Rudy Bilous, MD, FRCP
Richard Donnelly, MD, PHD, FRCP, FRACP
The starting points and mainstays of treatment for type 2 diabetes are diet and other modifications of lifestyle, such as increasing exercise and stopping smoking (Figure 11.1). The major aims are to reduce the weight of obese patients and improve glycaemic control, but also to reduce risk factors for cardiovascular disease (CVD), such as hyperlipidaemia and hypertension, which accounts for 70-80% of deaths in type 2 diabetes.
Weight loss is achieved by decreasing total energy intake and/or increasing physical activity and thus energy expenditure. Gradual weight loss is preferred – not more than 0.5-1 kg/week. For effective weight loss and improvement in glycaemic control, the amount of energy restriction is more important than dietary composition, though compliance may be greater with high monounsaturated fat diets (Figure 11.2). Weight loss of as little as 4 kg will often ameliorate hyperglycaemia. Reduced-calorie diets result in clinically significant weight loss regardless of which macronutrients they emphasize….
Antiobesity drugs have so far played only a minor part in the management of the obese patient with diabetes.
Sibutramine is a centrally acting serotonin and norepinephrine reuptake inhibitor that acts as an appetite suppressant. It has many contraindications, potential drug interactions and stringent requirements for monitoring, and little information on long-term efficacy and safety. Orlistat acts locally in the gastrointestinal tract, where it blocks enzymatic digestion of triglyceride by inhibiting pancreatic lipase. The absorption of up to 30% of ingested fat is thus prevented. Orlistat can result in a greater weight loss in obese patients with type 2 diabetes over the course of the first year’s treatment, though weight may be regained subsequently (Figure 11.3). Gastrointestinal side effects are common, including flatulence, steatorrhoea and, occasionally, faecal incontinence. A diet rich in fruit and vegetables is needed to avoid fat-soluble vitamin deficiency. Orlistat should be started only if diet alone has produced 2.5 kg weight loss over 1 month and should be discontinued if weight loss is <5% over 12 weeks. Orlistat may be helpful to prevent weight regain following a very-low-energy diet. The dietary recommendations are essentially the same for type 1 and type 2 diabetes and, indeed, follow a healthy eating plan suitable for the entire population (Box 11.1). Saturated fat should be reduced and replaced with monounsaturated fat such as olive oil or polyunsaturated fats. n-6 Polyunsaturated fat, found in vegetable oils, is also beneficial for cholesterol lowering and improving glycaemic control. Dietary cholesterol may be more detrimental in diabetics than in the general population, so the consumption of foods such as eggs should be limited. Fish oils are rich in n-3 fatty acids and have lower triglyceride levels, and there is evidence that higher fish intake is associated with less CVD in diabetes; accordingly, 2-3 servings of fish per week are recommended. Simple dietary guidelines in the form of recommended foods are normally best for patients, and are better understood than measures of fat, carbohydrate or protein. ‘Diabetic’ foods that contain sorbitol or fructose as sweeteners are not recommended. Sucrose need not be banned from the diabetic diet, and a moderate amount for sweetening is acceptable. The focus of dietary plans should be on balancing energy intake to energy expenditure and the quality of fat and carbohydrate, rather than the quantity alone. Foods that normally improve glycaemic control and CVD risk are whole grains (brown rice, wholewheat breads, oats) and high-fibre foods (grains, cereals, fruits, vegetables and nuts).
Box 11.1 Practical food recommendations for patients with diabetes
Several programmes have been developed in Europe and North America to educate patients about diabetes. An example in the UK for patients with type 2 diabetes is the diabetes education and self management for ongoing and newly diagnosed (DESMOND) structured education programme. Clinical studies have shown that structured education programmes focused on behaviour change can successfully engage those with newly diagnosed type 2 diabetes in starting effective lifestyle changes that are sustainable. Benefits of DESMOND include improvements in illness beliefs, weight loss, physical activity, smoking status (Figure 11.4) and depression.
Exercise should be tailored to the individual patient, according to physical condition and lifestyle, but simple advice might include moderate exercise as part of the daily schedule, such as walking for 30-60 minutes per day (preferably an extra 30-60 minutes). Exercise does not usually cause hypoglycaemia in type 2 diabetes (in contrast to type 1 diabetes), and therefore extra carbohydrate is generally unnecessary. Resistance exercise, such as weightlifting performed 2-3 times per week, may provide extra benefits over aerobic exercise; however, it should be done with proper instruction, progressively increased over some weeks, starting with a low-intensity workload and supervised. Regular exercise can reduce long-term mortality by 50-60% in patients with type 2 diabetes compared with patients with poor cardiorespiratory fitness.
Metabolic progression: effects on treatment
There is a progressive decline in beta-cell function and insulin sensitivity in type 2 diabetes, which results in deteriorating glycaemic control and the constant need to revise and intensify treatment. Diet and exercise are sufficient to achieve adequate glycaemic control in <10% of type 2 patients; when control worsens, an oral hypoglycaemic agent is generally introduced.
