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Medicinal Forms

There can be variation in the licensing of different medicines containing the same drug. Capsule CAUTIONARY AND ADVISORY LABELS 21 ▶Metopirone (HRA Pharma UK Ltd) Metyrapone 250 mg Metopirone 250mg capsules | 100 capsule P £363.66 DT = £363.66 Diabetes mellitus and hypoglycaemia 3.1 Diabetes mellitus Diabetes Endocrine system Description of condition Diabetes mellitus is a group of metabolic disorders in which persistent hyperglycaemia is caused by deﬁcient insulin secretion or by resistance to the action of insulin. This leads to the abnormalities of carbohydrate, fat and protein metabolism that are characteristic of diabetes mellitus. Type 1 diabetes mellitus p. 721 and Type 2 diabetes mellitus p. 723 are the two most common classiﬁcations of diabetes. Other common types of diabetes are gestational diabetes (develops during pregnancy and resolves after delivery) and secondary diabetes (may be caused by pancreatic damage, hepatic cirrhosis, or endocrine disease). Treatment with endocrine, antiviral, or antipsychotic drugs may also cause secondary diabetes. Driving Drivers with diabetes may be required to notify the Driver and Vehicle Licensing Agency (DVLA) of their condition depending on their treatment, the type of licence they hold, and whether they have diabetic complications (including episodes of hypoglycaemia). All drivers who are treated with insulin must inform the DVLA, with some exceptions for temporary treatment. Detailed guidance on notiﬁcation requirements, eligibility to drive, and precautions required, is available from the DVLA at www.gov.uk/guidance/diabetes- mellitus-assessing-fitness-to-drive. Advice from the DVLA The DVLA recommends (2018) that drivers with diabetes need to be particularly careful to avoid hypoglycaemia and should be informed of the warning signs and actions to take. Drivers treated with insulin should always carry a glucose meter and blood-glucose strips when driving, and check their blood-glucose concentration no more than 2 hours before driving and every 2 hours while driving. More frequent self-monitoring may be required if, for any reason, there is a greater risk of hypoglycaemia, such as after physical activity or altered meal routine. Blood-glucose should always be above 5 mmol/litre while driving. If blood-glucose falls to 5 mmol/litre or below, a snack should be taken. Drivers treated with insulin should ensure that a supply of fast-acting carbohydrate is always available in the vehicle. If blood-glucose is less than 4 mmol/litre, or warning signs of hypoglycaemia develop, the driver should not drive. If already driving, the driver should: . stop the vehicle in a safe place; . switch off the engine, remove keys from the ignition, and move from the driver’s seat; . eat or drink a suitable source of sugar; . wait until 45 minutes after blood-glucose has returned to normal, before continuing journey. Drivers must not drive if hypoglycaemia awareness has been lost and the DVLA must be notiﬁed; driving may resume if a medical report conﬁrms that awareness has been regained. Depending on the type of licence, notiﬁcation and monitoring may also be necessary for drivers taking oral antidiabetic drugs, particularly those which carry a risk of hypoglycaemia (e.g. sulfonylureas, nateglinide p. 739, repaglinide p. 740). Note: additional criteria apply for drivers of large goods or passenger carrying vehicles—consult DVLA guidance. Alcohol Alcohol can make the signs of hypoglycaemia less clear, and can cause delayed hypoglycaemia; specialist sources recommend that patients with diabetes should drink alcohol only in moderation, and when accompanied by food. Oral glucose tolerance tests The oral glucose tolerance test is used mainly for diagnosis of impaired glucose tolerance; it is not recommended or necessary for routine diagnostic use when severe symptoms of hyperglycaemia are present. In patients who have less severe symptoms and a blood-glucose concentration that does not establish or exclude diabetes (e.g. impaired fasting glycaemia), an oral glucose tolerance test may be required. It is also used to establish the presence of gestational diabetes. An oral glucose tolerance test involves measuring the blood-glucose concentration after fasting, and then 2 hours after drinking a standard anhydrous glucose drink. Anhydrous glucose may alternatively be given as the appropriate amount of Polycal ® or as Rapilose ® OGTT oral solution. HbA1c measurement Glycated haemoglobin (HbA1c) forms when red blood cells are exposed to glucose in the plasma. The HbA1c test reﬂects average plasma glucose over the previous 2 to 3 months and provides a good indicator of glycaemic control. Unlike the oral glucose tolerance test, an HbA1c test can be performed at any time of the day and does not require any special preparation such as fasting. HbA1c values are expressed in mmol of glycated haemoglobin per mol of haemoglobin (mmol/mol), a standardised unit speciﬁc for HbA1c created by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). HbA1c values were previously aligned to the assay used in the Diabetes Control and Complications Trial (DCCT) and expressed as a percentage. Equivalent values IFCC-HbA1c (mmol/mol) DCCT-HbA1c (%) 6.0 6.5 7.0 7.5 8.0 8.5 9.0 Diagnosis The HbA1c test is used for monitoring glycaemic control in both Type 1 diabetes p. 721 and Type 2 diabetes p. 723 and is now also used for diagnosis of type 2 diabetes. g HbA1c should not be used for diagnosis in those with suspected type 1 diabetes, in children, during pregnancy, or in women who are up to two months postpartum. It should also not be used for patients who have: . had symptoms of diabetes for less than 2 months; . a high diabetes risk and are acutely ill; . treatment with medication that may cause hyperglycaemia; . Acutepancreatic damage; . end-stage chronic kidney disease; . HIV infection. HbA1c used for diagnosis of diabetes should be interpreted with caution in patients with abnormal haemoglobin, anaemia, altered red cell lifespan, or who have had a recent blood transfusion. h Monitoring g HbA1c is also a reliable predictor of microvascular and macrovascular complications and mortality. Lower HbA1c is associated with a lower risk of long term vascular complications and patients should be supported to aim for an individualised HbA1c target (see Type 1 diabetes below and Type 2 diabetes p. 723). HbA1c should usually be measured in patients with type 1 diabetes every 3 to 6 months, and more frequently if blood- glucose control is thought to be changing rapidly. Patients with type 2 diabetes should be monitored every 3 to 6 months until HbA1c and medication are stable when monitoring can be reduced to every 6 months. h HbA1c monitoring is invalid for patients with disturbed erythrocyte turnover or for patients with a lack of, or abnormal haemoglobin. In these cases, quality-controlled plasma glucose proﬁles, total glycated haemoglobin estimation (if there is abnormal haemoglobin), or fructosamine estimation can be used. Laboratory measurement of fructosamine concentration measures the glycated fraction of all plasma proteins over the previous 14 to 21 days but is a less accurate measure of glycaemic control than HbA1c. Advanced Pharmacy Services Patients with diabetes may be eligible for the New Medicines Service / Medicines Use Review service provided by a community pharmacist. For further information, see Advanced Pharmacy Services in Medicines optimisation p. 18. Type 1 diabetes Description of condition Type 1 diabetes describes an absolute insulin deﬁciency in which there is little or no endogenous insulin secretory capacity due to destruction of insulin-producing beta-cells in the pancreatic islets of Langerhans. This form of the disease has an auto-immune basis in most cases, and it can occur at any age, but most commonly before adulthood. Loss of insulin secretion results in hyperglycaemia and other metabolic abnormalities. If poorly managed, the resulting tissue damage has both short-term and long-term adverse effects on health; this can