bodyweight plays a central role in the prevention and treatment of diabetes.
Agents to treat obesity consist of a) central nervous system agents that affect neurotransmitters or neural ion channels and b) leptin/insulin/central nervous system pathway agents. Efficient anti-obesity drugs must not only reduce fat mass
RECENT DEVELOPMENTS IN THE TREATMENT OF DIABETES TYPE 2 139 (adiposity) but must also correct fat dysfunction (adiposopathy) (Bays,2004). FDA approved medications currently available for the treatment of obesity in the elderly is listed inMathys,2005. Sibutramine (e.g. Meridia from Abbot) and Orlistat (e.g.
Xenical from Roche) are drugs currently approved for the long-term management of obesity.
Orlistat prevents gastrointestinal lipases from breaking down dietary fats into smaller molecules that can be absorbed by the body. Absorption of fat is decreased by about 30 percent. Since undigested triglycerides are not absorbed, the reduced caloric intake may have a positive effect on weight control (FDA,2006). Orlistat reduces the incidence of T2DM in patients with impaired glucose tolerance and lowers the required dose of metformin, sulfonylureas and insulin in patients with T2DM (Kiortsis et al.,2005).
Sibutramine is used as a short-term supplement to diet and exercise for the treatment of obesity (>30 BMI). Sibutramine works to suppress the appetite primarily by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin, and promotes thermogenesis (FDA,2006;Filippatos et al.,2005a;Kaplan, 2005). Rimonabant (i.e. Acomplia from Sanofi-Aventis) is a novel anti-obesity drug in late clinical trials that targets the endocannabinoid receptor CB1 in the brain and in other tissues such as fat, and appears to improve dramatically insulin sensitivity, and blood cholesterol and lipid levels (Despres et al.,2005).
The use of phentermine (e.g. Ionamin from Medeva Pharmaceuticals, Adipex-P from Gate Pharmaceuticals) has also been documented to have some anti-obesity effects. It acts on the central nervous system, affecting either adrenergic or serotoninergic neurotransmission or both. Other related drugs are diethylpropion, phendimetrazine, benzphetamine, and the amphetamines (Kahn et al.,2005).
The increase of energy expenditure by means of enhanced mitochondrial activity could improve metabolism especially in obese T2DM patients. Several thera- peutic targets to modulate energy expenditure to treat T2DM have been proposed (Auwerx,2006). Several other drugs to treat obesity are currently in the development phase (Wadman,2006). An overview of treatment methods including diet/nutrition, pharmacotherapy, behavioural therapy, weight management, exercise and surgery are revisited inKahn et al.,2005andShils et al.,2006.
Treatment of childhood obesity depends on the severity of the cases but it starts with lifestyle intervention with includes a change of diet, an increase in physical activity and a decrease in sedentary behaviors. Low-energy diets, pharmacological agents and even surgery may be used in severe cases (Steinbeck,2005;Kahn et al., 2005). Guidelines for the treatment of adolescent obesity have been put forward (Durant and Cox,2005;Kahn et al.,2005).
The most appropriate recommendation for obese patients with T2DM is a nutri- tionally balanced, moderately hypocaloric diet with a reduced intake of saturated fat and an increase in physical activity. The control of appetite and suppression of food cravings would also lead to better weight control. Finally, no conclusive evidence has been presented to claim that nutritional supplements or botanicals might have a significant role in weight reduction (Dwyer et al.,2005) but there
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are many examples of nutritional healing based on the use of natural hypoglycemic substances (Friedman and McLellan,2006).
3.2 Hypoglycemic Agents
Here are summarized some of the most popular pharmacological interventions used to ameliorate the symptoms of T2DM (English and Williams, 2001). A list of compounds to treat several symptoms of T2DM can be found in Table 1. The action of a group of drugs known as thiazolidinediones will be described in detail in section4(see below).
