A Textbook of Clinical Pharmacology and Therapeutics
A Textbook of Clinical Pharmacology and Therapeutics
A Textbook of Clinical Pharmacology and Therapeutics
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286 DIABETES MELLITUS<br />
can cause retinal haemorrhage <strong>and</strong> blindness. Cataracts are<br />
common. Diabetic neuropathy causes a glove <strong>and</strong> stocking<br />
distribution <strong>of</strong> loss <strong>of</strong> sensation with associated painful<br />
paraesthesiae. Approximately one-third <strong>of</strong> diabetic patients<br />
develop diabetic nephropathy, which leads to renal failure.<br />
Microalbuminuria is a forerunner <strong>of</strong> overt diabetic<br />
nephropathy.<br />
Macrovascular disease is the result <strong>of</strong> accelerated atheroma<br />
<strong>and</strong> results in an increased incidence <strong>of</strong> myocardial infarction,<br />
peripheral vascular disease <strong>and</strong> stroke. There is a strong association<br />
(pointed out by Reaven in his 1988 Banting Lecture at<br />
the annual meeting <strong>of</strong> the American Diabetes Association)<br />
between diabetes <strong>and</strong> obesity, hypertension <strong>and</strong> dyslipidaemia<br />
(especially hypertriglyceridaemia), <strong>and</strong> type 2 diabetes is<br />
strongly associated with endothelial dysfunction, an early<br />
event in atherogenesis (Chapter 27).<br />
PRINCIPLES OF MANAGEMENT<br />
It is important to define ambitious but achievable goals for each<br />
patient. In young type 1 patients there is good evidence that<br />
improved diabetic control reduces microvascular complications.<br />
It is well worth trying hard to minimize the metabolic derangement<br />
associated with diabetes mellitus in order to reduce the<br />
development <strong>of</strong> such complications. Education <strong>and</strong> support are<br />
essential to motivate the patient to learn how to adjust their<br />
insulin dose to optimize glycaemic control. This can only be<br />
achieved by the patient performing blood glucose monitoring at<br />
home <strong>and</strong> learning to adjust their insulin dose accordingly. The<br />
treatment regimen must be individualized. A common strategy<br />
is to combine injections <strong>of</strong> a short-acting insulin before each<br />
meal with a once daily injection <strong>of</strong> a long-acting insulin to provide<br />
a low steady background level during the night. Follow up<br />
must include structured care with assessment <strong>of</strong> chronic glycaemic<br />
control using HbA1c <strong>and</strong> regular screening for evidence<br />
<strong>of</strong> microvascular disease. This is especially important in the case<br />
<strong>of</strong> proliferative retinopathy <strong>and</strong> maculopathy, because prophylactic<br />
laser therapy can prevent blindness.<br />
By contrast, striving for tight control <strong>of</strong> blood sugar in type 2<br />
patients is only appropriate in selected cases. Tight control<br />
reduces macrovascular complications, but at the expense <strong>of</strong><br />
increased hypoglycaemic attacks, <strong>and</strong> the number <strong>of</strong> patients<br />
that needs to be treated in this way to prevent one cardiovascular<br />
event is large. In contrast, aggressive treatment <strong>of</strong> hypertension<br />
is <strong>of</strong> substantial benefit, <strong>and</strong> the target blood pressure<br />
should be lower than in non-diabetic patients (�130 mmHg systolic<br />
<strong>and</strong> �80 mmHg diastolic, see Chapter 28). In older type 2<br />
patients, hypoglycaemic treatment aims to minimize symptoms<br />
<strong>of</strong> polyuria, polydipsia or recurrent C<strong>and</strong>ida infection, <strong>and</strong> to prevent<br />
hyperosmolar coma.<br />
DIET IN DIABETES MELLITUS<br />
It is important to achieve <strong>and</strong> maintain ideal body weight on a<br />
non-atherogenic diet. Caloric intake must be matched with<br />
insulin injections. Patients who rely on injected insulin must<br />
time their food intake accordingly. Simple sugars should be<br />
restricted because they are rapidly absorbed, causing postpr<strong>and</strong>ial<br />
hyperglycaemia, <strong>and</strong> should be replaced by foods<br />
that give rise to delayed <strong>and</strong> reduced glucose absorption,<br />
analogous to slow release drugs (quantified by nutritionists as<br />
‘glycaemic index’). (Artificial sweeteners are useful for those<br />
with a ‘sweet tooth’.) A fibre-rich diet reduces peak glucose<br />
levels after meals <strong>and</strong> reduces the insulin requirement. Beans<br />
<strong>and</strong> lentils flatten the glucose absorption curve. Saturated fat<br />
<strong>and</strong> cholesterol intake should be minimized. Low fat sources<br />
<strong>of</strong> protein are favoured. There is no place for commercially<br />
promoted ‘special diabetic foods’, which are expensive <strong>and</strong><br />
also <strong>of</strong>ten high in fat <strong>and</strong> calories at the expense <strong>of</strong> complex<br />
carbohydrate.<br />
DRUGS USED TO TREAT DIABETES MELLITUS<br />
INSULINS<br />
Insulin is a polypeptide. Animal insulins have been almost<br />
entirely replaced by recombinant human insulin <strong>and</strong> related<br />
analogues. These are <strong>of</strong> consistent quality <strong>and</strong> cause fewer<br />
allergic effects. Insulin is available in several formulations<br />
(e.g. with protamine <strong>and</strong>/or with zinc) which differ in pharmacokinetic<br />
properties, especially their rates <strong>of</strong> absorption<br />
<strong>and</strong> durations <strong>of</strong> action. So-called ‘designer’ insulins are synthetic<br />
polypeptides closely related to insulin, but with small<br />
changes in amino acid composition which change their properties.<br />
For example, a lysine <strong>and</strong> a proline residue are<br />
switched in insulin lispro, which consequently has a very<br />
rapid absorption <strong>and</strong> onset (<strong>and</strong> can therefore be injected<br />
immediately before a meal), whereas insulin glargine is very<br />
slow acting <strong>and</strong> is used to provide a low level <strong>of</strong> insulin activity<br />
during the 24-hour period.<br />
Use<br />
Insulin is indicated in all patients with type 1 diabetes mellitus<br />
(although it is not strictly necessary during the early ‘honeymoon’<br />
period before islet cell destruction is complete) <strong>and</strong><br />
in about one-third <strong>of</strong> patients with type 2 disease. Insulin is<br />
usually administered by subcutaneous injection, although<br />
recently an inhaled preparation has been licensed for use in<br />
type 2 diabetics. (Note: This was not commercially successful,<br />
<strong>and</strong> has been withdrawn in the UK for this reason.) The effective<br />
dose <strong>of</strong> human insulin is usually rather less than that <strong>of</strong><br />
animal insulins because <strong>of</strong> the lack <strong>of</strong> production <strong>of</strong> blocking<br />
antibodies. Consequently, the dose is reduced when switching<br />
from animal to human insulin.<br />
Soluble insulin is the only preparation suitable for intravenous<br />
use. It is administered intravenously in diabetic emergencies<br />
<strong>and</strong> given subcutaneously before meals in chronic<br />
management. Formulations <strong>of</strong> human insulins are available in<br />
various ratios <strong>of</strong> short-acting <strong>and</strong> longer-lasting forms (e.g.<br />
30:70, commonly used twice daily). Some <strong>of</strong> these are marketed