result in retinopathy, nephropathy, neuropathy, premature cardiovascular disease, and peripheral arterial disease. Typical features in adult patients presenting with type 1 diabetes are hyperglycaemia (random plasma-glucose concentration above 11 mmol/litre), ketosis, rapid weight loss, a body mass index below 25 kg/m2, age younger than 50 years, and a personal/family history of autoimmune disease (though not all features may be present). Aims of treatment Treatment is aimed at using insulin regimens to achieve as optimal a level of blood-glucose control as is feasible, while avoiding or reducing the frequency of hypoglycaemic episodes, in order to minimise the risk of long-term microvascular and macrovascular complications. Disability from complications can often be prevented by early detection and active management of the disease (see Diabetic complications p. 726). g The target for glycaemic control should be individualised for each patient, considering factors such as daily activities, aspirations, likelihood of complications, adherence to treatment, comorbidities, occupation and history of hypoglycaemia. A target HbA1c concentration of 48 mmol/mol (6.5%) or lower is recommended in patients with type 1 diabetes. Blood-glucose concentration should be monitored at least four times a day, including before each meal and before bed. h Patients should aim for: . g a fasting blood-glucose concentration of 5–7 mmol/litre on waking; . a blood-glucose concentration of 4–7 mmol/litre before meals at other times of the day; . a blood-glucose concentration of 5–9 mmol/litre at least 90 minutes after eating; . a blood-glucose concentration of at least 5 mmol/litre when driving. h Overview Endocrine system g Type 1 diabetes requires insulin replacement, supported by active management of other cardiovascular risk factors, such as hypertension and high circulating lipids (see Diabetic complications p. 726). h Insulin replacement therapy aims to recreate normal ﬂuctuations in circulating insulin concentrations while supporting a ﬂexible lifestyle with minimal restrictions. Flexible insulin therapy usually involves self-injecting multiple daily doses of insulin, with doses adjusted according to planned exercise, intended food intake and other factors, including current blood-glucose, which the patient needs to test on a regular basis. g Patients who have a BMI of 25 kg/m2 or above (23 kg/m2 or above for patients of South Asian or related ethnicity) who wish to improve their blood-glucose control while minimising their effective insulin dose, may beneﬁt from metformin hydrochloride p. 730 [unlicensed indication] as an addition to insulin therapy. Dietary control is important in both type 1 and type 2 diabetes and patients should receive advice from a dietitian. Dietary advice should include information on weight control, cardiovascular risk, hyperglycaemic effects of different foods and appropriate changes in insulin doses according to food intake. Healthy eating can reduce cardiovascular risk and dietary modiﬁcations may be recommended to account for various associated features of diabetes such as excess weight and obesity, low body-weight, eating disorders, hypertension and renal failure. Patients with type 1 diabetes should be offered carbohydrate-counting training as part of a structured education programme. h Insulin therapy in type 1 diabetes g All patients with type 1 diabetes require insulin therapy (see also Insulin p. 722). Treatment should be initiated and managed by clinicians with relevant expertise; there are several different types of regimens. h Multiple daily injection basal-bolus insulin regimens One or more separate daily injections of intermediate-acting insulin or long-acting insulin analogue as the basal insulin; alongside multiple bolus injections of short-acting insulin before meals. This regimen offers ﬂexibility to tailor insulin therapy with the carbohydrate load of each meal. Mixed (biphasic) regimen One, two, or three insulin injections per day of short-acting insulin mixed with intermediate-acting insulin. The insulin preparations may be mixed by the patient at the time of injection, or a premixed product can be used. Continuous subcutaneous insulin infusion (insulin pump) A regular or continuous amount of insulin (usually in the form of a rapid-acting insulin analogue or soluble insulin), delivered by a programmable pump and insulin storage reservoir via a subcutaneous needle or cannula. Recommended insulin regimens g Patients with type 1 diabetes should be offered multiple daily injection basal-bolus insulin regimens as the ﬁrst-line choice. Twice-daily insulin detemir p. 756 should be offered as the long-acting basal insulin therapy. Once-daily insulin glargine p. 757 may be prescribed if insulin detemir is not tolerated, or if a twice-daily regimen is not acceptable to the patient. Insulin detemir may also be offered as an alternative once-daily regimen. Patients who are using alternative basal regimens may continue if agreed targets are being achieved; other basal insulin regimens should be considered only if the recommended regimens do not deliver agreed targets. Non- basal-bolus insulin regimens (e.g. twice-daily mixed [biphasic], basal-only, or bolus-only regimens) are not recommended for adults with newly diagnosed type 1 diabetes. A rapid-acting insulin analogue is recommended as the bolus or mealtime insulin replacement, rather than soluble Endocrine system human insulin or animal insulin (rarely used). The rapid- acting insulin analogue should be injected before meals— routine use after meals should be discouraged. Patients who have a strong preference for an alternative mealtime insulin should be offered their preferred insulin. Alternatively,if a multiple daily injection basal–bolus regimen is not possible, a twice-daily mixed insulin regimen should be considered if it is preferred. In patients who are using a twice-daily human insulin mixed regimen and have hypoglycaemia that affects their quality of life, a trial of a twice-daily analogue mixed insulin regimen should be considered. Continuous subcutaneous insulin infusion (insulin pump) therapy, should only be offered to adults who suffer disabling hypoglycaemia, or, who have high HbA1c concentrations (69 mmol/mol [8.5%] or above) with multiple daily injection therapy (including, if appropriate, the use of long-acting insulin analogues) despite a high level of care. Insulin pump therapy should be initiated by a specialist team. h Insulin requirements g The dosage of insulin must be determined individually for each patient and should be adjusted as necessary according to the results of regular monitoring of blood- glucose concentrations. h Persistent poor glucose control, leading to erratic insulin requirements or episodes of hypoglycaemia, may be due to many factors, including adherence, injection technique, injection site problems, blood-glucose monitoring skills, lifestyle issues (including diet, exercise and alcohol intake), psychological issues, and organic causes such as renal disease, thyroid disorders, coeliac disease, Addison’s disease or gastroparesis. Infection, stress, accidental or surgical trauma can all increase the required insulin dose. Insulin requirements may be decreased (and therefore susceptibility to hypoglycaemia increased) by physical activity, intercurrent illness, reduced food intake, impaired renal function, and in certain endocrine disorders. Risks of hypoglycaemia with insulin g Hypoglycaemia is an inevitable adverse effect of insulin treatment, and patients should be advised of the warning signs and actions to take (for guidance on management, see Hypoglycaemia p. 762). Impaired awareness of hypoglycaemia can occur when the ability to recognise usual symptoms is lost, or when the symptoms are blunted or no longer present. Patients’ awareness of hypoglycaemia should be assessed annually using the Gold score or the Clarke score. h An increase in the frequency of hypoglycaemic episodes may reduce the warning symptoms experienced by the patient. Impaired awareness of symptoms below 3 mmol/litre is