The anti-hyperglycemic drug metformin hydrochloride (e.g. Glucophage from Merck, Fortamet from FHRX, Riomet from Ranbaxy) may be the most usual drug given to overweight or obese subjects with T2DM whose diabetes cannot be controlled by diet alone. Presently, metformin is perhaps the first therapeutic option in the treatment of T2DM, as it may prevent some vascular complica- tions, and mortality. Metformin confers a good control of hyperglycemia, while it only results in moderate effects on weight, lipids, insulinemia and diastolic blood pressure (Lebovitz, 2005). Agents such as the sulphonylureas, the -glucosidase inhibitors, the thiazolidinediones, the meglitinides, insulin, and diet fail to show more benefit for glycemia control, body weight, or lipids, than metformin (Saenz et al., 2005). Metformin decreases hepatic gluconeogenesis and hepatic glucose output, and increases peripheral glucose uptake, reducing plasma glucose by 3–4 mmol/l. Metformin can inhibit complex 1 of the mitochondrial respiratory chain. However, metformin is not an insulin secretagogue and it does not result in meaningful hypoglycaemia (Owen et al.,2000). Metformin is considered an insulin sensitizer since administration to T2DM-patients results in a decrease in the hepatic insulin resistance (Lebovitz,2005).
Combination therapies that include metformin consist of metformin and glyburide, a sulphonylurea, such as Glucovance from Merck, metformin and rosigli- tazone such as Avandamet from GSK, metformin and glipizide such as Metaglip from Merck, etc. (FDA,2006; web drug sources). The anti-hyperglycemic effects of agents with different modes of action are additive (Kahn et al.,2005).
The sulphonylureas are insulin segregatogues (stimulators of insulin secretion) that bind to the sulphonylurea receptor (SUR-1) on the K+-ATP channel on the membranes of -cells, closing it, and then trigger opening of Ca++
channels, increasing intracellular calcium concentration that stimulates insulin release (Speight and Holford, 1997; Lebovitz, 2005). They generally reduce plasma glucose levels by 3–4 mmol/l and are more effective in newly T2DM diagnosed patients (English and Williams,2001). Several sulphonylureas have been described such as Glibenclamide/Glyburide (e.g. Diabeta from Aventis, Glynase and Micronase from Pfizer), Glipizide (e.g. Glucotrol from Pfizer), chlorpropamide (e.g. Diabenese from Pfizer), gliclazide (e.g. Diamicron from Servier), glimepiride (e.g. Amaryl from Aventis), tolazamide (e.g. Tolinase from Pfizer), tolbutamide (e.g.
Orinase from Pfizer), etc.
RECENT DEVELOPMENTS IN THE TREATMENT OF DIABETES TYPE 2 141 An insulin segregatogue that does not contain a sulphonylurea moiety is nateglinide. Nateglinide (Starlix from Novartis-Ajinomoto) is a D-phenylalanine derivative that is used as a novel anti-diabetic agent. It also can inhibit the pancreatic -cell K+-ATP channel and reduces glucose levels that are inadequately controlled by diet and exercise in T2DM patients (Lebovitz,2005).
The meglitinides are hypoglycemic agents (non-sulphonylureas) to treat T2DM that are used in mono-therapy or in combination with metformin. These drugs stimulate the pancreas to release insulin, concentrating their effects around meal time glucose load, leveling off spikes in blood sugar levels. An example is Repaglinide (Prandin-Novonorm from Novo Nordisk) (Lebovitz,2005; web drug sources).
The inhibitors of-glucosidases, insulin sensitizers commonly known as “starch blockers” are based on the inhibition of intestinal enzymes that participate in the degradation of disaccharides, oligosaccharides and polysaccharides, leading to a dose-dependent delay of carbohydrate digestion, and the glucose released from these molecules enters bloodstream more slowly reducing the glycemic fluctuations during the day. Among the inhibitors of -glucosidases it is possible to name acarbose, a pseudo-tetrasaccharide (e.g. Precose and Glucobay from Bayer), miglitol (e.g. Glyset from Bayer) and voglibose (e.g. Volix from Ranbaxy) (Lebovitz,2005;
FDA,2006; web drug sources).