The particular drug treatment used in an individual patient with type 2 diabetes is decided on the basis of clinical judgement about the balance of beta-cell impairment and insulin resistance in that particular case (Table 11.1). Overweight and obese patients are likely to be insulin resistant: here, the insulin sensitiser metformin is a logical first choice. Thin patients generally have substantial beta-cell failure, and sulphonylureas (which stimulate insulin secretion) are likely to be effective. Beta-cell function declines at about 4% per year, so sulphonylureas are less effective later in the disease. About 50% of type 2 diabetic patients need insulin within 6 years of diagnosis, although newer agents are providing alternative options for combination therapy.
Oral antidiabetic drugs
Metformin is a derivative of guanidine, the active ingredient of goat’s rue (Galega officianalis), used as a treatment for diabetes in medieval Europe (Figure 11.7). Metformin increases insulin action (the exact mechanism is unclear), lowering glucose mainly by decreasing hepatic glucose output. Unlike sulphonylureas, it does not cause hypoglycaemia or weight gain and, indeed, has some appetite-suppressing activity that may encourage weight loss. A typical starting dose of metformin is 500 mg daily or twice daily, rising to 850 mg thrice daily. Major side effects are nausea, anorexia or diarrhoea, which affect about one-third of patients. Lactic acidosis is a rare but serious side effect that carries high mortality. It can be avoided by not giving metformin to patients with renal, hepatic, cardiac or respiratory failure or those with a history of alcohol abuse.
Sulphonylureas stimulate insulin secretion by binding to sulphonylurea (SU) receptors (SUR-1) on the beta-cell plasma membrane, which leads to closure of the ATP-sensitive K+ channel (Kir6.2), membrane depolarisation, opening of calcium channels, calcium influx and exocytosis of insulin granules (Figure 11.8). The most serious side effect is hypoglycaemia, which is more likely to occur with glibenclamide, especially in older patients and those with renal impairment. Modest weight gain may also accompany sulphonylurea use. The thiazolidinediones (TZD) (‘glitazones’) are insulin sensitisers that enter the beta-cell and bind to the peroxisome proliferator-activated receptor- (PPARy), a nuclear receptor found predominantly in adipocytes but also in muscle and liver (Figure 11.9). PPARy forms a complex with the retinoid X receptor (RXR), and binding of a TZD leads to enhanced expression of certain insulin-sensitive genes, such as GLUT- 4, lipoprotein lipase, fatty acid transporter protein and fatty acyl CoA synthase. This increases glucose uptake and utilisation, increases adipocyte lipogenesis and decreases circulating fatty acid levels. There is also decreased production of the cytokine TNF- and of resistin.
The first TZD, troglitazone, was associated with serious hepatotoxicity and withdrawn. Rosiglitazone and pioglitazone do not have adverse effects on the liver – in fact, they may reverse fatty infiltration of the liver and improve liver function in some patients – but they are associated with fluid retention, weight gain and oedema. More importantly, some patients may develop features of heart failure. Because PPARy receptors are widely expressed in the vasculature, there has been considerable interest in the cardiovascular effects of these drugs. In one trial (the PROACTIVE study), pioglitazone as add-on therapy (versus placebo) was associated with significant reductions in fatal and non-fatal myocardial infarction (MI) and stroke (secondary endpoints in the trial) (Figure 11.10). Meanwhile, a meta-analysis of studies concluded that, relative to other antidiabetic agents, rosiglitazone was associated with a 2-3-fold increased risk of myocardial infarction. Differential effects on LDL-cholesterol might explain the different effects of pioglitazone and rosiglitazone on cardiovascular outcomes.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are orally active and generally well tolerated. As add-on therapy to metformin, they lower HbA1c to the same extent as sulphonylureas but have a lower incidence of hypoglycaemia because GLP-1 effects on pancreatic and beta-cells are dependent upon glucose. DPP-4 inhibitors are weight neutral, and as yet there are no long-term studies to confirm their safety and efficacy on clinically important diabetes-related outcomes. They are licensed as add-on to metformin, SU or TZD, and as triple therapy. GLP-1 analogues, such as exenatide and liraglutide, are administered by fixed-dose subcutaneous injection, once or twice daily, and are best suited to obese patients (BMI >35) who have inadequate HbA1c control despite combination oral therapy. GLP-1 agonists facilitate weight loss, but 20-30% of patients may experience nausea or sickness (Figures 11.11, 11.12). These drugs have also been associated with pancreatitis.
For very obese patients with type 2 diabetes (BMI >35), bariatric surgery is an increasingly recognised treatment option. The results with laparascopic adjustable gastric banding or gastric bypass demonstrate significant weight loss (often >20 kg) and improved glycaemic control (Figure 11.13). Patients need careful selection, and lifelong follow-up.
It is common for many patients with type 2 diabetes to progress from treatment by diet alone to monotherapy with metformin or a sulphonylurea, then to a combination of the two (and/or the introduction of a ‘glitazone’), before finally starting insulin. Insulin can be given alone or in combination with oral agents, either metformin or pioglitazone (or both). A single daily injection of basal insulin can be given as add-on to oral therapy (e.g. at bedtime), and twice-daily injections of premixed insulin (e.g. 30% short-acting/70% isophane) via a ‘pen’ are also convenient and effective in many patients. When obesity and insulin resistance predominate, the doses may range up to 2-3 U/kg.
Next Week: Diabetic ketoacidosis, hyperglycemic hyperosmolar state and lactic acidosis
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