associated with a signiﬁcantly increased risk of severe hypoglycaemia. Beta-blockers can also blunt hypoglycaemic awareness, by reducing warning signs such as tremor. Loss of warning of hypoglycaemia among insulin-treated patients can be a serious hazard, especially for drivers and those in dangerous occupations. Advice should be given in line with the Driver and Vehicle Licensing Agency (DVLA) guidance (see Driving under Diabetes p. 720). g To restore the warning signs, episodes of hypoglycaemia must be minimised. Insulin regimens, doses and blood-glucose targets should be reviewed and continuous subcutaneous insulin infusion therapy and real- time continuous blood-glucose monitoring should be considered. Patients should receive structured education to ensure they are following the principles of a ﬂexible insulin regimen correctly, with additional education regarding avoiding and treating hypoglycaemia for those who continue to have impaired awareness. Relaxation of individualised blood-glucose targets should be avoided as a strategy to improve impaired awareness of symptoms. If recurrent severe episodes of hypoglycaemia continue despite appropriate interventions, the patient should be referred to a specialist centre. h There is conﬂicting evidence regarding reports that some patients may experience loss of awareness of hypoglycaemia after transfer from animal to human insulin; clinical studies do not conﬁrm that human insulin decreases hypoglycaemia awareness. Manufacturers advise any switch between brands or formulation of insulin (including switching from animal to human insulin) should be done under strict supervision; a change in dose may be required. Hypodermic equipment g Patients should be advised on the safe disposal of lancets, single-use syringes, and needles, and should be provided with suitable disposal containers. Arrangements should be made for the suitable disposal of these containers. h Lancets, needles, syringes, and accessories are listed under Hypodermic Equipment in Part IXA of the Drug Tariff (Part III of the Northern Ireland Drug Tariff, Part 3 of the Scottish Drug Tariff). The drug Tariffs can be access online at: . National Health Service Drug Tariff for England and Wales: www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance- contractors/drug-tariff . Health and Personal Social Services for Northern Ireland Drug Tariff: www.hscbusiness.hscni.net/services/2034.htm . Scottish Drug Tariff: www.isdscotland.org/Health-Topics/Prescribing-and-Medicines/ Scottish-Drug-Tariff Useful Resources Type 1 diabetes in adults: diagnosis and management. National Institute for Health and Care Excellence. Clinical guideline NG17. August 2015. www.nice.org.uk/guidance/ng17 Insulin Overview For recommended insulin regimens see Type 1 diabetes p. 721 and Type 2 diabetes p. 723. Insulin is a polypeptide hormone secreted by pancreatic beta-cells. Insulin increases glucose uptake by adipose tissue and muscles, and suppresses hepatic glucose release. The role of insulin is to lower blood-glucose concentrations in order to prevent hyperglycaemia and its associated microvascular, macrovascular and metabolic complications. The natural proﬁle of insulin secretion in the body consists of basal insulin (a low and steady secretion of background insulin that controls the glucose continuously released from the liver) and meal-time bolus insulin (secreted in response to glucose absorbed from food and drink). Sources of insulin Three types of insulin are available in the UK: human insulin, human insulin analogues, and animal insulin. Animal insulins are extracted and puriﬁed from animal sources (bovine or porcine insulin). Although widely used in the past, animal insulins are no longer initiated in people with diabetes but may still be used by some adult patients who cannot, or do not wish to, change to human insulins. Human insulins are produced by recombinant DNA technology and have the same amino acid sequence as endogenous human insulin. Human insulin analogues are produced in the same way as human insulins, but the insulin is modiﬁed to produce a desired kinetic characteristic, such as an extended duration of action or faster absorption and onset of action. Immunological resistance to insulin is uncommon and true insulin allergy is rare. Human insulin and insulin analogues are less immunogenic than animal insulins. Administration of insulin Insulin is inactivated by gastro-intestinal enzymes and must therefore be given by injection; the subcutaneous route is ideal in most circumstances. Insulin should be injected into a body area with plenty of subcutaneous fat—usually the abdomen (fastest absorption rate) or outer thighs/buttocks (slower absorption compared with the abdomen or inner thighs). Absorption from a limb site can vary considerably (by as much as 20–40%) day-to-day, particularly in children. Local tissue reactions, changes in insulin sensitivity, injection site, blood ﬂow, depth of injection, and the amount of insulin injected can all affect the rate of absorption. Increased blood ﬂow around the injection site due to exercise can also increase insulin absorption. g Lipohypertrophy can occur due to repeatedly injecting into the same small area, and can cause erratic absorption of insulin, and contribute to poor glycaemic control. Patients should be advised not to use affected areas for further injection until the skin has recovered. Lipohypertrophy can be minimised by using different injection sites in rotation. Injection sites should be checked for signs of infection, swelling, bruising, and lipohypertrophy before administration. h Insulin preparations Insulin preparations can be broadly categorised into three groups based on their time-action proﬁles: short-acting insulins (including soluble insulin and rapid-acting insulins), intermediate-acting insulins and long-acting insulins. The duration of action of each particular type of insulin varies considerably from one patient to another, and needs to be assessed individually. Short-acting insulins Short-acting insulins have a short duration and a relatively rapid onset of action, to replicate the insulin normally produced by the body in response to glucose absorbed from a meal. These are available as soluble Insulin p. 722 (human and, bovine or porcine—both rarely used), and the rapid- acting insulin analogues (insulin aspart p. 752, insulin glulisine p. 753 and insulin lispro p. 754). Soluble insulin Soluble insulin is usually given subcutaneously but some preparations can be given intravenously and intramuscularly. For maintenance regimens, it is usual to inject the insulin 15 to 30 minutes before meals, depending on the insulin preparation used. When injected subcutaneously, soluble insulin has a rapid onset of action (30 to 60 minutes), a peak action between 1 and 4 hours, and a duration of action of up to 9 hours. When injected intravenously, soluble insulin has a short half-life of only a few minutes and its onset of action is instantaneous. Soluble insulin administered intravenously is the most appropriate form of insulin for use in diabetic emergencies e.g. Diabetic ketoacidosis p. 726 and peri-operatively. Rapid-acting insulin Insulin aspart, insulin glulisine, and insulin lispro have a faster onset of action (within 15 minutes) and shorter duration of action (approximately 2–5 hours) than soluble insulin, and are usually given by subcutaneous injection. g For maintenance regimens, these insulins should ideally be injected immediately before meals. Rapid-acting insulin, administered before meals, has an advantage over short-acting soluble insulin in terms of improved glucose control, reduction of HbA1c, and reduction in the incidence Endocrine system of severe hypoglycaemia, including nocturnal hypoglycaemia. The routine use of post-meal injections of rapid-acting insulin should be avoided—when given during or after meals, they are associated with poorer glucose control, an increased risk of high postprandial-glucose concentration, and subsequent hypoglycaemia. h Intermediate-acting insulin Intermediate-acting insulins (isophane insulin