Therapeutic strategies in type 2 diabetes

Type 2 diabetes is a heterogeneous disease with varying levels of insulin resistance and beta-cell failure. Moreover, the patient will often have comorbid conditions like hypertension and dyslipidemia and may already have complications such as myocardial infarction. All of these factors will influence therapeutic choices, so, first and foremost, any therapeutic strategy should be tailored to the individual patient. This includes careful consideration of the optimal glycemic target. The aggressive therapy that may be warranted in a young, severely obese patient may actually be harmful in in an older leaner person. Recent guidelines on glucose-lowering strategies offer more flexibility in therapeutic choice, but many of the newer and expensive drugs implicitly advocated in these guidelines still lack solid evidence regarding their effect on clinical outcomes and safety. Lifestyle advice, metformin, sulfonylurea derivatives and insulin are still the mainstay of efficacious treatment. Moreover, while glucose control is of importance for microvascular complications, macrovascular outcomes are probably more determined by age and the years of prior exposure to smoking, dyslipidemia, hypertension and other vascular risk factors. Thus, integrated cardiovascular risk management is of key importance. Finally, consideration has to be given to the prevention and treatment of complications such as neuropathy and associated diseases such as depression.

Guidelines

Many professional societies offer guidelines on various aspects of diabetes but it should be noted that solid clinical evidence based upon outcomes is lacking for many of the therapeutic choices that are made in clinical practice. For instance, very few studies have specifically looked at the elderly, even though these constitute the majority of type 2 diabetes patients. Also, due to the lack of evidence, these guidelines often reflect expert opinion and as such different societies may offer different guidance on the same topic. Finally, guideline committee members often have links with pharmaceutical companies and some guidelines favour expensive newer drugs in the absence of demonstrated benefits in clinically meaningful endpoints. A detailed collection and discussion of the more prominent guidelines on the treatment of diabetes can be found here.

Individualising targets

When discussing treatment, one should first be clear about the goals that should be achieved. For many years the target HbA1c has been 7% (53 mmol/mol) or lower for all patients with diabetes. In the light of recent studies, this 'one size fits all' approach is no longer tenable. On the one hand, there is evidence from the United Kingdom Prospective Diabetes Study [UKPDS] that in those with new-onset diabetes each 1% further reduction in HbA1c will translate in a further reduced risk of complications. On the other hand several randomized trials that specifically looked at glycemic targets of below 6.5% in those with diabetes of some duration had less favourable results. While in the ADVANCE trial there was still a small benefit on microvascular (renal) outcomes of this more intensive approach, the ACCORD trial was prematurely halted because of an excess (cardiovascular) mortality.

Observational data from general practices in the United Kingdom suggest that for those Figure 1. Hazard ratio for mortality in a large cohort of type 2 diabetes patients using oral therapy with metformin and sulfonylurea derivative. (Adapted from Currie et al. Lancet 2010;375:481)
Figure 1. Hazard ratio for mortality in a large cohort of type 2 diabetes patients using oral therapy with metformin and sulfonylurea derivative. (Adapted from Currie et al. Lancet 2010;375:481)
using only metformin and/or SU derivatives there is actually a range of HbA1c values between 7 and about 9% which confer a similarly low mortality risk with increased risk both above and below this range (figure 1). For those using insulin therapy, the optimum range actually starts at a higher HbA1c value of around 7.5%. These data can only be reconciled by assuming that factors such as age, diabetes duration, type of therapy and polypharmacy influence both the optimal and the achievable HbA1c target.

Achieving glycaemic control

There is widespread consensus that a healthy lifestyle (diet, exerciseand if possible weight loss) should be advocated for all patients with type 2 diabetes and that the first-line drug of choice is metformin. A wide range of drugs are vying for second position but for reasons of long-term safety, cost and availability sulfonylurea derivatives still seem the most reasonable choice. After this, insulin therapy or triple therapy incorporating any of the newer drugs can be considered. However, all therapeutic choices will have to take into account the specific circumstances of the individual patient.

Cardiovascular risk management

The majority of diabetes patients will die from cardiovascular causes, but this is not so much attributable to diabetes itself as to the other cardiovascular risk factors that accompany it. Therefore an integral approach assessing and addressing all modifiable cardiovascular risk factors is necessary.

Smoking cessation

Smoking is the single most important risk factor for cardiovascular disease and patients should be encouraged and supported in efforts to stop. While the percentage of patients that will stop can be disappointing this remains a very cost-effective intervention due to large effects on the mortality, morbidity and quality of life of those that do manage to stop smoking.

Cholesterol-lowering therapy

All patients with proven cardiovascular disease, and most patients without cardiovascular disease will qualify for cholesterol-lowering therapy using statins to reduce overall cardiovascular risk. Depending on age, a 1 mmol/l lowering of LDL-cholesterol using statins will reduce mortality risks by 10% in older patients, and by up to 40% in those below 50 years of age. Current evidence does not support an equivalent effect of other cholesterol-lowering agents, suggesting that statins may have cardiovascular benefits over and beyond their cholesterol-lowering properties.

Blood pressure-lowering therapy

Those with high blood pressures will qualify for anti-hypertensive treatment, usually with ACE-inhibition followed by a range of other drug classes. In addition, those without hypertension but with micro-albuminuria should also be treated with ACE-inhibition to reduce albuminuria and the risk of progressive nephropathy.

Anti-platelet therapy

Despite major benefits in the secondary prevention of cardiovascular events in those with a prior cardiovasular event, the effects of anti-platelet therapy, specifically acetyl-salicylic acid in the primary prevention of cardiovascular events in those with diabetes are not convincingly proven. Therefore, a careful assessment of the patient and his/her comoribidities is necessary to determine whether the benefits will outweigh the (bleeding) risks associated with anti-platelet therapy.

Influenza vaccination

Influenza vaccination is generally recommended in the elderly and those with diabetes. However, this is not uncontroversial. Due to the yearly changing nature of the influenza virus, trials specifically proving that this year's influenza vaccine will truly prevent a patient from getting influenza and -more importantly- serious adverse consequences of influenza such as pneumonia, hospitalisation or death are never performed. And even observational data do not unambiguously support an important preventive effect of vaccination on serious sequelae.

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