Rang & Dale's Pharmacology 9th Edition - Drugs Affecting Major Organ Systems PDF

SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS 32 The control of blood glucose and drug treatment of diabetes mellitus intermittent food intake and variable metabolic demands...

SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS 32 The control of blood glucose and drug treatment of diabetes mellitus intermittent food intake and variable metabolic demands. OVERVIEW More fuel is made available by feeding than is required immediately, and excess calories are stored as glycogen or In this chapter we describe the endocrine control of fat. During fasting, these energy stores need to be mobilised blood glucose by pancreatic hormones, especially in a regulated manner. The most important regulatory insulin but also glucagon and somatostatin, and the hormone is insulin, the actions of which are described below. gut hormones (incretins) glucagon-like peptide-1 Increased blood glucose stimulates insulin secretion (Fig. (GLP-1) and gastric inhibitory peptide (GIP, which is 32.1), whereas reduced blood glucose reduces insulin also known as glucose-dependent insulinotropic secretion. The effect of glucose on insulin secretion depends peptide). This underpins coverage of diabetes mellitus on whether the glucose load is administered intravenously and its treatment with insulin preparations (including or by mouth. Glucose administered by mouth is more insulin analogues), and other hypoglycaemic agents effective in stimulating insulin secretion because it stimulates – metformin, sulfonylureas, α-glucosidase inhibitors, release from the gut of incretin hormones which promote long-acting incretin mimetics such as exenatide, insulin secretion (see Fig. 32.1). Glucose is less effective in gliptins, which potentiate incretins by blocking their stimulating insulin secretion in patients with diabetes (Fig. degradation, and renal tubular sodium–glucose co- 32.2). Hypoglycaemia, caused by excessive exogenous insulin, transport inhibitors. not only reduces endogenous insulin secretion but also elicits secretion of an array of ‘counter-regulatory’ hormones, including glucagon, adrenaline (Ch. 15), glucocorticoids (Ch. INTRODUCTION 34) and growth hormone (Ch. 34), all of which increase blood glucose. Their main effects on glucose uptake and carbo- Insulin is the main hormone controlling intermediary hydrate metabolism are summarised and contrasted with metabolism. Its most striking acute effect is to lower blood those of insulin in Table 32.1. glucose. Reduced (or absent) secretion of insulin causes The kidneys also have an important role in glucose diabetes mellitus. It is often coupled with reduced sensitivity regulation. Substantial amounts of glucose (approximately to its action, ‘insulin resistance’, which is closely related 900 mmol or 160 g) are filtered each day from the plasma to obesity. Diabetes mellitus, recognised since ancient times, into the renal tubules (Abdul-Ghani et al., 2015). However, is named for the production of sugary urine in copious in those with normal glucose homeostasis, very little or no volumes (due to the osmotic diuretic action of the high glucose is excreted in the urine because renal tubular urine glucose concentration). Diabetes is rapidly increasing sodium–glucose co-transporters (SGLT) reclaim all the to epidemic proportions (in step with obesity, Ch. 33), and filtered glucose. The co-transporters are large transmem- its consequences are dire – especially accelerated athero- brane proteins (670 amino acids) that actively transport sclerosis (myocardial and cerebral infarction, gangrene glucose against the concentration gradient through a or limb amputation), kidney failure, neuropathy and mechanism that involves coupling with sodium transport blindness. (Abdul-Ghani et al., 2011). There are two SGLT variants In this chapter, we first describe the control of blood in the kidney – SGLT2 (located in the early convoluted sugar. The second part of the chapter is devoted to the segment of the proximal tubule) has low affinity but high different kinds of diabetes mellitus and the role of drugs capacity, and is responsible for reclaiming about 90% of in their treatment. Diabetes, along with obesity (Ch. 33), the filtered renal glucose, whilst the remaining 10% is hypertension (Ch. 23), dyslipidaemia (Ch. 24), and fatty reclaimed by high affinity, low capacity SGLT1 (located infiltration of the liver, comprise a ‘metabolic syndrome’, further on in the distal straight segment of the proximal a common pathological cluster and a rapidly growing tubule; DeFronzo et al., 2012). SGLT1 is also found in the problem that is associated with many life-threatening heart, lungs and gastrointestinal (GI) tract, whereas SGLT2 conditions. Drugs that act on some of the many mechanisms is principally located in the kidney so selective inhibitors that become deranged in metabolic syndrome, including of SGLT2 can promote glucose excretion without influencing several directed at controlling blood sugar, have been glucose transport in other organs. developed, but clinical success has so far been modest. The evolutionary role of SGLT in the kidney has been attributed to the benefits of retaining glucose in times when starvation or food shortages were commonplace. However, CONTROL OF BLOOD GLUCOSE when the renal capacity for glucose re-absorption is exceeded in diabetes, glucose spills over into the urine (glycosuria) Glucose is the obligatory source of energy for the adult and causes an osmotic diuresis (polyuria) which, in turn, brain, and physiological control of blood glucose reflects results in dehydration, thirst and increased drinking 408 the need to maintain adequate fuel supplies in the face of (polydipsia). The chronically elevated glucose concentrations  THE CONTROL OF BLOOD GLUCOSE AND DRUG TREATMENT OF DIABETES MELLITUS 32 Table 32.1 The effect of hormones on blood glucose Hormone Main actions Main stimuli for secretion Main effect Main regulatory hormone ↑ Glucose uptake ↑ Glycogen synthesis Acute rise in blood glucose Insulin ↓ Blood glucose ↓ Glycogenolysis Incretins (GIP and GLP-1) ↓ Gluconeogenesis Main counter-regulatory hormones Glucagon ↑ Glycogenolysis ↑ Glyconeogenesis Adrenaline (epinephrine) ↑ Glycogenolysis Hypoglycaemia (i.e. blood glucose Glucocorticoids ↓ Glucose uptake 7.0 mmol/L, or plasma 37) and has weak calcitonin-like actions on calcium metabolism and glucose >11.1 mmol/L, 2 h after a meal) – caused by insulin osteoclast activity. It is also about 50% identical with calcitonin gene- deficiency, often combined with insulin resistance. There related peptide (CGRP; see Ch. 19), and large intravenous doses cause are two main types of diabetes mellitus: vasodilatation, presumably by an action on CGRP receptors. Pramlintide, an amylin analogue with three proline substitu- 1. Type 1 diabetes (previously known as tions that reduce its tendency to aggregate into insoluble insulin-dependent diabetes mellitus – IDDM – or fibrils, is approved in the United States to treat patients juvenile-onset diabetes), in which there is an absolute with type 1 diabetes and for type 2 diabetics who use deficiency of insulin. 2. Type 2 diabetes (previously known as non insulin-dependent diabetes mellitus – NIDDM – or 4 Octreotide is used either short term before surgery on the pituitary maturity-onset diabetes), in which there is a relative tumour, or while waiting for radiotherapy of the tumour to take effect, deficiency of insulin associated with reduced or if other treatments have been ineffective. sensitivity to its action (insulin resistance). 