p. 755) have an intermediate duration of action, designed to mimic the effect of endogenous basal insulin. When given by subcutaneous injection, they have an onset of action of approximately 1–2 hours, a maximal effect at 3–12 hours, and a duration of action of 11–24 hours. Isophane insulin is a suspension of insulin with protamine; it may be given as one or more daily injections alongside separate meal-time short-acting insulin injections, or mixed with a short-acting (soluble or rapid- acting) insulin in the same syringe—for recommended insulin regimens see Type 1 diabetes p. 721 and Type 2 diabetes below. Isophane insulin may be mixed with a short- acting insulin by the patient, or a pre-mixed biphasic insulin can be supplied (biphasic isophane insulin p. 754, biphasic insulin aspart p. 755 and biphasic insulin lispro p. 755). Biphasic insulins (biphasic isophane insulin, biphasic insulin aspart, biphasic insulin lispro) are pre-mixed insulin preparations containing various combinations of short- acting insulin (soluble insulin or rapid-acting analogue insulin) and an intermediate-acting insulin. The percentage of short-acting insulin varies from 15% to50%. These preparations should be administered by subcutaneous injection immediately before a meal. Long-acting insulin Like intermediate-acting insulins, the long-acting insulins (protamine zinc insulin, insulin zinc suspension, insulin detemir p. 756, insulin glargine p. 757, insulin degludec p. 756) mimic endogenous basal insulin secretion, but their duration of action may last up to 36 hours. They achieve a steady-state level after 2–4 days to produce a constant level of insulin. Insulin glargine and insulin degludec are given once daily and insulin detemir is given once or twice daily according to individual requirements. The older long-acting insulins, (insulin zinc suspension and protamine zinc insulin) are now rarely prescribed. Type 2 diabetes Description of condition Type 2 diabetes is a chronic metabolic condition characterised by insulin resistance. Insufﬁcient pancreatic insulin production also occurs progressively over time, resulting in hyperglycaemia. It is commonly associated with obesity, physical inactivity, raised blood pressure, dyslipidaemia and a tendency to develop thrombosis; therefore it increases cardiovascular risk. It is associated with long-term microvascular and macrovascular complications, together with reduced quality of life and life expectancy. Type 2 diabetes typically develops later in life but is increasingly diagnosed in children, despite previously being considered a disease of adulthood. Aims of treatment Treatment is aimed at minimising the risk of long-term microvascular and macrovascular complications by effective blood-glucose control and maintenance of HbA1c at or below the target value set for each individual patient. Endocrine system Overview g Weight loss, smoking cessation and regular exercise can help to reduce hyperglycaemia and reduce cardiovascular risk, and should be encouraged (with input from a dietitian where appropriate). For guidance on reducing cardiovascular risk, see Cardiovascular disease risk assessment and prevention p. 201. Antidiabetic drugs should be prescribed to augment lifestyle interventions, when these changes are not adequate to control blood-glucose alone. h Antidiabetic drugs There are several classes of non-insulin antidiabetic drugs available for the treatment of type 2 diabetes. g The choice of drug should be based on effectiveness, safety, tolerability and should also take into consideration the patient’s comorbidities and concomitant medication. For recommended treatment regimens and the place in therapy of each drug, see Drug treatment, antidiabetic drugs (below). h Metformin hydrochloride p. 730 has an anti- hyperglycaemic effect, lowering both basal and postprandial blood-glucose concentrations. It does not stimulate insulin secretion and therefore, when given alone, does not cause hypoglycaemia. g The dose of standard-release metformin hydrochloride should be increased gradually to minimise the risk of gastro-intestinal side effects. Modiﬁed- release metformin hydrochloride should be offered if standard treatment is not tolerated. h The sulfonylureas (glibenclamide p. 748, gliclazide p. 748, glimepiride p. 748, glipizide p. 749, tolbutamide p. 749) may cause hypoglycaemia; it is more likely with long-acting sulfonylureas such as glibenclamide, which have been associated with severe, prolonged and sometimes fatal cases of hypoglycaemia. Sulfonylureas are also associated with modest weight gain, probably due to increased plasma- insulin concentrations. Acarbose p. 729 has a poorer anti-hyperglycaemic effect than many other antidiabetic drugs, including the sulfonylureas, metformin hydrochloride, and pioglitazone p. 749. The meglitinides, nateglinide p. 739 and repaglinide p. 740, have a rapid onset of action and short duration of activity. These drugs can be used ﬂexibly around mealtimes and adjusted to ﬁt around individual eating habits which may be beneﬁcial for some patients, but generally are a less preferred option than the sulfonylureas. The thiazolidinedione, pioglitazone, is associated with several long-term risks and its ongoing beneﬁt to the patient should be reviewed regularly and treatment stopped if response is insufﬁcient (see Important safety information under pioglitazone). The dipeptidylpeptidase-4 inhibitors (gliptins), alogliptin p. 731, linagliptin p. 732, sitagliptin p. 733, saxagliptin p. 732, and vildagliptin p. 734, do not appear to be associated with weight gain and have less incidence of hypoglycaemia than the sulfonylureas. The sodium glucose co-transporter 2 inhibitors, canagliﬂozin p. 740, dapagliﬂozin p. 742, and empagliﬂozin p. 744, may be suitable for some patients when ﬁrst-line options are not appropriate. g Canagliﬂozin and empagliﬂozin can be beneﬁcial in patients with type 2 diabetes and established cardiovascular disease. h Sodium glucose co-transporter 2 inhibitors are associated with a risk of diabetic ketoacidosis. The glucagon-like peptide-1 receptor agonists, dulaglutide p. 735, exenatide p. 736, liraglutide p. 737 and lixisenatide p. 738, should be reserved for combination therapy when other treatment options have failed. g Liraglutide has proven cardiovascular beneﬁt and should be considered in patients with type 2 diabetes and established cardiovascular disease. h Polycystic ovary syndrome g Metformin hydrochloride (initiated by a specialist) is prescribed as an insulin sensitising drug in women with polycystic ovary syndrome who are not planning pregnancy [unlicensed indication]. h Long-term beneﬁt or superiority over other treatment options has not been conﬁrmed by good quality evidence. Metformin hydrochloride may improve short-term insulin sensitivity and reduce androgen concentrations, but there is insufﬁcient supporting evidence that metformin improves weight gain, hirsutism, acne or regulation of the menstrual cycle. Treatment should only be initiated by a specialist. Metformin hydrochloride does not exert a hypoglycaemic action in non-diabetic patients except in overdose. Drug treatment, antidiabetic drugs g Type 2 diabetes should initially be treated with a single oral antidiabetic drug. A target HbA1c concentration of 48 mmol/mol (6.5%) is generally recommended when type 2 diabetes is managed by diet and lifestyle alone or when combined with a single antidiabetic drug not associated with hypoglycaemia (such as metformin hydrochloride). Adults prescribed a single drug associated with hypoglycaemia (such as a sulphonylurea), or two or more antidiabetic drugs in combination, should usually aim for an HbA1c concentration of 53 mmol/mol (7.0%). Targets may differ and should be individualised and agreed with each patient. Note: Consider relaxing the target HbA1c level on a case- by-case basis, with particular consideration for people who are older, frail, or where tight blood-glucose control is not appropriate or poses a high risk of the consequences of hypoglycaemia. If HbA1c concentrations are poorly controlled despite