David Levy, MD, FRCP
Introduction: Type 2 Diabetes as a Progressive Condition
Glycemia in type 2 diabetes progressively deteriorates with time, usually thought to be related to progressive beta-cell failure. This was demonstrated dramatically in the United Kingdom Prospective Diabetes Study (UKPDS 1998), but the glycemic trends have been less marked in more recent studies and even in non-treat-to-target studies (e.g. PROactive, 2005) deterioration in control was barely discernible. Some agents, for example the sulphonylureas, give less sustainable control than others, for example metformin and the glitazones, due to more rapid depletion of progressive beta-cell function….
The mean preclinical duration of significant hyperglycemia is between 7 and 10 years, and 20% of type 2 patients have microvascular complications at diagnosis, most commonly retinopathy and microalbuminuria. A similar proportion has subclinical or clinical macrovascular disease as a result of the even longer duration, perhaps 20 years or more, of insulin resistance/metabolic syndrome, hence the high proportion of newly diagnosed type 2 patients presenting with ACS (see Chapter 3). The concepts of ‘early’ and ‘late’ type 2 diabetes, increasingly emphasized in discussing the results of the surge of clinical trials reported in 2008 and 2009, becomes even more important yet increasingly elusive to define. Further complexity was added by the widely quoted studies that used increasing HbA1c levels as a surrogate for progression from ‘early’ to ‘late’ diabetes: an orderly progression of hyperglycemia, initially postprandial, followed by deterioration in control in the first part of the day and finally persistent overnight hyperglycemia . However, behind this scheme lie both enormous individual variation and the continuously changing phenotypic spectrum of type 2 diabetes. Guidelines emphasizing the homogeneity of type 2 diabetes will therefore progressively fail to reflect the type 2 diabetic population presenting to the clinician. In our present state of knowledge, polypharmacy with continued emphasis on sustainable lifestyle changes, as we are accustomed to practising in hypertension, is the best way to manage the hyperglycemia of type 2 diabetes (Fig. 5.1).
The general approach to the newly diagnosed type 2 patient
Most patients are overweight or obese at diagnosis, for example BMI 31–33 (women higher BMI than men), but perhaps 20% will be normal weight or overweight. These patients may have late-onset type 1 diabetes (see Chapter 1) and a reasonable initial response to oral hypoglycemic agents, but control may subsequently deteriorate rapidly. Patients with persistent 1+ or more ketonuria, especially in the presence of continuing weight loss or failure to regain lost weight with medication, should be considered to have type 1 diabetes (or LADA) and insulin treatment considered. GADA may be helpful in confirming immune-mediated diabetes and the likelihood of more rapid progression to insulin requirement (see Chapter 1).
Initial examination should include:
- height, weight and BMI;
- blood pressure;
- urinalysis for protein and ketones;
- examination of peripheral pulses (listen for carotid, femoral and renal bruits) and for peripheral neuropathy (see Chapter 10).
Laboratory tests should include the following.
- Creatinine and electrolytes, HbA1c.
- Liver functions, including gamma-glutamyltransferase.
- Fasting lipids (though mixed hyperlipidemia, sometimes severe, at presentation of type 2 diabetes is common; see Chapter 12).
- Thyroid function: note the high prevalence of subclinical hypothyroidism (up to 1 in 12) in white female type 2 diabetic patients.
- Resting 12-lead ECG.
Defer investigation of abnormal liver functions and lipids until glycemic control has stabilized. Although most patients will have ‘usual’ type 2 diabetes in association with obesity, always bear in mind other underlying diagnoses, especially in non-overweight patients:
- pancreatic causes, especially alcohol, and underlying pancreatic carcinoma in the over fifties;
- genetic hemochromatosis;
- late-onset type 1 diabetes;
- syndromic type 2 diabetes, suggested by multisystem involvement, family history of diabetes/deafness, consanguineous parents, and insulin resistance in the absence of obesity.
At diagnosis, all patients should see a dietitian, a nurse practitioner/practice nurse/community diabetes specialist nurse, and a podiatrist. They should be offered a structured educational programme and entered into the local retinopathy screening service and, where appropriate, smoking cessation programme. The DESMOND group education and self-management programme, now widely available in the UK, has been formally evaluated; at 12 months, compared with usual care, weight loss and smoking cessation were greater, as were understanding of diabetes and positive beliefs about illness. Depression scores were lower, though there was no difference in HbA1c .