413 32 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS Hyperglycaemia occurs because of uncontrolled hepatic including immunosuppression, early insulin therapy, glucose output and reduced uptake of glucose by skeletal antioxidants, nicotinamide and many others; so far these muscle with reduced glycogen synthesis. Insulin deficiency have disappointed, but this remains a very active field. causes muscle wasting through increased breakdown and Type 2 diabetes is accompanied both by insulin resistance reduced synthesis of proteins. Diabetic ketoacidosis is an (which precedes overt disease) and by impaired insulin acute emergency that is predominantly seen in patients secretion, each of which are important in its pathogenesis. with type 1 diabetes. It develops in the absence of insulin Such patients are often obese and usually present in adult because of accelerated breakdown of fat to acetyl-CoA, life, the incidence rising progressively with age as β-cell which, in the absence of aerobic carbohydrate metabolism, function declines. Treatment is initially dietary, although is converted to acetoacetate and β-hydroxybutyrate (which oral hypoglycaemic drugs usually become necessary, and cause acidosis) and acetone (a ketone). most patients ultimately benefit from exogenous insulin. Various complications develop as a consequence of the Prospective studies have demonstrated a relentless deteriora- metabolic derangements in diabetes, often over several tion in diabetic control6 with increasing age and duration years. Many of these are the result of disease of blood of disease. vessels, either large (macrovascular disease) or small Insulin secretion (basal, and in response to a meal) in a (microangiopathy). Dysfunction of vascular endothelium type 1 and a type 2 diabetic patient is contrasted schemati- (see Ch. 23) is an early and critical event in the development cally with that in a healthy control in Fig. 32.2. of vascular complications. Oxygen-derived free radicals, There are many other less common forms of diabetes protein kinase C and non-enzymic products of glucose and mellitus in addition to the two main ones described earlier albumin called advanced glycation end products (AGE) have (for example, syndromes associated with autoantibodies been implicated. Macrovascular disease consists of acceler- directed against insulin receptors which cause severe insulin ated atheroma (Ch. 24) and its thrombotic complications resistance, functional α-cell tumours, ‘glucagonomas’, and (Ch. 25), which are commoner and more severe in diabetic many other rarities), and hyperglycaemia can also be a patients. Microangiopathy is a distinctive feature of diabetes clinically important adverse effect of several drugs, including mellitus and particularly affects the retina, kidney and glucocorticoids (Ch. 34), high doses of thiazide diuretics peripheral nerves. Diabetes mellitus is the commonest cause (Ch. 30) and several of the protease inhibitors used to treat of chronic renal failure, a huge and rapidly increasing HIV infection (Ch. 53). problem, and a major burden to society as well as to individual patients. Co-existent hypertension promotes DRUGS USED IN THE TREATMENT OF DIABETES progressive renal damage, and treatment of hypertension The main groups of drugs used are: slows the progression of diabetic nephropathy and reduces Agents given by injection the risk of myocardial infarction. Angiotensin-converting nsulin in various or s and or ulations used in enzyme inhibitors or angiotensin receptor antagonists (Ch. type 1 and type 2 diabetes) 23) are more effective in preventing diabetic nephropathy ncretin i etics e exenatide, liraglutide) than other antihypertensive drugs, perhaps because they Oral agents (used in type 2 diabetes) prevent fibroproliferative actions of angiotensin II and i uanides e metformin) aldosterone. ul onylureas e tolbutamide, glibenclamide, Diabetic neuropathy5 is associated with accumulation of glipizide) and related drugs (e.g. repaglinide, osmotically active metabolites of glucose, produced by the nateglinide) action of aldose reductase, but aldose reductase inhibitors hia olidinediones e pioglitazone) have been disappointing as therapeutic drugs (see Farmer li tins e sitagliptin) et al., 2012, for a review). lucose trans ort inhibitors e empagliflozin) Type 1 diabetes can occur at any age, but patients are usually young (children or adolescents) and not obese when they first develop symptoms. There is an inherited predis- INSULIN TREATMENT position, with a 10- to 15-fold increased incidence in The effects of insulin and its mechanism of action are first-degree relatives of an index case, and strong associations described earlier. Here we describe pharmacokinetic aspects with particular histocompatibility antigens (HLA types). and adverse effects, both of which are central to its thera- Identical twins are less than fully concordant, so environ- peutic use. Insulin for clinical use was once either porcine mental factors such as viral infection (e.g. with coxsackie or bovine but is now almost entirely human (made in virus or echovirus) are believed to be necessary for geneti- expression systems by recombinant DNA technology, Ch. cally predisposed individuals to express the disease. Viral 5). Animal insulins are liable to elicit an immune response; infection may damage pancreatic β cells and expose antigens this is less of an issue with recombinant human insulins. that initiate a self-perpetuating autoimmune process. The Although recombinant insulin is more consistent in quality patient becomes overtly diabetic only when more than 90% than insulins extracted from pancreases of freshly slaugh- of the β cells have been destroyed. This natural history tered animals, doses are still quantified in terms of units provides a tantalising prospect of intervening in the pre- of activity (Ch. 8), with which doctors and patients are diabetic stage, and a variety of strategies have been mooted, familiar, rather than of mass. 6 Diabetic control is not easily estimated by determination of blood 5 Neuropathy (‘disease of the nerves’) causes dysfunction of peripheral glucose, because this is so variable. Instead, glycated haemoglobin nerve fibres, which can be motor, sensory or autonomic. Diabetic (haemoglobin A1C) is measured. This provides an integrated measure of neuropathy often causes numbness in a ‘stocking’ distribution caused control over the lifespan of the red cell: approximately 120 days. In by damage to sensory fibres, and postural hypotension and erectile healthy individuals, 4%–6% (20–42 mmol/mol) of haemoglobin is 414 dysfunction due to autonomic neuropathy. glycated; levels above 6.5% (48 mmol/mol) are indicative of diabetes.  THE CONTROL OF BLOOD GLUCOSE AND DRUG TREATMENT OF DIABETES MELLITUS 32 Pharmacokinetic aspects and insulin preparations insulins twice daily, before breakfast and before the evening Insulin is destroyed in the GI tract, and is ordinarily given meal. Improved control of blood glucose can be achieved by injection – usually subcutaneously, but intravenously or with multiple daily injections of rapid-acting insulin occasionally intramuscularly in emergencies. Intraperito- analogues given with meals, and a basal insulin analogue neal insulin can be used in rare instances in patients with injected once daily (often at night). Insulin pumps are used diabetes, through a continuous infusion pump, or through in hospital to control blood glucose acutely and are also ambulatory peritoneal dialysis for those with end stage renal available in a portable form that delivers continuous failure. Other potential approaches include incorporation subcutaneous infusion for outpatients. The most sophisti- of insulin into biodegradable polymer microspheres as a cated forms of pump regulate the dose by means of a sensor slow-release formulation, and its encapsulation with a lectin that continuously measures blood glucose, but these are in a glucose-permeable membrane.7 Once absorbed, insulin not yet used routinely – this seemingly logical approach has an elimination half-life of approximately 10 min. It is is limited by the complexity of insulin’s effects on intermedi- inactivated enzymically in the liver and kidney, and 10% ary metabolism (see Table 32.2, Fig. 32.3) which are is excreted in the urine. Renal impairment reduces insulin imperfectly captured by existing continuous glucose requirement. monitoring technology, and by risks of infection. One of the main problems in using insulin is to avoid wide fluctuations in plasma concentration and thus in blood Unwanted effects glucose. Different formulations vary in the timing of their The main undesirable effect of insulin is hypoglycaemia. peak effect and duration of action. Soluble insulin produces This is common and, if very severe, can cause brain damage a rapid and short-lived effect. Longer-acting preparations or sudden cardiac death. In the Diabetes Control and are made by precipitating insulin with protamine or zinc, Complications Trial mentioned before, intensive insulin thus forming finely divided amorphous solid or relatively therapy resulted in a three-fold increase in severe hypo- insoluble crystals, which are injected as a suspension from glycaemic episodes compared with usual care. The treatment which insulin is slowly absorbed. These preparations include of hypoglycaemia is to take a sweet drink or snack or, if isophane insulin and amorphous or crystalline insulin zinc the patient is unconscious, to give intravenous glucose or suspensions. Mixtures of different forms in fixed proportions intramuscular glucagon (see clinical box, p. 413). Rebound are available. hyperglycaemia (‘Somogyi effect’) can follow insulin- More recently, modifications of insulin molecules have induced hypoglycaemia, because of the release of counter- focused on two different areas – one being the production regulatory hormones (e.g. adrenaline, glucagon and of molecules with a more rapid onset of action to cover glucocorticoids). This can cause hyperglycaemia before mealtimes, and the other being even longer-acting formula- breakfast following an unrecognised hypoglycaemic attack tions. Development of rapid-acting analogues is based on during sleep in the early hours of the morning. It is essential amino acid substitutions that promote formation of insulin to appreciate this possibility to avoid the mistake of increas- monomers for faster absorption, whilst reducing the ing (rather than reducing) the evening dose of insulin in aggregation of insulin dimers and hexamers (Atkin et al., this situation. 