treatment with a single drug (usually considered to be a rise of HbA1c to 58 mmol/mol (7.5%) or higher), the drug treatment should be intensiﬁed, alongside reinforcement of advice regarding diet, lifestyle, and adherence to drug treatment. When two or more antidiabetic drugs are prescribed, an HbA1c concentration target of 53 mmol/mol (7.0%) is recommended for patients in which it is appropriate, but a relaxation of the target may be more appropriate in some individual cases (for example, those at high risk of the consequences of hypoglycaemia, poor life expectancy, or signiﬁcant comorbidities). h Initial treatment g Metformin hydrochloride is recommended as the ﬁrst choice for initial treatment for all patients, due to its positive effect on weight loss, reduced risk of hypoglycaemic events and the additional long-term cardiovascular beneﬁts associated with its use. h If metformin is contra-indicated or not tolerated, see Alternative non-metformin regimens below. First intensification of treatment g If metformin hydrochloride (alongside modiﬁcation to diet) does not control HbA1c to below the agreed threshold, treatment should be intensiﬁed, and metformin hydrochloride combined with one of the following: . a sulfonylurea (glibenclamide, gliclazide, glimepiride, glipizide, tolbutamide); . Pioglitazone; . a dipeptidylpeptidase-4 inhibitor (linagliptin, saxagliptin, sitagliptin, or vildagliptin); . a sodium glucose co-transporter 2 inhibitor (canagliﬂozin, dapagliﬂozin or empagliﬂozin) only when sulfonylureas are contra-indicated or not tolerated, or if the patient is at signiﬁcant risk of hypoglycaemia or its consequences. h g Elderly patients or those with renal impairment are at particular risk of hypoglycaemia; if a sulfonylurea is indicated, a shorter-acting sulfonylurea, such as gliclazide p. 748 or tolbutamide p. 749 should be prescribed. l The place in therapy of alogliptin p. 731 (a dipeptidylpeptidase-4 inhibitor) is not yet known. Second intensification of treatment g If dual therapy is unsuccessful, treatment should be intensiﬁed again, and one of the following triple therapy regimens prescribed: . Metformin hydrochloride p. 730 and a dipeptidylpeptidase-4 inhibitor and a sulfonylurea; . Metformin hydrochloride and pioglitazone p. 749 and a sulfonylurea; . Metformin hydrochloride and a sulfonylurea and one of the sodium glucose co-transporter 2 inhibitors; . Metformin hydrochloride and pioglitazone and a sodium glucose co-transporter 2 inhibitor (canagliﬂozin p. 740 or empagliﬂozin p. 744; note that dapagliﬂozin is not recommended in a triple therapy regimen with pioglitazone). Alternatively,it may be appropriate to start insulin-based treatment at this stage—see Drug treatment, insulin. h Glucagon-like peptide-1 receptor agonists g If triple therapy with metformin hydrochloride and two other oral drugs is tried and is not effective, not tolerated or contra-indicated, a glucagon-like peptide-1 receptor agonist may be prescribed as part of a triple combination regimen with metformin hydrochloride and a sulfonylurea. These should only be prescribed for patients who have a BMI of 35 kg/m2or above (adjusted for ethnicity) and who also have speciﬁc psychological or medical problems associated with obesity; or for those who have a BMI lower than 35 kg/m2 but for whom insulin therapy would have signiﬁcant occupational implications or if the weight loss associated with glucagon-like peptide-1 receptor agonists would beneﬁt other signiﬁcant obesity-related comorbidities. After 6 months, the drug should be reviewed and only continued if there has been a beneﬁcial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body-weight). Insulin should only be prescribed in combination with a glucagon-like peptide-1 receptor agonist under specialist care advice and with ongoing support from a consultant-led multidisciplinary team. h Alternative non-metformin regimens g If metformin is contra-indicated or not tolerated, initial treatment should be single therapy with: . a sulfonylurea (glibenclamide p. 748, gliclazide, glimepiride p. 748, glipizide p. 749, or tolbutamide) (ﬁrst choice) or . a dipeptidyl peptidase-4 inhibitor (linagliptin p. 732, saxagliptin p. 732, sitagliptin p. 733, or vildagliptin p. 734), or . Pioglitazone. h The sodium glucose co-transporter 2 inhibitors canagliﬂozin, dapagliﬂozin p. 742, or empagliﬂozin are also options for monotherapy when metformin is contra- indicated or not tolerated, only if a dipeptidylpeptidase-4 inhibitor would otherwise be prescribed and neither a sulfonylurea nor pioglitazone is appropriate. g Repaglinide p. 740 is also an effective alternative option for single therapy, but it has a limited role in treatment because, should an intensiﬁcation of treatment be required, it is not licensed to be used in any combination other than with metformin hydrochloride; it would therefore require a complete change of treatment in those patients who have started it due to intolerance or contra-indication to metformin. h Intensiﬁcation g If the initial single drug does not control HbA1c to below the agreed threshold, treatment should be intensiﬁed and one of the following dual combinations prescribed: Endocrine system . a dipeptidylpeptidase-4 inhibitor and pioglitazone; . a dipeptidylpeptidase-4 inhibitor and a sulfonylurea; or . Pioglitazone and a sulfonylurea. If dual therapy does not provide adequate glucose control, insulin-based treatment should be considered—see Drug treatment, insulin. h Drug treatment, insulin g When indicated for intensiﬁcation, insulin (see also, Insulin p. 722) should be started with a structured support programme covering insulin dose titration, injection technique, self-monitoring, and knowledge of dietary effects and glucose control. Metformin hydrochloride should be continued unless it is contra-indicated or not tolerated. Other antidiabetic drugs should be reviewed and stopped if necessary. Recommended insulin regimens include: . human isophane insulin p. 755 injected once or twice daily, according to requirements; . a human isophane insulin in combination with a short- acting insulin, administered either separately or as a pre- mixed (biphasic) human insulin preparation (this may be particularly appropriate if HbA1c is 75 mmol/mol (9.0%) or higher); . Insulin detemir p. 756 or insulin glargine p. 757 as an alternative to human isophane insulin. This can be preferable if a once daily injection would be beneﬁcial (for example if assistance is required to inject insulin), or if recurrent symptomatic hypoglycaemic episodes are problematic, or if the patient would otherwise need twice- daily human isophane insulin injections in combination with oral glucose-lowering drugs. Also consider switching to insulin detemir or insulin glargine from human isophane insulin if signiﬁcant hypoglycaemia is problematic, or in patients who cannot use the device needed to inject human isophane insulin; . biphasic preparations (pre-mixed) that include a short- acting human analogue insulin (rather than short-acting human soluble insulin) can be preferable for patients who prefer injecting insulin immediately before a meal, or if hypoglycaemia is a problem, or if blood-glucose concentrations rise markedly after meals. When starting insulin therapy, bedtime basal insulin should be initiated and the dose titrated against morning (fasting) glucose. Patients who are prescribed a basal insulin regimen (human isophane insulin, insulin detemir or insulin glargine) should be monitored for the need for short-acting insulin before meals (or a biphasic insulin preparation). Patients who are prescribed a biphasic insulin should be monitored for the need for a further injection of short-acting insulin before meals or for a change to a basal-bolus regimen with human isophane insulin or insulin detemir or insulin glargine if blood-glucose control remains inadequate. h Advanced Pharmacy Services Patients with type 2 diabetes may be eligible for the New Medicines Service / Medicines Use Review service provided by a community pharmacist. For further information, see Advanced Pharmacy