Glucagon-like-peptide-1 (GLP-1) is a hormone secreted by intestinal cells in response to fat and carbohydrate ingestion. GLP-1 and its derivatives (e.g. liraglutide from Novo Nordisk, exenatide-Byetta from Amylin) are sought as T2DM thera- peutic agents, adjunct to metformin and/or sulphonylureas. They can stimulate glucose-dependent insulin production and secretion from pancreatic-cells, as well as the growth and differentiation of -cells. They are considered as adyuvant therapies in severe forms of T2DM (Sturis et al.,2003; List and Habener,2004;
Gallwitz,2005).
It appears that combination therapies rather than mono-therapies work more efficiently to reduce plasma glucose levels (Lebovitz, 2005). For several of the available hypoglycemic agents there are generic drugs already available.
3.3 Insulin, Hypolipidemic and Anti-Hypertensive Agents
Failure to respond to oral hypoglycemic agents initially (primary failure) is often due to a severe underlying insulin deficiency. In this situation, insulin therapy is required. However, many patients may not respond to oral agents because of severe initial hyperglycemia. Thus, a much higher dosage of oral anti-diabetic agents may be needed initially, and then reduced subsequently, sparing these particular patients the unnecessary insulin treatment. Among insulin preparations given to T2DM patients with insulin deficiency are the short-acting, the intermediate-acting and the long-acting insulins as well as the insulin analogues. Examples are: Iletin, Humulin and Humalog from Lilly, Lantus from Aventis, Novolin, Novolog and Levemir from Novo Nordisk, etc. (web drug sources).
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Angiotensin-converting enzyme (ACE) inhibitors and some angiotensin II receptor blockers (ARBs) may improve insulin sensitivity and decrease the risk for T2DM. One ARB in particular, telmisartan, has been found to effectively activate PPARgamma, a well-known target for insulin-sensitizing, anti-diabetic drugs (see below) (Kurtz and Pravenec, 2004). Anti-hypertensive compounds used in the treatment of T2DM are reviewed byAsfaha and Padwal,2005.
Diabetic patients have a higher incidence of vascular disease due to elevated plasma triglycerides occurring together with reduced high-density lipoprotein (HDL) cholesterol concentrations. Lipid-lowering treatments should be imple- mented aggressively in patients with existing clinical vascular disease (Kahn et al., 2005;Shils et al.,2006).
Hypocholesterolemic drugs include fibric acid derivatives (fibrates), bile acid sequestrants (Cholestyramine, Colestipol, Colesevelam), nicotinic acid prepara- tions (Niacin), an intestinal absorption inhibitor (Ezetemibe), and the statins.
In T2DM patients with particularly high triglyceride levels and lower levels of LDL-cholesterol, the fibrates should be considered as the initial therapy (Kahn et al.,2005).
The fibrates lower triglycerides and may increase HDL cholesterol levels. The fibrates are effective in lowering blood triglyceride levels to prevent heart disease.
By reducing the production of serum triglycerides and increasing HDL cholesterol, they can also reduce the levels of LDL-cholesterol. Two classes of fibrates are commonly being used: fenofibrate (e.g. Tricor from Abbot, Antara from Reliant) and gemfibrozil. Gemfibrozil (e.g. Lopid from Pfizer) (see 4.1.1) is often prescribed early in patients with grossly elevated triglycerides (hypertriglyceridemia), which is associated with an increased risk of acute pancreatitis (Kahn et al.,2005, web drug sources).
Compounds of benefit in the primary prevention of cardiovascular disease (CVD) in T2DM patients (low-density lipoprotein (LDL)-cholesterol-lowering therapy) are the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and aspirin (acetylsalicylic acid) (Hovens et al.,2005). Hyper- cholesterolaemia is treated by inhibiting the HMG-CoA reductase enzyme which is the rate-limiting step in cellular cholesterol biosynthesis. Cholesterol-reducing medications include statins such as lovastatin (e.g. Mevacor from Merck), pravastatin (e.g. Pravachol from Bristol-Myers-Squibb), simvastatin (e.g. Zocor from Merck), fluvastatin (e.g. Lescol from Novartis), atorvastin (e.g. Lipitor from Pfizer), rosuvastatin (e.g. Crestor from Astra Zeneca), etc.