2015). Example of these analogues include insulin aspart, Allergy to human insulin is unusual but can occur. It insulin lispro and insulin glulisine, which involve different may take the form of local or systemic reactions. Insulin amino acid switches at positions such as B28 or B29 in the resistance as a consequence of antibody formation is rare. insulin molecule. These analogues act more rapidly (onset Theoretical concerns regarding mitogenic effects of insulin of action 40 h. lipoprotein (LDL and VLDL, respectively, see Ch. 24). Various dosage regimens are used. Some type 1 patients inject a combination of short- and intermediate-acting 8 Metformin had a very slow start. It was first synthesised in 1922, one of a large series of biguanides with many different pharmacological 7 This could, in theory, provide variable release of insulin controlled by actions, which proved largely unsuitable for clinical use. Its glucose- the prevailing glucose concentration, because glucose and glycated lowering effect was noted early on, but was eclipsed by the discovery insulin compete for binding sites on the lectin. of insulin. It did not receive FDA approval until 1995. 415 32 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS Clinical use Clinical uses of insulin and other Metformin is used to treat patients with type 2 diabetes. It hypoglycaemic drugs for injection does not stimulate appetite (rather the reverse; see earlier!) and is the drug of first choice in the majority of type 2 Patients with type 1 diabetes require long-term patients who are obese, provided they have unimpaired insulin: renal and hepatic function. It can be combined with other – an intermediate-acting preparation (e.g. isophane glucose-lowering agents if blood glucose is inadequately insulin) or a long-acting analogue (e.g. glargine) is controlled. Potential uses outside type 2 diabetes include often combined with soluble insulin or a short-acting other syndromes with accompanying insulin resistance analogue (e.g. lispro) taken before meals. including polycystic ovary syndrome, non-alcoholic fatty Soluble insulin is used (intravenously) in treatment of liver disease, gestational diabetes and some forms of hyperglycaemic emergencies (e.g. diabetic premature puberty. ketoacidosis). Sulfonylureas Approximately one-third of patients with type 2 The sulfonylureas were developed following the chance diabetes ultimately require insulin. observation that a sulfonamide derivative (which was Short-term treatment of patients with type 2 diabetes being used to treat typhoid) caused hypoglycaemia. or impaired glucose tolerance during intercurrent Numerous sulfonylureas are available. The first used events (e.g. operations, infections, myocardial therapeutically were tolbutamide and chlorpropamide. infarction). Chlorpropamide has a long duration of action and a During pregnancy, for gestational diabetes not substantial fraction is excreted in the urine. Conse- controlled by diet alone. quently, it can cause severe hypoglycaemia, especially Emergency treatment of hyperkalaemia: insulin is in elderly patients in whom renal function declines given with glucose to lower extracellular K+ via inevitably but insidiously (Ch. 30). It causes flushing redistribution into cells. after alcohol because of a disulfiram-like effect (Ch. 50), Glucagon-like peptide-1 (GLP-1) agonist for type 2 and has an action like that of antidiuretic hormone on diabetes in addition to oral agents to improve control the distal nephron, giving rise to hyponatraemia and and lose weight. water intoxication. Williams (1994) comments that ‘time honoured but idiosyncratic chlorpropamide should now be laid to rest’ – a sentiment with which we concur. Tolbutamide, however, remains useful. So-called second- generation sulfonylureas (e.g. glibenclamide, glipizide; Table 32.3) are more potent, but their maximum hypo- Reduced hepatic gluconeogenesis is especially important. glycaemic effect is no greater and control of blood Metformin decreases hepatic glucose production directly glucose no better than with tolbutamide. These drugs or indirectly by inhibiting the mitochondrial respiratory all contain the sulfonylurea moiety and act in the same chain complex I (reviewed by Viollet et al., 2012). The way, but different substitutions result in differences in resulting increase in AMP activates AMP-activated protein pharmacokinetics and hence in duration of action (see kinase (AMPK) which is a master regulator of energy Table 32.3). homeostasis in eukaryotes (Myers et al., 2017). Activation of AMPK in the duodenum triggers release of GLP-1 which Mechanism of action stimulates a gut–brain–liver vagal network that regulates The principal action of sulfonylureas is on β cells (see Fig. hepatic glucose production (Duca et al., 2015). Chronic 32.1), stimulating insulin secretion and thus reducing plasma administration of metformin alters recirculation of bile acids glucose. High-affinity binding sites for sulfonylureas are and composition of the gut microbiome in type 2 leading present on the KATP channels (Ch. 4) in the surface mem- to increased GLP-1 secretion in diabetes patients (Napolitano branes of β cells, and the binding of various sulfonylureas et al., 2014). parallels their potency in stimulating insulin release. Block Metformin has a half-life of about 3 h and is excreted by sulfonylurea drugs of KATP channel activation causes unchanged in the urine. depolarisation of β cells, Ca2+ entry and insulin secretion. (Compare this with the physiological control of insulin Unwanted effects secretion, see Fig. 32.1.) Metformin, while preventing hyperglycaemia, does not cause hypoglycaemia, and the commonest unwanted effects Pharmacokinetic aspects are dose-related GI disturbances (e.g. anorexia, diarrhoea, Sulfonylureas are well absorbed after oral administration, nausea), which are usually, but not always, transient. Lactic and most reach peak plasma concentrations within 2–4 h. acidosis is a rare but potentially fatal toxic effect, and The duration of action varies (see Table 32.3). All bind metformin should not be given routinely to patients with strongly to plasma albumin and are implicated in interac- renal or hepatic disease, hypoxic pulmonary disease or tions with other drugs (e.g. salicylates and sulfonamides) shock. Such patients are predisposed to lactic acidosis that compete for these binding sites (see Ch. 9). Most because of reduced drug elimination or reduced tissue sulfonylureas (or their active metabolites) are excreted in oxygenation. It should be avoided in other situations that the urine, so their action is increased and prolonged in the predispose to lactic acidosis including alcohol intoxication, elderly and in patients with renal disease. and some forms of mitochondrial myopathy that are associ- Most sulfonylureas cross the placenta and enter breast ated with diabetes. Long-term use may interfere with milk and their use is contraindicated in pregnancy and in 416 absorption of vitamin B12. breastfeeding.  THE CONTROL OF BLOOD GLUCOSE AND DRUG TREATMENT OF DIABETES MELLITUS 32 Table 32.3 Oral hypoglycaemic sulfonylurea drugs Relative Duration of action Drug potencya and (half-life) (hours) Pharmacokinetic aspectsb General comments Some converted in liver to weakly A safe drug; least likely to active hydroxytolbutamide; some cause hypoglycaemia Tolbutamide 1 6–12 (4) carboxylated to inactive May decrease iodide uptake compound by thyroid Renal excretion Contraindicated in liver failure Some is oxidised in the liver to May cause hypoglycaemia c moderately active products and The active metabolite Glibenclamide 150 18–24 (10) is excreted in urine; 50% is accumulates in renal failure excreted unchanged in the faeces Peak plasma levels in 1 h May cause hypoglycaemia Most is metabolised in the liver to Has diuretic action Glipizide 100 16–24 (7) inactive products, which are Only inactive products excreted in urine; 12% is accumulate in renal failure excreted in faeces a Relative to tolbutamide. b All are highly protein bound (90%–95%). c Termed glyburide in the United States. Unwanted effects with a sulfonylurea. The probable basis of most of these The sulfonylureas are usually well tolerated. Unwanted interactions is competition for metabolising enzymes, but effects are specified in Table 32.3. The commonest adverse interference with plasma protein binding or with transport effect is hypoglycaemia, which can be severe and pro- mechanisms facilitating excretion may play some part. longed, the highest incidence occurring with long-acting Agents that decrease the action of sulfonylureas on blood chlorpropamide and glibenclamide and