Services in Medicines optimisation p. 18. Useful Resources Type 2 diabetes in adults: management. National Institute for Health and Care Excellence. Clinical guideline NG28. December 2015. www.nice.org.uk/guidance/ng28 Pharmacological management of glycaemic control in people with type 2 diabetes. Scottish Intercollegiate Guidelines Network. Clinical guideline 154. November 2017. www.sign.ac.uk/assets/sign154.pdf Endocrine system Patient decision aid: Type 2 diabetes in adults: controlling your blood glucose by taking a second medicine—what are your options? National Institute for Health and Care Excellence. December 2015. www.nice.org.uk/about/what-we-do/our-programmes/nice- guidance/nice-guidelines/shared-decision-making Diabetic complications See also Diabetes p. 720 Type 1 diabetes p. 721 Type 2 diabetes p. 723 Diabetic foot infections, antibacterial therapy p. 533. For guidance on other diabetic foot problems, see NICE guideline Diabetic foot problems at: https://www.nice.org.uk/guidance/ng19. Diabetes and cardiovascular disease Diabetes is a strong risk factor for cardiovascular disease. g Other risk factors for cardiovascular disease that should also be addressed are: smoking, hypertension, obesity, and dyslipidaemia. h Cardiovascular risk in patients with diabetes can be further reduced by the use of an ACE inhibitor (or an angiotensin-II receptor antagonist) and lipid-regulating drugs. For full guidance on the assessment and prevention of cardiovascular disease, see Cardiovascular disease risk assessment and prevention p. 201. Diabetic nephropathy g In diabetic patients with nephropathy, blood pressure should be reduced to the lowest achievable level to slow the rate of decline of glomerular ﬁltration rate and reduce proteinuria. Provided there are no contra-indications, all diabetic patients with nephropathy causing proteinuria or with established microalbuminuria should be treated with an ACE inhibitor or an angiotensin-II receptor antagonist, even if the blood pressure is normal. ACE inhibitors or angiotensin-II receptor antagonists should also be given as monotherapy, or combined therapy, in patients with chronic kidney disease and proteinuria, to reduce the rate of progression of chronic kidney disease. h ACE inhibitors can potentiate the hypoglycaemic effect of insulin and oral antidiabetic drugs; this effect is more likely during the ﬁrst weeks of combined treatment and in patients with renal impairment. See also treatment of hypertension in diabetes in Hypertension p. 151. Diabetic neuropathy g Optimal diabetic control is beneﬁcial for the management of painful neuropathy. Monotherapy with antidepressant drugs, including tricyclics (such as amitriptyline hydrochloride p. 390 and imipramine hydrochloride p. 394 [unlicensed use]), duloxetine p. 385, and venlafaxine p. 386 [unlicensed use] should be considered in patients for the treatment of painful diabetic peripheral neuropathy. Antiepileptic drugs, such as pregabalin p. 341 and gabapentin p. 331, can also be considered. Opioid analgesics in combination with gabapentin can be considered if pain is not controlled with monotherapy. h In autonomic neuropathy, diabetic diarrhoea can often be managed by tetracycline p. 600 [unlicensed use], or codeine phosphate p. 475 as the best alternative; other antidiarrhoeal preparations can also be tried. Erythromycin p. 569 (especially when given intravenously) may be beneﬁcial for gastroparesis [unlicensed use]. In neuropathic postural hypotension, increased salt intake and the use of the mineralcorticoid ﬂudrocortisone acetate p. 713 [unlicensed use] may help by increasing plasma volume, but uncomfortable oedema is a common side-effect. Fludrocortisone can also be combined with ﬂurbiprofen p. 1203 and ephedrine hydrochloride p. 286 [both unlicensed]. Midodrine [unlicensed], an alpha agonist, may also be useful in postural hypotension. Gustatory sweating can be treated with an antimuscarinic such as propantheline bromide p. 93; side-effects are common. See also, the management of hyperhidrosis (Hyperhidrosis p. 1331). In some patients with neuropathic oedema, ephedrine hydrochloride [unlicensed use] offers effective relief. See also the management of Erectile dysfunction p. 857. Visual impairment g Optimal diabetic control (HbA1c ideally around 7% or 53 mmol/mol) and blood pressure control (<130/80 mmHg) should be maintained to prevent onset and progression of diabetic eye disease. h Diabetic ketoacidosis Management The management of diabetic ketoacidosis involves the replacement of ﬂuid and electrolytes and the administration of insulin. Guidelines for the Management of Diabetic Ketoacidosis in Adults, published by the Joint British Diabetes Societies Inpatient Care Group (available at www.diabetes.org.uk/Professionals/Position-statements-reports/ Specialist-care-for-children-and-adults-and-complications/The- Management-of-Diabetic-Ketoacidosis-in-Adults/), should be followed. . To restore circulating volume if systolic blood pressure is below 90 mmHg (adjusted for age, sex, and medication as appropriate), give 500 mL sodium chloride 0.9% by intravenous infusion over 10–15 minutes; repeat if blood pressure remains below 90 mmHg and seek senior medical advice. . When blood pressure is over 90 mmHg, sodium chloride 0.9% should be given by intravenous infusion at a rate that replaces deﬁcit and provides maintenance; see guideline or suggested regimen. . Include potassium chloride in the ﬂuids unless anuria is suspected; adjust according to plasma-potassium concentration (measure at 60 minutes, 2 hours, and 2 hourly thereafter; measure hourly if outside the normal range). . Start an intravenous insulin infusion: soluble insulin should be diluted (and mixed thoroughly) with sodium chloride 0.9% intravenous infusion to a concentration of 1 unit/mL; infuse at a ﬁxed rate of 0.1 units/kg/hour. . Established subcutaneous therapy with long-acting insulin analogues (insulin detemir p. 756 or insulin glargine p. 757) should be continued during treatment of diabetic ketoacidosis. . Monitor blood-ketone and blood-glucose concentrations hourly and adjust the insulin infusion rate accordingly. Blood-ketone concentration should fall by at least 0.5 mmol/litre/hour and blood-glucose concentration should fall by at least 3 mmol/litre/hour. . Once blood-glucose concentration falls below 14 mmol/litre, glucose 10% should be given by intravenous infusion (into a large vein through a large- gauge needle) at a rate of 125 mL/hour, in addition to the sodium chloride 0.9% infusion. . Continue insulin infusion until blood-ketone concentration is below 0.3 mmol/litre, blood pH is above 7.3 and the patient is able to eat and drink; ideally give subcutaneous fast-acting insulin and a meal, and stop the insulin infusion 1 hour later. The management of hyperosmolar hyperglycaemic state or hyperosmolar hyperglycaemic nonketotic coma is similar to that of diabetic ketoacidosis, although lower rates of insulin infusion are usually necessary and slower rehydration may be required. Diabetes, surgery and medical illness Management of diabetes during surgery Peri-operative management of blood-glucose concentrations depends on factors including the required duration of fasting, timing of surgery (morning or afternoon), usual treatment regimen (insulin, antidiabetic drugs or diet), prior glycaemic control, other co-morbidities, and the likelihood that the patient will be capable of self-managing their diabetes in the immediate post-operative period. g All patients should have emergency treatment for hypoglycaemia written on their drug chart on admission. l Note: The following recommendations provide general guidance for the management of diabetes during surgery. Local protocols and guidelines should be followed where they exist. Use of insulin during surgery Elective surgery—minor procedures in patients with good glycaemic control g Patients usually treated with insulin who have good glycaemic control (HbA1c less than 69 mmol/mol or 8.5 %) and are undergoing minor procedures, can be managed during the operative period by adjustment of their