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C H A P T E R 3 8 Agents to control blood glucose levels

development of lactic acidosis. Both acarbose and met- formin can cause GI distress. Metformin is approved for use in children 10 years of age and older. It is also being used in the treatment of women with polycystic ovary syndrome (see Box 38.7). The thiazolidinediones ( Actos and others) are drugs that decrease insulin resistance; they are used in combi- nation with sulfonylureas, insulin or metformin to treat individuals with insulin resistance. The first drug of this class, troglitazone, was withdrawn from the market after reports of serious hepatotoxicity. The two drugs that are available now—pioglitazone and rosiglitazone—are not associated with the same severe liver toxicity, although in late 2007 reports were published linking these drugs to an increase in cardiovascular events. Rosiglitazone was withdrawn from the New Zealand market in April 2011 due to safety concerns related to increased cardiovasular risk. People should still be monitored for any change in liver function while they are taking these drugs. These drugs are also being studied for use in increasing ovu- lation frequency in woman who have polycystic ovary syndrome (Box 38.7). Box 38.8 describes some of the new fixed combination oral agents, which provide two different agents in one tablet to make it easier for the person to be compliant. Therapeutic actions and indications, pharmaco­ kinetics, contraindications and cautions, adverse effects and clinically important drug–drug interac- tions for these drugs are basically the same as for the Polycystic ovary syndrome is an ovarian function disorder associated with obesity, infrequent or absent menses and infertility. Women who have this disorder have elevated insulin levels with normal fasting blood glucose levels, elevated luteinising hormone (LH) levels, and normal oestrogen and follicle-stimulating hormone levels. Because of the alterations in hormone activity, follicles develop on the ovaries, but ovulation does not occur, and the developed follicles turn into cysts. The high LH levels tend to cause an increase in androgen production, which is associated with insulin resistance. Treatment is aimed at altering the metabolic changes to allow ovulation (if pregnancy is desired) or stop the follicle development (if pregnancy is not desired). Weight loss is very important and may correct the alterations in metabolism and allow ovulation to occur without medical treatment. Metformin and pioglitazone have proven effective in increasing insulin sensitivity and decreasing androgen and LH levels to break the ■■ BOX 38.7  Polycystic ovary syndrome and oral hypoglycaemic drugs cycle and allow ovulation to occur if pregnancy is desired. A fertility drug is often used with the oral hypoglycaemic agent. Hormonal contraceptives are used if pregnancy is not desired, to halt the development of the follicles and stop the cyst production.

sulfonylureas. The safety and efficacy of these drugs for use in children have not been established, except for the use of metformin in children 10 years of age and older. The newest of the oral hypoglycaemic agents include: exenatide, which was released in 2005; the glucagon-like peptide 1 analogue liraglutide released in 2005; the DPP-4 inhibitors which first became available in 2007; and the sodium-glucose co-transporter inhibitors, cana- gliflozin and dapagliflozin released in 2013. Exenatide and liraglutide mimic the effects of GLP-1: leading to enhancement of glucose-dependent insulin secretion by the beta cells in the pancreas, depression of elevated glucagon secretion and slowed gastric emptying to help moderate and lower blood glucose levels. Exenatide is given by subcutaneous injec- tion twice a day, within 60 minutes before the morning and evening meals. It has a rapid onset of action and peaks within 2 hours; its effects last 8 to 10 hours. It is given in combination with oral agents to improve glycae- mic control in type 2 diabetes individuals who cannot achieve glycaemic control on oral agents alone. It should not be given if the person is unable to eat. Liraglutide Several fixed-combination oral hypoglycaemic agents have become available in the last 5 years. These combination products are intended to decrease the number of tablets the person needs to take each day and thereby increase compliance with the drug regimen. The person should be stabilised on the individual product first and then switched to the combination product after the correct dose combination for that person has been established. The person should be reminded that diet and exercise are still the key parts of the diabetes management regimen. • Avandamet is a combination of rosiglitazone and metformin and is available in four sizes: 2 mg rosiglitazone with 1000 mg metformin, 2 mg rosiglitazone with 500 mg metformin, 4 mg rosiglitazone with 1000 mg metformin, 4 mg rosiglitazone with 500 mg metformin. • Galvusmet is a combination of vildagliptin and metformin and is available in three sizes: 50 mg vildagliptin with 1000 mg metformin, 50 mg vildagliptin with 500 mg metformin, 50 mg vildagliptin with 850 mg metformin. • Glucovance is a combination of metformin and glibenclamide and is available in three sizes: 250 mg metformin with 1.25 mg glibenclamide, 500 mg metformin with 2.5 mg glibenclamide, 500 mg metformin with 5 mg glibenclamide. • Janumet is a combination of sitagliptin and metformin and is available in three sizes: 50 mg sitagliptin with 1000 mg metformin, 50 mg sitagliptin with 500 mg metformin, 50 mg sitagliptin with 850 mg metformin. ■■ BOX 38.8  Available fixed-combination oral agents