the lowest with glucose include high doses of thiazide diuretics (Chs 22 and tolbutamide. Long-acting sulfonylureas are best avoided 30) and glucocorticoids (pharmacodynamic interactions). in the elderly and in patients with even mild renal impair- ment because of the risk of hypoglycaemia. Sulfonylureas Clinical use stimulate appetite and often cause weight gain. This is Sulfonylureas are used to treat type 2 diabetes in its early a major concern in obese diabetic patients. About 3% of stages, but because they require functional β cells, they are patients experience GI upsets. Allergic rashes can occur, not useful in type 1 or late-stage type 2 diabetes. They can and bone marrow toxicity (Ch. 58), although rare, can be be combined with metformin. severe. During and for a few days after acute myocardial infarc- OTHER DRUGS THAT STIMULATE INSULIN SECRETION tion in diabetic patients, insulin must be substituted for Several drugs that act, like the sulfonylureas, by blocking sulfonylurea treatment. Such substitution is associated with the sulfonylurea receptor on KATP channels in pancreatic β a substantial reduction in short-term mortality, although cells but lack the sulfonylurea moiety have been developed. it remains unclear if this is due to a beneficial effect specific These include repaglinide and nateglinide which, though to insulin or to avoiding a detrimental effect of sulfonylurea much less potent than most sulfonylureas, have rapid onset drugs in this setting, or both. Another vexing question is and offset kinetics leading to short duration of action and whether prolonged therapy with oral hypoglycaemic drugs a low risk of hypoglycaemia.9 These drugs are administered has adverse cardiovascular effects. Blockade of KATP in heart shortly before a meal to reduce the postprandial rise in and vascular tissue could theoretically have adverse effects, blood glucose in type 2 diabetic patients inadequately and an observational study recorded an increased risk of controlled with diet and exercise. They may cause less death and cardiovascular disease during follow-up for up weight gain than conventional sulfonylureas. Later in the to 8 years in newly diagnosed type 2 diabetic patients treated course of the disease, they can be combined with metformin with sulfonylureas compared with those treated with or other oral hypoglycaemic agents. Unlike glibenclamide, metformin (Evans et al., 2006). these drugs are relatively selective for KATP channels on β cells versus KATP channels in vascular smooth muscle. Drug interactions Several drugs augment the hypoglycaemic effect of sulfo- Thiazolidinediones (glitazones): pioglitazone nylureas. Non-steroidal anti-inflammatory drugs, warfarin, The thiazolidinediones (or glitazones) were developed fol- some uricosuric drugs (e.g. sulfinpyrazone), alcohol, lowing the chance observation that a clofibrate analogue, monoamine oxidase inhibitors, some antibacterial drugs (including sulfonamides, trimethoprim and chlorampheni- 9 It is ironic that these aggressively marketed drugs share many of the col) and some imidazole antifungal drugs have all been properties of tolbutamide, the oldest, least expensive and least reported to produce severe hypoglycaemia when given fashionable of the sulfonylureas. 417 32 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS ciglitazone, which was being screened for effects on lipids, without other agents. It delays carbohydrate absorption, unexpectedly lowered blood glucose. Ciglitazone caused reducing the postprandial increase in blood glucose. The liver toxicity, and this class of drugs (despite consider- commonest adverse effects are related to its main action able commercial success) has been dogged by adverse and consist of flatulence, loose stools or diarrhoea, and effects (especially cardiovascular), regulatory withdraw- abdominal pain and bloating. Like metformin, it may be als and controversy. No clinical trials of these agents particularly helpful in obese type 2 patients, and it can be have demonstrated a beneficial effect on mortality, and co-administered with metformin. they were licensed on the basis of statistically significant effects on haemoglobin A1c (a surrogate marker of longer- Incretin mimetics and related drugs term diabetes status) of uncertain clinical significance. Exenatide is a synthetic version of exendin-4, a peptide Pioglitazone is the only drug of this class that remains in found in the saliva of the Gila monster (a lizard that presum- clinical use, its predecessors, rosiglitazone and troglitazone, ably evolved this as means to disable its prey by rendering having faced regulatory action because of increased risk them hypoglycaemic). of heart attacks and liver damage, respectively – at the GLP-1 agonists lower blood glucose after a meal by time, a cause célèbre, and very expensive for the companies increasing insulin secretion, suppressing glucagon secretion involved. and slowing gastric emptying (see earlier). They reduce food intake (by an effect on satiety, see Ch. 33) and are Effects associated with modest weight loss. They reduce hepatic The effect of thiazolidinediones on blood glucose is slow fat accumulation. in onset, the maximum effect being achieved only after 1–2 GLP-1 agonists are administered by subcutaneous months of treatment. They act by enhancing the effectiveness injection, either once daily (exenatide, liraglutide, lixi- of endogenous insulin, thereby reducing hepatic glucose senatide) or once weekly (extended release exenatide, output, and increasing glucose uptake into muscle. albiglutide, dulaglutide). Pancreatitis is rare but potentially They reduce the amount of exogenous insulin needed severe. to maintain a given level of blood glucose by approximately GLP-1 agonists are used in patients with type 2 diabetes 30%. Reduced blood glucose concentration is accompanied in combination with other drugs (metformin with or without by reduced insulin and free fatty acid concentrations. Weight a sulfonylurea, pioglitazone, insulin). gain of 1–4 kg is common, usually stabilising in 6–12 months. Some of this is attributable to fluid retention: there is an Gliptins increase in plasma volume of up to 500 mL, with a con- Gliptins (e.g. sitagliptin, vildagliptin, saxagliptin, lina- comitant reduction in haemoglobin concentration caused gliptin) are synthetic drugs that competitively inhibit by haemodilution; there is also an increase in extravascular dipeptidyl peptidase-4 (DPP-4), thereby lowering blood fluid, and increased deposition of subcutaneous (as opposed glucose by potentiating endogenous incretins (GLP-1 and to visceral) fat. GIP, see p. 413) which stimulate insulin secretion. They do not cause weight loss or weight gain. Mechanism of action They are absorbed from the gut and administered once Thiazolidinediones bind to a nuclear receptor called the (or, in the case of vildagliptin, twice) daily by mouth. They peroxisome proliferator-activated receptor-γ (PPARγ), which is are eliminated partly by renal excretion and are also complexed with retinoid X receptor (RXR; see Ch. 3).10 It metabolised by hepatic CYP enzymes. They are usually remains something of a mystery that glucose homeostasis well tolerated with a range of mild GI adverse effects; liver should be so responsive to drugs that bind to receptors disease, heart failure (particularly with saxagliptin or found mainly in fat cells; it has been suggested that the alogliptin) and pancreatitis (incidence approximately explanation may lie in resetting of the glucose–fatty acid 0.1%–1%) are less common but potentially serious. There (Randle) cycle by the reduction in circulating free fatty is also concern that they may act as tumour promoters (see acids. Ch. 58). Gliptins are used for type 2 diabetes in addition to other oral hypoglycaemic drugs (see clinical box on uses Unwanted effects of oral hypoglycaemic drugs, p. 420). Clinical trial data have demonstrated significantly increased Evidence of cardiovascular efficacy or effect on mortality risk of a range of adverse events with pioglitazone, including is inconsistent, with liraglutide the only agent to produce heart failure, bone fracture, oedema, and weight gain. (Liao a demonstrable reduction in major adverse cardiac events et al., 2017), and glitazones are now far less frequently used. (Paneni & Luscher, 2017), whereas neither sitagliptin nor exenatide have shown such benefits in large-scale clinical Clinical use trials. Pioglitazone is additive with other oral hypoglycaemic drugs in terms of effect on blood glucose, and a combination Glucose transport inhibitors tablet with metformin is marketed. Several SGLT2 inhibitors are licensed for use in type 2 diabetes. Examples include canagliflozin, dapagliflozin, α-Glucosidase inhibitors and empagliflozin. Acarbose, an inhibitor of intestinal α-glucosidase, is used in type 2 diabetes inadequately controlled by diet with or Mechanism of action The SGLT2 inhibitors act by promoting