usual insulin regimen, which should be adjusted depending on the type of insulin usually prescribed, following detailed local protocols (which should also include intravenous ﬂuid management, monitoring and control of electrolytes and avoidance of hyperchloraemic metabolic acidosis). On the day before the surgery, the patient’s usual insulin should be given as normal, other than once daily long-acting insulin analogues, which should be given at a dose reduced by 20 %. l Elective surgery—major procedures or poor glycaemic control g Patients usually treated with insulin, who are either undergoing major procedures (surgery requiring a long fasting period of more than one missed meal) or whose diabetes is poorly controlled, will usually require a variable rate intravenous insulin infusion (continued until the patient is eating/drinking and stabilised on their previous glucose-lowering medication). The aim is to achieve and maintain glucose concentration within the usual target range (6–10 mmol/litre; but up to 12 mmol/litre is acceptable) by infusing a constant rate of glucose-containing ﬂuid as a substrate, while also infusing insulin at a variable rate. Detailed local protocols should be consulted. In general, the following steps should be followed: . on the day before surgery, once daily long-acting insulin analogues should be given at 80 % of the usual dose; otherwise the patient’s usual insulin should be given as normal; . on the day of surgery and throughout the intra-operative period, once daily long-acting insulin analogues should be continued at 80 % of the usual dose; all other insulin should be stopped until the patient is eating and drinking again after surgery; . on the day of surgery, start an intravenous substrate infusion of potassium chloride with glucose and sodium chloride p. 1100 (based on serum electrolytes which must be measured frequently), and infuse at a rate appropriate to the patient’s ﬂuid requirements. To prevent hypoglycaemia, this infusion must not be stopped while the insulin infusion is running; . a variable rate intravenous insulin infusion of soluble Endocrine system human insulin p. 751 in sodium chloride 0.9 % p. 1101 (made either according to locally agreed protocols or using preﬁlled syringes) should be given via a syringe pump at an initial infusion rate determined by bedside capillary blood- glucose measurement. Hourly blood-glucose measurement should be taken to ensure that the intravenous insulin infusion rate is correct for at least the ﬁrst 12 hours; the insulin infusion rate should be adjusted according to local protocol to maintain blood-glucose concentrations within the usual target range (6–10 mmol/litre; up to 12 mmol/litre is acceptable); . intravenous glucose 20 % p. 1102 should be given if blood- glucose drops below 6 mmol/litre, and blood-glucose checked every hour, to prevent a drop below 4 mmol/litre. If blood-glucose drops below 4 mmol/litre, intravenous glucose 20 % should be adjusted and blood-glucose checked every 15 minutes, until blood-glucose is above 6 mmol/litre (testing can then revert to hourly). If blood- glucose rises above 12 mmol/litre, check ketones and consider other signs of diabetic ketoacidosis (see Diabetic ketoacidosis p. 726). Conversion back to a subcutaneous insulin should not begin until the patient can eat and drink without nausea or vomiting. Once the patient’s previous insulin regimen is re- started, the usual insulin dose may require adjustment, as insulin requirements can change due to post-operative stress, infection or altered food intake. Previous subcutaneous basal-bolus regimens, should be restarted when the ﬁrst postoperative meal-time insulin dose is due (e.g. with breakfast or lunch); doses may need adjustment due to postoperative stress, infection or altered food intake. The variable rate intravenous insulin infusion and intravenous ﬂuids should be continued until 30–60 minutes after the ﬁrst meal-time short-acting insulin dose. If the patient was previously on a long-acting insulin analogue, this should have been continued throughout the operative period at 80 % of the normal dose, and should now just continue at that same dose until the patient leaves hospital; only the short-acting insulin needs to be restarted as above. Previous subcutaneous twice-daily mixed insulin regimens, should be restarted before breakfast or an evening meal (not at any other time). The variable rate intravenous insulin infusion should be maintained for 30–60 minutes after the ﬁrst subcutaneous insulin dose has been given. Patients who were previously managed with a continuous subcutaneous insulin infusion should be referred to a specialist team. The subcutaneous infusion should be restarted at the normal basal rate, not at bedtime, and the insulin infusion continued until the next meal bolus has been given. Patients not previously prescribed insulin, who are to start a subcutaneous insulin regimen post-surgery, should have an insulin dose calculated with advice from a specialist diabetes team, considering the patient’s sensitivity to insulin, degree of glycaemic control, weight, age, and the average hourly insulin dose used in the peri-operative period. l Emergency surgery g Patients with diabetes (type 1 and 2) requiring emergency surgery, should always have their blood-glucose, blood or urinary ketone concentration, serum electrolytes and serum bicarbonate checked before surgery. If ketones are high or bicarbonate is low, blood gases should also be checked. If ketoacidosis is present, recommendations for Diabetic ketoacidosis p. 726 should be followed immediately, and surgery delayed if possible. If there is no acidosis, intravenous ﬂuids and an insulin infusion should be started and managed as for major elective surgery (above). l Use of antidiabetic drugs during surgery Endocrine system g Manipulation of antidiabetic drug may not be appropriate for all surgery or for all patients; particularly when fasting time is more than one missed meal, in patients with poor glycaemic control, and when there is risk of renal injury. In these cases, a variable rate intravenous insulin infusion p. 751 should be used as for major elective surgery (above), and usual antidiabetic medication adjusted in the peri-operative period. Insulin is almost always required in medical and surgical emergencies. When insulin is required and given during surgery, acarbose p. 729, meglitinides, sulfonylureas, pioglitazone p. 749, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium glucose co-transporter 2 inhibitors should be stopped once the insulin infusion is commenced and not restarted until the patient is eating and drinking normally. Glucagon-like peptide-1 receptor agonists can be continued as normal during the insulin infusion. If elective minor surgical procedures only require a short- fasting period (just one missed meal), it may be possible to adjust antidiabetic drugs to avoid a switch to a variable rate intravenous insulin infusion; normal drug treatment can continue. In suitable cases, acarbose, nateglinide p. 739 and repaglinide p. 740 can be continued with just the dose omitted on the morning of surgery if fasting (the morning dose may be given if the patient is not fasting and surgery is in the afternoon). Pioglitazone, dipeptidylpeptidase-4 inhibitors (gliptins) and glucagon-like peptide-1 receptor agonists can be taken as normal during the whole peri-operative period. Sodium glucose co-transporter 2 inhibitors should be omitted on the day of surgery and not restarted until the patient is stable; their use during periods of dehydration and acute illness is associated with an increased risk of developing diabetic ketoacidosis. Sulfonylureas are associated with hypoglycaemia in the fasted state and therefore should always be omitted on the day of surgery until the patient is eating and drinking again. Capillary blood-glucose should be checked hourly. If hyperglycaemia occurs, an appropriate dose of subcutaneous rapid-acting insulin may be given. A second dose may be given 2 hours later, and a variable rate intravenous insulin infusion considered if