Lifestyle intervention: diet and exercise
Retarding the progression of IGT to type 2 diabetes through intensive lifestyle intervention, with some evidence for a long-term legacy effect, is now established through many formal clinical trials (see Chapter 1). With perhaps the exception of the glitazones, which are not used in this situation, lifestyle interventions are more effective than drug treatment, though in practice both approaches are likely to be used. Whether these interventions translate into reduced cardiovascular events will not be known for several years.
Similarly, there is no evidence at present that intensive lifestyle intervention in people with established type 2 diabetes reduces cardiovascular outcomes but the Look AHEAD trial is a huge prospective 12-year study powered to demonstrate any such benefits . Although not completed, it has already yielded much valuable information on intermediate outcome measures (Table 5.1). The interventions and methods are similar to those of the Diabetes Prevention Program, but even more ambitious:
- individual weight loss target, 10% (mean 7% for the intensive intervention group), with mean weight loss 8.6 kg after 1 year;
- activity goal, 175 min/week.
Aims of dietary therapy in type 2 diabetes
- Weight loss that is usually described as modest (5–10%, i.e. about 4–8 kg). However, weight regain usually starts from a nadir at 3–6 months, although sustaining this degree of weight loss over a long period is possible in a clinical trial with intensive input (see below).
- Limit postprandial glucose excursions.
- Achieve a healthy evidence-based balance of macronutrient and micronutrient intake, avoiding those that might do harm.
- Combine judiciously with exercise therapy, rational pharmacotherapy and, in some cases, bariatric surgery.
Role of anti-obesity agents
A worthy goal, to safely reduce weight significantly using pharmacological agents in patients with type 2 diabetes, has remained largely elusive. Rimonabant, a cannabinoid receptor antagonist, was withdrawn in 2008, and sibutramine in 2010, leaving only orlistat, a lipase inhibitor. In RCTs orlistat 120 mg t.d.s. results in modest weight loss (about 3–5 kg), and in clinical practice it is most effective when used as part of a comprehensive weight-management programme. Where this is not available, success is more limited; the fat malabsorption induced by orlistat hinders compliance in the early stages of treatment. Orlistat may have a limited role in delaying progression of IGT to diabetes (see Chapter 1).
In future, the GLP-1 analogues may have a role in managing obesity, whatever the degree of glucose tolerance (see Chapter 6). Liraglutide, given at 1.2–3.0 mg/day with a 500 kcal/day energy-deficit diet, causes moderate weight loss (2.0–4.4 kg, placebo-corrected) over a short period in people with normal glucose tolerance or pre-diabetes. Even at the lowest dose, 1.2 mg daily, weight loss was significantly greater than with orlistat. Much longer studies (e.g. similar to Look AHEAD) will be required to demonstrate any useful effect on cardiovascular end points and progression to diabetes .
In recent years the concept of the obese individual who is nevertheless metabolically ‘healthy’ (the ‘fit fat’) has, not surprisingly, gained popularity. At any given BMI, low or high, individuals may be very insulin resistant or sensitive, or any point in between; of those with high insulin sensitivity, many do not, at least in cross-sectional studies, have associated hypertension, hyperglycemia or high visceral fat mass, a key component of unhealthy obesity. Perhaps 10–25% of obese people fall into this category . However, over a 30-year follow-up, overweight and obese Swedish men without the metabolic syndrome had a similar cardiovascular event rate and total mortality to those with the metabolic syndrome. ‘Fit fat’ may be a product of collective wishful thinking; certainly all obese people require follow-up for the development of the characteristics of the metabolic syndrome and associated cardiovascular risks.
Qualitative aspects of diet
While consistent reductions in calorie intake are inevitably required for sustained weight loss, there has been a great deal of interest over the past decade in whether diets of specific composition can more successfully maintain weight loss. Long-term adherence to the traditional Mediterranean diet has been shown to reduce risks of cardiovascular disease and of cancer by up to 50%, with presumably similar or greater benefits in people with diabetes compared with the general population (Fig. 5.2) . Both Mediterranean and low-carbohydrate diets are more effective than the traditional high-carbohydrate low-fat diet (better glycemic control with the Mediterranean diet, more favourable lipid profile with the low-carbohydrate diet, better sustained weight loss with both), and were safe and effective in a 2-year clinical trial . These options should be offered to type 2 patients at diagnosis, where determination and adherence are at their greatest.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)