glucose excretion into the urine, thereby reducing the concentration of circulat- 10 Compare with fibrates (to which thiazolidinediones are structurally ing glucose. The resulting glycosuria is associated with an related), which bind to PPARα (see Ch. 24). osmotic diuresis and salt excretion 418  THE CONTROL OF BLOOD GLUCOSE AND DRUG TREATMENT OF DIABETES MELLITUS 32 recommended option in patients who are susceptible to Effects hypoglycaemia. Clinical studies have found elevated amounts of glucose in the urine over sustained periods, and an associated TREATMENT OF DIABETES MELLITUS increase in urinary volume. As the efficacy of SGLT2 inhibi- Insulin is essential for the treatment of type 1 diabetes, and tors rely on adequate renal function and urine output, these a valuable component of the treatment of many patients agents have limited or no effect in patients with chronic with type 2 disease. kidney disease. Clinical trials have confirmed improvements in fasting and post-prandial glucose concentrations, and ▼ For many years it was assumed, as an act of faith, that normalis- significant reduction in glycosylated haemoglobin (Storgaard ing plasma glucose would reduce the risk of diabetic complications. The Diabetes Control and Complications Trial (American Diabetes et al., 2016). The osmotic diuretic effect and the caloric loss Association, 1993) showed that this faith was well placed: type 1 (from glucose in the urine) also leads to reduction in systolic diabetic patients were randomly allocated to intensive or conven- blood pressure and body weight (Abdul-Ghani et al., 2015). tional management. Mean fasting blood glucose concentration was A clinical trial of empaglifozen (EMPA-REG OUTCOME) 2.8 mmol/L lower in the intensively treated group, who had a reported substantial reductions in cardiovascular endpoints, substantial reduction in the occurrence and progression of retinopathy, to which these haemodynamic effects probably contributed nephropathy and neuropathy over a period of 4–9 years. Benefits, substantially (Paneni & Luscher, 2017). including reduced atheromatous as well as microvascular disease, were long-lasting and outweighed adverse effects, which included a Pharmacokinetic aspects three-fold increase in severe hypoglycaemic attacks and modest excess weight gain. SGLT2 inhibitors are rapidly absorbed, with time to peak plasma concentrations of less than 2 h. They are highly The UK Prospective Diabetes Study showed that lowering blood pressure markedly improves outcome in type 2 diabetes. Normalisation of bound to plasma proteins (>80%). blood glucose was not achieved even in intensively treated patients. Better metabolic control did improve outcome, but (in contrast to Unwanted effects lowering blood pressure) the magnitude of the benefit was disap- A significant increase in the risk of urinary tract and fungal pointing and statistically significant only for microvascular complica- infections such as candidal vaginitis or balanitis has been tions. In long-term follow-up, patients from this study who had been reported with SGLT2 inhibition, presumably due to the allocated to intensive treatment continued to have better outcomes glycosuria (Storgaard et al., 2016). Natriuresis with diuresis than patients treated with diet alone (despite diabetic control becoming can lead to increased urinary volume, hypotension and similar in the two groups after the blinded treatment period had dehydration, and is accentuated with concomitant use of finished), suggesting that early diabetic control (within the first 12 years from diagnosis) is important (Holman et al., 2008). By contrast, thiazide diuretics. studies of intensive control later in the course of the disease have Safety signals that are currently under regulatory evalu- been disappointing with harm from hypoglycaemia outweighing any ation include potential serious adverse events such as benefit. increased susceptibility to diabetic ketoacidosis, and lower Realistic goals in type 2 diabetic patients are usually less ambitious limb amputations. than in younger type 1 patients. Dietary restriction leading to weight loss in overweight and obese patients is the cornerstone (albeit one Clinical use with a tendency to crumble), combined with increased exercise. Oral SGLT2 inhibitors are licensed for use in type 2 diabetes, agents are used to control symptoms from hyperglycaemia, as well either alone (when metformin is inappropriate) or in as to limit microvascular complications, and are introduced early. combination with insulin or other oral glucose lowering Dietary measures and statins to prevent atheromatous disease (Ch. therapies. Typically, this would involve SGLT2 use in dual 24) are crucial. Details of dietary management and treatment for specific diabetic complications are beyond the scope of this book. or triple therapy where sulfonylureas are not tolerated or Glitazones and drugs that mimic or potentiate incretins reduce have not been sufficiently efficacious. A potential advantage glycated haemoglobin (typically by 0.5–1 percentage points) but their of SGLT2 inhibition in those with inadequate diabetes effects (if any) on clinical outcomes such as diabetic complications control is that the amount of glucose excreted in the urine have not been consistently demonstrated. There is some evidence will be proportionately greater in patients whose plasma that pioglitazone, liraglutide and empagliflozin can improve glucose concentrations are high. cardiovascular outcomes in type 2 diabetic patients (Paneni & Lüscher, The SGLT2 inhibitors are also considered to have a rela- 2017) – possibly due to cardiovascular actions distinct from their tively low risk of hypoglycaemia, and are therefore a metabolic effects. 419 32 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS Drugs used in diabetes mellitus Insulin and other injectable drugs – can cause hypoglycaemia (which stimulates appetite Human insulin is made by recombinant DNA and leads to weight gain) technology. For routine use, it is given subcutaneously – are effective only if β cells are functional (by intravenous infusion in emergencies). – block ATP-sensitive potassium channels in β cells Different formulations of insulin differ in their duration of – are well tolerated but promote weight gain and are action: associated with more cardiovascular disease than is – fast- and short-acting soluble insulin: peak action metformin after subcutaneous dose 2–4 h and duration 6–8 h; Thiazolidinediones have been associated with serious it is the only formulation that can be given cardiac toxicity. intravenously Pioglitazone is the only one still widely marketed; it: – intermediate-acting insulin (e.g. isophane insulin) – increases insulin sensitivity and lowers blood glucose – long-acting forms (e.g. insulin zinc suspension) in type 2 diabetes The main unwanted effect is hypoglycaemia. – can cause weight gain and oedema Altering the amino acid sequence (insulin analogues, e.g. – increases osteoporotic fractures lispro and glargine) can usefully alter insulin kinetics. – is a peroxisome proliferator-activated receptor-γ (a Insulins are used for all type 1 diabetic patients and nuclear receptor) agonist approximately one-third of patients with type 2 diabetes. Gliptins (e.g. sitagliptin): Exenatide and liraglutide are injectable glucagon-like – potentiate endogenous incretins by blocking dipeptidyl peptide-1 (GLP-1) agonists used as add-on treatment in peptidase-4 (DPP-4) certain inadequately controlled type 2 diabetic patients. – are added to other orally active drugs to improve Unlike insulin they cause weight loss. control in patients with type 2 diabetes Oral hypoglycaemic drugs – are weight-neutral; they are usually well tolerated but These are used in type 2 diabetes. pancreatitis is a concern Biguanides (e.g. metformin): Sodium–glucose co-transporter (SGLT)2 inhibitors (e.g. – have complex peripheral actions in the presence of empagliflozin) residual insulin, increasing glucose uptake in striated – Promote urinary excretion of glucose muscle and inhibiting hepatic glucose output and – Have potentially beneficial effects on weight, blood intestinal glucose absorption pressure and cardiovascular outcome – cause anorexia and encourage weight loss – Increase the risk of dehydration and urinary tract – can be combined with sulfonylureas infections Sulfonylureas and other drugs that stimulate insulin α-Glucosidase inhibitor, acarbose: secretion (e.g. tolbutamide, glibenclamide, – reduces carbohydrate absorption nateglinide): – causes flatulence and diarrhoea Clinical uses of oral hypoglycaemic drugs Type 2 diabetes mellitus, to reduce symptoms from retention and increases risk of fractures. Glucagon-like hyperglycaemia (e.g. thirst, excessive urination). (‘Tight’ peptide (GLP)-1 agonists (e.g. exenatide, lixisenatide, control of blood glucose has only a small effect on or liraglutide) are injected once daily or (extended vascular complications in this setting.) release exenatide) once weekly in obese patients Metformin is preferred, especially for obese patients inadequately controlled on two hypoglycaemic drugs. unless contraindicated by factors that predispose to These agents are associated with the potential for weight lactic acidosis (renal or liver failure, poorly compensated loss or prevention of weight gain in overweight or obese heart failure, hypoxaemia). patients. Acarbose (α-glucosidase inhibitor) reduces carbohydrate Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins, e.g. absorption; it causes flatulence and diarrhoea. sitagliptin) improve control, are well tolerated and Drugs that act on the sulfonylurea receptor (e.g. weight-neutral, but outcome evidence is inconsistent. tolbutamide, glibenclamide) are well tolerated but Pancreatitis and heart failure are possible adverse effects often promote weight gain. They are associated with of concern. increased cardiovascular risk compared with metformin. Sodium–glucose co-transporter (SGLT)2 inhibitors Pioglitazone improves control (reduces haemoglobin improve control, but long-term outcomes and safety data A1C) but increases weight, causes heart failure, fluid are still emerging. 