hyperglycaemia persists. Metformin hydrochloride p. 730 is renally excreted; renal impairment may lead to accumulation and lactic acidosis during surgery. If only one meal will be missed during surgery, and the patient has an eGFR greater than 60 mL/minute/1.73m2 and a low risk of acute kidney injury (and the procedure does not involve administration of contrast media), it may be possible to continue metformin hydrochloride throughout the peri-operative period—just the lunchtime dose should be omitted if the usual dose is prescribed three times a day. If the patient will miss more than one meal or there is signiﬁcant risk of the patient developing acute kidney injury, metformin hydrochloride should be stopped when the pre- operative fast begins. A variable rate intravenous insulin infusion should be started if the metformin hydrochloride dose is more than once daily. Otherwise insulin should only be started if blood-glucose concentration is greater than 12 mmol/litre on two consecutive occasions. Metformin should not be recommenced until the patient is eating and drinking again, and normal renal function has been assured. There is no need to stop metformin hydrochloride after contrast medium in patients missing only one meal or who have an eGFR greater than 60 mL/minute/1.73m2. If contrast medium is to be used, and eGFR is less than 60 mL/minute/1.73m2, metformin should be omitted on the day of the procedure and for the following 48 hours. l Use of antidiabetic drugs during medical illness Manufacturers of some antidiabetic drugs recommend that they may need to be replaced temporarily with insulin during intercurrent illness when the drug is unlikely to control hyperglycaemia (such as myocardial infarction, coma, severe infection, trauma and other medical emergencies). Consult individual product literature. Sodium glucose co-transporter 2 inhibitors are associated with increased risk of developing diabetic ketoacidosis during periods of dehydration, stress, surgery, trauma, acute medical illness or any other catabolic state, and should be used with caution during these times. The MHRA has advised (2016) that these drugs should be temporarily stopped in patients who are hospitalised for acute serious illness until the patient is medically stable. Diabetes, pregnancy and breast-feeding Description of condition Diabetes in pregnancy is associated with increased risks to the woman (such as pre-eclampsia and rapidly worsening retinopathy), and to the developing fetus, compared with pregnancy in non-diabetic women. Effective blood-glucose control before conception and throughout pregnancy reduces (but does not eliminate) the risk of adverse outcomes such as miscarriage, congenital malformation, stillbirth, and neonatal death. Management of pre-existing diabetes g Women with pre-existing diabetes who are planning on becoming pregnant should aim to keep their HbA1c concentration below 48 mmol/mol (6.5%) if possible without causing problematic hypoglycaemia. Any reduction towards this target is likely to reduce the risk of congenital malformations in the newborn. Women with pre-existing diabetes who are planning to become pregnant should be advised to take folic acid at the dose for women who are at high-risk of conceiving a child with a neural tube defect, see folic acid p. 1084. h Overview Oral antidiabetic drugs g All oral antidiabetic drugs, except metformin hydrochloride p. 730, should be discontinued before pregnancy (or as soon as an unplanned pregnancy is identiﬁed) and substituted with insulin therapy. Women with diabetes may be treated with metformin hydrochloride [unlicensed in type 1 diabetes] as an adjunct or alternative to insulin in the preconception period and during pregnancy, when the likely beneﬁts from improved blood-glucose control outweigh the potential for harm. Metformin hydrochloride can be continued, or glibenclamide p. 748 resumed, immediately after birth and during breast-feeding for those with pre-existing Type 2 diabetes p. 723. All other antidiabetic drugs should be avoided while breast-feeding. h Insulin Limited evidence suggests that the rapid-acting insulin analogues (insulin aspart p. 752 and insulin lispro p. 754) can be associated with fewer episodes of hypoglycaemia, a reduction in postprandial glucose excursions and an improvement in overall glycaemic control compared with regular human insulin. g Isophane insulin p. 755 is the ﬁrst-choice for long- acting insulin during pregnancy, however in women who have good blood-glucose control before pregnancy with the long-acting insulin analogues (insulin detemir p. 756 or insulin glargine p. 757), it may be appropriate to continue using them throughout pregnancy. Continuous subcutaneous insulin infusion p. 751 (insulin pump therapy) may be appropriate for pregnant women who have difﬁculty achieving glycaemic control with multiple daily injections of insulin p. 751 without signiﬁcant disabling hypoglycaemia. All women treated with insulin p. 751 during pregnancy should be aware of the risks of hypoglycaemia, particularly in the ﬁrst trimester, and should be advised to always carry a fast-acting form of glucose, such as dextrose tablets or a glucose-containing drink. Pregnant women with Type 1 diabetes p. 721 should also be prescribed glucagon p. 763 for use if needed. Women with pre-existing diabetes treated with insulin p. 751 during pregnancy are at increased risk of hypoglycaemia in the postnatal period and should reduce their insulin immediately after birth. Blood-glucose levels should be monitored carefully to establish the appropriate dose. h Medication for diabetic complications g Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists should be discontinued and replaced with an alternative antihypertensive suitable for use in pregnancy before conception or as soon as pregnancy is conﬁrmed (see Hypertension in pregnancy under Hypertension p. 151). Statins should not be prescribed during pregnancy and should be discontinued before a planned pregnancy. h Gestational diabetes g Women with gestational diabetes who have a fasting plasma glucose below 7 mmol/litre at diagnosis, should ﬁrst attempt a change in diet and exercise alone in order to reduce blood-glucose. If blood-glucose targets are not met within 1 to 2 weeks, metformin hydrochloride p. 730 may be prescribed [unlicensed use]. Insulin p. 751 may be prescribed if metformin is contra-indicated or not acceptable, and may also be added to treatment if metformin is not effective alone. Women who have a fasting plasma glucose above 7 mmol/litre at diagnosis should be treated with insulin immediately, with or without metformin hydrochloride, in addition to a change in diet and exercise. Women who have a fasting plasma glucose between 6 and 6.9 mmol/litre alongside complications such as macrosomia or hydramnios should be considered for immediate insulin treatment, with or without metformin hydrochloride. Glibenclamide p. 748 [unlicensed use] may be considered for women from 11 weeks gestation (after organogenesis) who cannot tolerate metformin, or for those in whom metformin is not effective and do not wish to have insulin therapy. Women with gestational diabetes should discontinue hypoglycaemic treatment immediately after giving birth. h Useful Resources Management of diabetes. Scottish Intercollegiate Guidelines Network. Clinical guideline 116. March 2010 (updated November 2017). www.sign.ac.uk/assets/sign116.pdf Diabetes in pregnancy: management from preconception to the postnatal period. National Institute for Health and Care Excellence. Clinical guideline NG3. February 2015. www.nice.org.uk/guidance/ng3 BLOOD GLUCOSE LOWERING DRUGS › ALPHA GLUCOSIDASE INHIBITORS

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Metyrapone

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Dose text by age group

Metyrapone

Overview

Drug Action

Indications And Dose

Contra Indications

Cautions

Safety

Interactions

Side Effects

Pregnancy

Breast Feeding

Hepatic Impairment

Dose and formulations

Medicinal Forms

Clinical care

Patient And Carer Advice

Dose text by age group