420  THE CONTROL OF BLOOD GLUCOSE AND DRUG TREATMENT OF DIABETES MELLITUS 32 REFERENCES AND FURTHER READING References Further reading Abdul-Ghani, M.A., Norton, L., DeFronzo, R.A., 2011. Role of Physiological and pathophysiological aspects sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of Lavin, D.P., White, M.F., Brazil, D.P., 2016. IRS proteins and diabetic type 2 diabetes. Endocr. Rev. 32 (4), 515–531. complications. Diabetologia 59, 2280–2291. (Reviews the role of IRS Abdul-Ghani, M.A., Norton, L., DeFronzo, R.A., 2015. Renal proteins in linking cell surface receptors to intracellular signalling cascades sodium-glucose cotransporter inhibition in the management of and potential mechanisms that lead to development and progression of type 2 diabetes mellitus. Am. J. Physiol. Renal Physiol. 309 (11), diabetic complications’) F889–F900. Withers, D.J., Gutierrez, J.S., Towery, H., et al., 1998. Disruption of IRS-2 American Diabetes Association, 1993. Implications of the diabetes causes type 2 diabetes in mice. Nature 391, 900–904. (Dysfunction of control and complications trial. Diabetes 42, 1555–1558. (Landmark IRS-2 may ‘contribute to the pathophysiology of human type 2 diabetes’; see clinical trial) also accompanying commentary by Avruch, J., A signal for β-cell failure, pp. Atkin, S., Javed, Z., Fulcher, G., 2015. Insulin degludec and insulin 846–847) aspart: novel insulins for the management of diabetes mellitus. Ther. Zimmet, P., Alberti, K.G.M.M., Shaw, J., 2001. Global and societal Adv. Chronic. Dis. 6 (6), 375–388. (Excellent summary of development and implications of the diabetes epidemic. Nature 414, 782–787. (Changes pharmacokinetics of insulin analogues) in human behaviour have resulted in a dramatic increase in type 2 diabetes DeFronzo, R.A., Davidson, J.A., Del Prato, S., 2012. The role of the worldwide) kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes. Metab. 14 (1), 5–14. (Good review article Insulins discussing glucose homeostasis and the kidney) Owens, D.R., Zinman, B., Bolli, G.B., 2001. Insulins today and beyond. Duca, F.A., Cote, C.D., Rasmussen, B.A., et al., 2015. Metformin Lancet 358, 739–746. (Reviews the physiology of glucose homeostasis, activates a duodenal Ampk-dependent pathway to lower hepatic genetically engineered ‘designer’ insulins and developments in insulin glucose production in rats. Nat. Med. 21, 506–511. delivery and glucose sensing) Evans, J.M.M., Ogston, S.A., Emslie-Smith, A., Morris, A.D., 2006. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: Oral hypoglycaemic drugs a comparison of patients treated with sulfonylureas and metformin. Gale, E.A.M., 2001. Lessons from the glitazones: a story of drug Diabetologia 49, 930–936. (Observational cohort study in 5700 newly development. Lancet 357, 1870–1875. (Fighting stuff: ‘Troglitazone was treated type 2 patients, 1000 deaths in up to 8 years follow-up. Sulfonylurea voluntarily withdrawn in Europe, but went on to generate sales of over $2 use was associated with increased risk of death and of cardiovascular disease. billion in the USA and caused 90 cases of liver failure before being Not proof but pretty suggestive!) withdrawn. Rosiglitazone and pioglitazone reached the USA for use alone or Holman, R.R., Sanjoy, K.P., Bethel, M.A., et al., 2008. 10-year follow-up in combination with other drugs whereas in Europe the same dossiers were of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, used to apply for a limited licence as second-line agents. How should we use 1577–1589. them? How did they achieve blockbuster status without any clear evidence of Liao, H.W., Saver, J.L., Wu, Y.L., Chen, T.H., Lee, M., Ovbiagele, B., advantage over existing therapy?’) 2017. Pioglitazone and cardiovascular outcomes in patients with Guan, Y., Hao, C., Cha, D.R., et al., 2005. Thiazolidinediones expand insulin resistance, pre-diabetes and type 2 diabetes: a systematic body fluid volume through PPARγ stimulation of ENaC-mediated review and meta-analysis. BMJ open. 7 (1), e013927. renal salt absorption. Nat. Med. 11, 861–865. (Mechanism of fluid Myers, R.W., Guan, H.P., Ehrhart, J., et al., 2017. Systemic pan-AMPK retention caused by thiazolidinediones and suggestion that amiloride may activator MK-8722 improves glucose homeostasis but induces cardiac provide a specific therapy for this) hypertrophy. Science 357, 507–511. Napolitano, A., Miller, S., Nicholls, A.W., et al., 2014. Novel gut-based Other drugs for diabetes, and therapeutic aspects pharmacology of metformin in patients with type 2 diabetes mellitus. Brenner, B.M., Cooper, M.E., de Zeeuw, D., et al., 2001. Effects of PLoS ONE 9, e100778. losartan on renal and cardiovascular outcomes in patients with type 2 Paneni, F., Luscher, T.F., 2017. Cardiovascular protection in the diabetes and nephropathy. N. Engl. J. Med. 345, 861–869. (Significant treatment of type 2 diabetes: a review of clinical trial results across renal benefits from the AT1 antagonist; see also two adjacent articles: Lewis, drug classes. Science 120, S17–S27. (Good summary of cardiovascular E.J., et al., pp. 851–860, and Parving, H.-H., et al., pp. 870–878, and an outcomes in trials of different classes of hypoglycaemic agents) editorial on prevention of renal disease caused by type 2 diabetes by Storgaard, H., Gluud, L.L., Bennett, C., et al., 2016. Benefits and harms Hostetter, T.H., pp. 910–911) of sodium-glucose co-transporter 2 inhibitors in patients with type 2 Farmer, K.L., Li, C.Y., Dobrowsky, R.T., 2012. Diabetic neuropathy: diabetes: a systematic review and meta-analysis. PLoS ONE 11 (11). should a chaperone accompany our therapeutic approach? Pharmacol. Viollet, B., Guigas, B., Garcia, N.S., Leclerc, J., Foretz, M., Andreelli, F., Rev. 64, 880–900. (Currently no satisfactory therapy) 2012. Cellular and molecular mechanisms of metformin: an overview. Younk, L.M., Mikeladze, M., Davis, S.N., 2011. Pramlintide and the Clin. Sci. 122, 253–270. (Reviews mechanisms as a setting for novel treatment of diabetes: a review of the data since its introduction. therapeutic uses, for example in non-alcoholic fatty liver disease) Expert Opin. Pharmacother. 12, 1439–1451. (‘Pramlintide significantly Waumans, Y., Baerts, L., Kehoe, K., Lambeir, A.M., De Meester, I., 2015. reduces hemoglobin A(1c) and body weight in patients with type 1 and type The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl 2 diabetes mellitus. Newer research is focusing on weight loss effects of carboxypeptidase in the immune system and inflammatory disease, pramlintide and pramlintide plus metreleptin in nondiabetic obese including atherosclerosis. Front. Immunol. 6, 387. individuals’) Williams, G., 1994. Management of non-insulin dependent diabetes mellitus. Lancet 343, 95–100. Yu, D.M.T., Yao, T.W., Chowdhary, S., 2010. The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J. 277, 1126–1144. (Discusses current understanding of this unique family of enzymes) 421 33 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS factors, and suggested a relatively minor role for environ- mental influences (Barsh et al., 2000). The updated Human Obesity Obesity Gene Map (Rankinen et al., 2006) identified >250 quantitative trait loci7 that contribute to obesity in humans. Obesity is a multifactorial disorder of energy balance, The prevailing view is that susceptibility to obesity is largely in which long-term calorie intake exceeds energy determined genetically, while environmental factors regulate output. the expression of the disease. A sub ect with a body mass index (BMI) (W/h2) of Obesity is conventionally classified as being monogenic, 20–25 kg/m2 is considered as having a healthy body syndromic or common (polygenic), depending upon the weight, one with a BMI of 25–30 kg/m2 as overweight, genetic background to the disease. As the name implies, and one with a BMI >30 kg/m2 as obese. monogenic obesity arises through the action of a single gene. Obesity is a growing problem in most rich nations; the The discovery that spontaneous mutations arising in single incidence – at present approximately >30% in the genes (e.g. the Ob/Ob genotype) produced obese phenotypes United States and >20% in Europe – is increasing. in mice led to a search for equivalent genes in humans. A BMI >30 kg/m2 significantly increases the risk of A review (Pérusse et al., 2005) identified over 170 human type 2 diabetes, hypercholesterolaemia, hypertension, obesity cases that could be traced to single gene mutations ischaemic heart disease, gallstones and some in 10 different genes. Mutations in the POMC gene, the gene cancers. for FTO gene (fat mass- and obesity-associated gene), the The causes of obesity include: leptin gene itself or the gene for its receptor are sometimes the culprits. Melanocortin MC4 receptor mutations are the – dietary, exercise, social, financial and cultural most common (1%–6%) in obese patients but there are many factors; other potential candidates (e.g. see Barsh et al., 2000). – genetic susceptibility; Polygenic (common) obesity comprises most of the – deficiencies in the synthesis or action of leptin or cases of the disease. Here, obesity is usually the result of other gut hormone signals; contributions of many genes, each of which has a small effect – defects in the hypothalamic neuronal systems on the overall phenotype. Other genes that may influence responding to any of these signals; obesity include the neurotransmitter receptors involved – defects in the systems controlling energy in the central processing of appetite/energy expenditure expenditure (e.g. reduced sympathetic activity), (e.g. the CB1, D2, 5-HT2C receptors), the β3 adrenoceptor and decreased metabolic expenditure of energy or the glucocorticoid receptor. Decreased function of the β3 decreased thermogenesis caused by a reduction in adrenoceptor gene could be associated with impairment of β3 adrenoceptor-mediated tone and/or dysfunction lipolysis in white fat or with thermogenesis in brown fat. of the proteins that uncouple oxidative A mutation of this gene has been found to be associated phosphorylation. with abdominal obesity, insulin resistance and early-onset type 2 diabetes in some subjects and a markedly increased propensity to gain weight in a separate group of morbidly obese subjects. Alterations in the function of the glucocor- ticoid receptor could be associated with obesity through short-term efficacy, leaving surgical techniques (such as the permissive effect of glucocorticoids on several aspects gastric stapling or bypass) or drug therapy as a viable of fat metabolism and energy balance. The significance alternative. Bariatric (weight loss) surgery is much more of polymorphisms in the ghrelin gene has already been effective than currently licensed drugs, and is believed to mentioned. work chiefly, not by mechanically limiting gastric capacity, In syndromic obesity, the obesity is associated with a but by its effects on gut hormone responses to feeding, distinctive clinical picture. Prader–Willi syndrome is the acting, for example, to produce earlier satiety. This may most common (at 1 in 15,000–25,000 live births) and is be construed as indirect evidence for the utility of associated with defects in gene expression on chromosome pharmacological measures designed to interrupt these 15q. The clinical picture is multifaceted and obesity is only messengers. one component. The attempt to control body weight with drugs has had Recently, the interpretation of genetic data in obesity a long and regrettably, a largely undistinguished8 history. has become even more complicated with the recognition Many types of ‘anorectic’ (appetite suppressant) agents of the importance of epigenetic modification of the genome. have been tested in the past, including the uncoupling agent The subject cannot be discussed here but is well reviewed dinitrophenol (DNP), amphetamine and derivatives such by Lopomo et al. (2016). Clearly it will be a while before as dexfenfluramine and fenfluramine. All have been we have a clear appreciation of all these issues. withdrawn from clinical use because of serious adverse effects. DNP, an industrial chemical, is advertised online for slimmers and body-builders as a weight loss and ‘fat- PHARMACOLOGICAL APPROACHES TO burning agent’, and has caused deaths among those who THE PROBLEM OF OBESITY use it for this purpose. It blocks mitochondrial ATP produc- tion, diverting energy metabolism to generate heat instead The first weapons in the fight against obesity are diet and exercise. Unfortunately, these often fail or show only 8 As the showman Bynum said: ‘There’s a sucker born every minute … and one born to take him’ … thyroxine (to increase metabolic rate, Ch. 7 In other words, a stretch of DNA which correlates with the 35), swallowing parasites (intestinal worms compete for ingested food), development of obesity and which is likely therefore to contain – or be amphetamines (Ch. 59), drugs that cause malabsorption, hence leaking 428 linked to – a relevant gene. fat per rectum (see later in this chapter) … really!  OBESITY 33 POMC levels in the hypothalamus. In clinical trials it 0 enhanced weight loss through dieting, but patients regained 2 weight after stopping the drug. Qsymia, a mixture of an old appetite suppressant drug, phentermine and an 4 anticonvulsant, topiramate was approved in the United Weight loss (kg) 6 States in 2012 despite some reservations about cardiovascular and other side effects. The drug stimulates the synaptic 8 release of serotonin as well as noradrenaline and dopamine 10 (and increases GABA action). Other centrally acting drugs that are used in some 12 countries for treating obesity include Contrave, a mixture 14 of the opioid-receptor antagonist naltrexone and the 16 noradrenaline–dopamine uptake–reuptake inhibitor, 0 3 6 10 18 40 52 bupropion. The cannabinoid pathway was the target of the CB1 receptor antagonist rimonabant which was originally Weeks developed to promote smoking cessation (see Ch. 20). This drug was introduced as an appetite suppressant following Sibutramine alone Sibutramine some encouraging clinical trials but was eventually with- + brief therapy drawn in the United States in 2008 because of adverse effects Lifestyle modification Combined therapy on mood seen in some patients. A similar fate overtook alone another promising CB1 antagonist, taranabant. Fig. 33.3 The effect of treatment with the centrally acting ORLISTAT appetite suppressant, sibutramine, alone or in combination with lifestyle modification. In this study, 224 obese patients The only drug currently (2017) licensed in the United were given sibutramine alone, lifestyle modification counselling Kingdom for the treatment of obesity is the lipase inhibitor alone or sibutramine together with a ‘brief’ or more extensive orlistat, used with concomitant dietary and other therapy programme of lifestyle counselling. The Y axis shows the weight (e.g. exercise). loss in kg (± standard error) over time (X axis). It is evident that In the intestine, orlistat reacts with serine residues at the sibutramine is far more effective as a weight-loss therapy when active sites of gastric and pancreatic lipases, irreversibly combined with lifestyle changes. This is a common experience inhibiting these enzymes and thereby preventing the break- when treating obesity. Note: Sibutramine has been withdrawn down of dietary fat to fatty acids and glycerol. It therefore because of adverse cardiovascular side effects. (Redrawn from decreases absorption (and correspondingly causes faecal Wadden et al., 2005.) excretion) of some 30% of dietary fat. Given in conjunction with a low-calorie diet in obese individuals, it produces a modest but consistent loss of weight compared with of ATP and increasing the overall metabolic rate, which placebo-treated control subjects. In a meta-analysis of 11 can cause life-threatening hyperthermia.9 long-term placebo-controlled trials encompassing more than 6000 patients, orlistat was found to produce a 2.9% greater CENTRALLY ACTING APPETITE SUPPRESSANTS reduction in body weight than in the control group, and There have been many attempts to use centrally acting 12% more patients lost 10% or more of their body weight drugs to control appetite and this is an area which is still compared with the controls (Padwal et al., 2003). being actively exploited by drug hunters. Sibutramine (now Orlistat is also reported to be effective in patients suffering withdrawn in most countries because of clinical trial evi- from type 2 diabetes and other complications of obesity. dence demonstrating increased cardiovascular risk) inhibits It reduces leptin levels and blood pressure, protects against the reuptake of 5-HT and noradrenaline at the hypothalamic weight loss-induced changes in biliary secretion, delays sites that regulate food intake.10 Its main effects are to reduce gastric emptying and gastric secretion and improves several food intake and cause dose-dependent weight loss (Fig. important metabolic parameters without interfering with 33.3). It enhanced satiety and was reported to produce a the release or action of thyroid or other important hormones reduction in waist circumference, a decrease in plasma (Curran & Scott, 2004). It does not induce changes in energy triglycerides and very-low-density lipoproteins, but an expenditure. increase in high-density lipoproteins. Like many similar drug regimes, sibutramine was much more effective when PHARMACOKINETIC ASPECTS AND combined with lifestyle modification (Wadden et al., 2005). UNWANTED EFFECTS However, other serotoninergic drugs have shown promise. Virtually all (97%) of orlistat is excreted in the faeces (83% Lorcaserin, a 5-HT2C receptor agonist (see Chs 16 and 38), unchanged), with only negligible amounts of the drug or was approved in the United States in 2012 for uses as an its metabolites being absorbed. appetite suppressant in certain patients. It acts by increasing Abdominal cramps, flatus with discharge and faecal incontinence can occur, as can intestinal borborygmi (rumbling) and oily spotting. Surprisingly, in view of the 9 DNP is reported to have been given to Russian soldiers in the Second possibility of these antisocial effects occurring, the drug is World War, to keep them warm. well tolerated. Supplementary therapy with fat-soluble 10 Many antidepressant drugs act by the same mechanism (see Ch. 48), vitamins may be needed. The absorption of contraceptive and also cause weight loss by reducing appetite. However, sibutramine does not have antidepressant properties. Furthermore, depressed pills and ciclosporin (see Ch. 27) may be decreased. The patients are often obese, and antidepressant drugs are used to treat both former is not usually clinically significant but the latter is conditions (see Appolinario et al., 2004). potentially more serious. Given its good safety record, 429 33 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS orlistat has recently been licensed for inclusion in some (Ch. 32), also has anorexic actions (Astrup et al., 2009) and over-the-counter medicines for weight loss. is approved in the United States for obesity treatment (by injection only). Other peptides trialled include amylin, Clinical uses of anti-obesity drugs oxyntomodulin and leptin analogues and NPY antagonists. Even vaccination against ghrelin or somatostatin has been The main treatment of obesity is a suitable diet and mooted as a therapeutic strategy (Bhat et al., 2017). increased exercise. Other strategies aim to alter the CNS levels of neuro- Orlistat, which causes fat malabsorption, is used transmitters such as NPY or melanocortins, which transduce hormonal signals regulating appetite (Halford, 2006). The together with dietary restriction in obese individuals, tractability of the MC4 receptor itself as a drug target, and also in overweight patients who have additional coupled with the observation that defects in MC4 signalling cardiovascular risk factors (e.g. diabetes mellitus, are prevalent in obesity, has attracted much interest from hypertension). the pharmaceutical industry. – Orlistat therapy should be stopped after 12 weeks if Given the importance of the sympathetic nervous system the patient has not been able to lose at least 5% of in the control of energy regulation, one might predict that their body weight from the time of drug initiation. β3-adrenoceptor agonists might be useful therapeutics. Many centrally acting appetite suppressants (e.g. Disappointingly, whilst having been extensively researched fenfluramine, sibutramine) have been withdrawn (see Arch, 2008), they have so far failed to yield an acceptable because of addiction, pulmonary hypertension or other therapeutic lead. In contrast, the serotonergic system remains serious adverse effects. squarely in the frame for the development of further anti- Gastrointestinal (‘bariatric’) surgery for obesity obesity agents (Oh et al., 2016). influences incretin secretion, and is effective in severe Kang and Park (2012) highlight the value of combination obesity. therapies targeting complex pathways involved in appetite regulation. Most drug therapies are much more effective when used in conjunction with lifestyle and other behav- NEW APPROACHES TO ioural modification. The importance of this joint approach OBESITY THERAPY is reviewed by Vetter et al. (2010). In summary, at the time of writing, it is disappointing As might be imagined, the quest for further effective anti- to report that the number of drugs licensed for use in obesity, obesity agents is the subject of prodigious efforts by the at least in the United Kingdom, seems to be inversely pharmaceutical industry. proportional to the growing magnitude of the associated Rare cases of leptin deficiency in patients have been health problem. In some other countries, such as the United successfully treated by long-term treatment with the States, the situation is slightly better (Daneschvar et al., hormone, but this is unlikely to be of more than limited 2016) although there has been some debate about how useful use in the future. Many other approaches are being piloted this latest group of drugs will really prove to be (Kim, (see Kang & Park, 2012). Some aim to exploit the action or 2016). All in all, it is depressing that despite all the ground- production of neuroendocrine satiety signals such as CCK breaking work on the neuroendocrine control of feeding to produce appetite suppression. Many of these GI satiety and body weight, so few really novel drugs have found hormones produce such effects when given systemically their way on to the market. The lack of sustained success to humans or rodents, although these are not always useful; with pharmacological therapies has led to the emergence for example, CCK reduces meal size but increases meal of bariatric surgery as a more promising long-term option frequency (West et al., 1984). Glucagon-like peptides such for reducing complications such as hypertension and as liraglutide, which is used for treating type 2 diabetes diabetes mellitus in patients with severe obesity. REFERENCES AND FURTHER READING Body weight regulation and obesity English, P.J., Ghatei, M.A., Malik, I.A., et al., 2002. Food fails to Adan, R.A., Vanderschuren, L.J., la Fleur, S.E., 2008. Anti-obesity drugs suppress ghrelin levels in obese humans. J. Clin. Endocrinol. Metab. and neural circuits of feeding. Trends Pharmacol. Sci. 29, 208–217. 87, 2984–2987. (Very accessible overview of the area. Recommended) Farooqi, I.S., Jebb, S.A., Langmack, G., et al., 1999. Effects of Ahima, R.S., Osei, S., 2001. Molecular regulation of eating behaviour: recombinant leptin therapy in a child with congenital leptin new insights and prospects for future strategies. Trends Mol. deficiency. N. Engl. J. Med. 341, 879–884. (A classic clinical paper on the Med. 7, 205–213. (Praiseworthy short review; excellent figures and useful role of leptin in the control of feeding behaviour and weight control) tables of the mediators involved in stimulation and inhibition of feeding Kennedy, G.C., 1953. The role of depot fat in the hypothalamic control behaviour) of food intake in the rat. Proc. R. Soc. Lond. B. Biol Sci 140, 578–592. Barsh, G.S., Farooqi, I.S., O’Rahilly, S., 2000. Genetics of body-weight (The paper that put forward the proposal, based on experiments on rats, that regulation. Nature 404, 644–651. there was a hypothalamus-based homeostatic mechanism for controlling Colditz, G.A., Willett, W.C., Rotnitzky, A., Manson, J.E., 1995. Weight body fat) gain as a risk factor for clinical diabetes mellitus in women. Ann. Kopelman, P.G., 2000. Obesity as a medical problem. Nature 404, Intern. Med. 122, 481–486. 635–643. Cornejo, M.P., Hentges, S.T., Maliqueo, M., Coirini, H., Becu-Villalobos, Pérusse, C., Rankinen, T., Zuberi, A., et al., 2005. The human obesity D., Elias, C.F., 2016. Neuroendocrine regulation of metabolism. J. gene map: the 2004 update. Obes. Res. 13, 381–490. (Detailed review of Neuroendocrinol. 28, 1–12. (A readable account of the latest developments the genes, markers and chromosomal regions that have been shown to be in the field of neuroendocrine control of apetite and feeding. Covers some associated with human obesity) material not included here. Recommended) Lopomo, A., Burgio, E., Migliore, L., 2016. Epigenetics of obesity. Prog. Duranti, S., Ferrario, C., van Sinderen, D., Ventura, M., Turroni, F., Mol. Biol. Transl. Sci. 140, 151–184. 2017. Obesity and microbiota: an example of an intricate relationship. McKinsey Global Institute, 2014. Overcoming obesity: an initial 430 Genes Nutr. 12 (18). (Review role of gut bacteria in obesity) economic analysis, p. 120.