Last year there were three main reasons for the update in recommendations which were published by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD): 

• New insights into the benefit/risk ratio of tight glycaemic control 
• The new drug regimens for type 2 diabetes (T2D) management and their impact on therapeutic choices 
• The global move towards patient-centred care. 

It has become increasingly obvious that glycaemic control is an individual matter that does not meld well with algorithmic guidelines.¹

Previous guidelines, based upon algorithms, were limited by the fact that there is a paucity of comparative data between different drug classes that could potentially guide choice of one over the other.²

Pathophysiology

T2D is a leading cause of cardiovascular (CV) disorders, blindness, end-stage renal failure and amputations, all of which contribute to high rates of hospitalisation. The physiology of T2D is as follows: while fasting, hyperglycaemia is caused by increased glucose production by the liver. Post-prandially, patients with diabetes fail to suppress this glucose release, in addition to having defective insulin production and release. Glycosuria can curb, but not prevent, further hyperglycaemia.¹ Absolute insulin production in patients with diabetes may be normal but it is disproportionately low for their reduced-insulin sensitivity. Additionally, their ß-cells are unable to release adequate insulin relative to rising glycaemia, while a-cells over-secrete glucagon and cause further hepatic glucose production.²

Goals of treatment

The general goals of glycaemic control consist of a mean plasma glucose of 8mmol/L: < 7.2mmol/L fasting and preprandially; and < 10mmol/L postprandially. However, the goal of maintaining a HbA1c of < 7% is inconsistent with an individualised treatment regimen and may be an unattainable and, indeed, in elderly patients, a dangerous aim. Achieving tight glycaemic control can lead to a significant risk of hypoglycaemia, and failure to set realistic standards based on individual patient needs and level of care leads to poor adherence and, ultimately, poor glycaemic control.^1,2

Lifestyle changes

Treatment starts with weight reduction, which improves glycaemic control and cardiovascular risk factors. Weight reduction may also improve non-alcoholic steatohepatitis, which is associated with insulin resistance and T2D. The effect of weight loss is posited to be through the depletion of hepatic glycogen stores. The amount of weight loss required to reach blood glucose targets depends somewhat on the initial fasting glucose. A measurement between 6-8mmol/L requires approximately 10kg weight loss; a measurement between 10-12mmol/L requires 22kg weight loss. Despite the clear benefits, only a small amount of patients are able to achieve the required weight loss. 

A three-to-six-month trial of lifestyle changes before instituting pharmacological therapy is only recommended in highly motivated patients, as delay in attaining glycaemic control is associated with more long-term complications. Bariatric surgery is an increasingly popular option in severe obesity. However, in the long term the effects are less clear and the treatment is limited in certain areas by accessibility and affordability.^1,2

Pharmacotherapy

The first-line pharmacological agent is metformin, which may facilitate weight loss by decreasing insulin resistance and does not cause hypoglycaemia. It acts by reducing hepatic glucose production. Its main side-effects are gastrointestinal and care must be taken to avoid lactic acidosis. Barring complications, metformin is the agent recommended for initial use, with addition of second-line agents and/or insulin as needed. 

The 2012 guidelines do not specify which combinations should be used as first line, instead suggesting that patient factors (such as cost) and physician familiarity with certain drug classes should be the leading consideration in drug choice. Sulphonylureas close ATP-sensitive potassium channels on ß-cells, stimulating insulin release. However, they can promote weight gain and hypoglycaemia. This is particularly marked in older people, who may have another risk factor for hypoglycaemia – poor nutrition – and may be at greater risk of morbidity from falls secondary to low blood glucose levels. 

Thiazolidinediones (TZDs) are activated PPAR-g agents that improve insulin sensitivity and reduce liver glucose production. Their main side-effects are weight gain, fluid retention (which may worsen CCF) and increased risk of fractures. Injectable GLP-1 receptor agonists mimic endogenous GLP-1 by stimulating pancreatic insulin secretion and slowing gastric emptying, hence reducing appetite. Their main advantage is weight loss; their main disadvantages, besides the need to inject them, are nausea and vomiting. DPP-4 inhibitors act by increasing the concentration of active GLP-1 and hence regulating insulin and glucagon secretion.^1,2 They are weight neutral. 

The newest agents coming online are the SGLT-2 inhibitors. Their mechanism of action is via inhibition of glucose resorption from renal tubules, thus reducing plasma glucose levels by promoting urinary glucose excretion. They act independently of pancreatic ß-cells. Their main side-effect has been an increase in genital and urinary infections. Dapagliflozin is the agent currently in trials.³ Lastly, as weight loss is a key element in T2D control, agents designed to treat obesity remain a consideration. One such is phentermine/topiramate ER (Qysmia), which has been approved by the US Food and Drug Administration (FDA) and has been available since September 2012. As yet, it is not approved by the European Medicines Agency (EMA). 

The indication for a second anti-hyperglycaemic agent is worsening glycaemic control over time, itself an almost inevitable decline caused by multiple factors including decreased compliance with diet and exercise regimens, polypharmacy (particularly in elderly patients) with drugs that increase insulin resistance, latent autoimmune diabetes of adults (LADA) and slow implementation of changes to mediation regimens by physicians.^1,2

Injectable therapy

Many patients with T2D end up requiring insulin due to progressive ß-cell dysfunction. However, as some level of function is retained, most do not require the intensive regimes that characterise patients with type 1 diabetes. The aim of insulin therapy in T2D is to achieve a personalised ideal glycaemic profile without causing weight gain or hypoglycaemia. Initial insulin therapy usually takes the form of basal insulin, which suppresses hepatic glucose production between meals and at night.

If the patient’s baseline HbA1c is over 9%, then they are unlikely to achieve their target with monotherapy. In this case two agents, possibly including insulin, may be indicated. If they present with symptoms or a plasma glucose over 16mmol/L or a HbA1c over 10%, insulin therapy may be considered as first-line therapy. Insulin is mandatory when catabolic features or ketonuria are present. 

Basal insulin is usually started at 0.1-0.2units/kg body weight. When fasting glucose has normalised but HbA1c has not, a basal bolus regimen is the next step. However, not all patients will be in a position to cope with the intensity of this regime. Indeed, insulin carries a stigma for patients, raising concerns that their disease is worsening and about their ability to manage self-injections. For older patients or those with poorer compliance, twice-daily premixed insulins will lower HbA1c, but at the expense of increased risk of hypoglycaemia and weight gain. 

Once insulin is started, the question of continuing oral agents is often asked. Metformin is usually continued with basal insulin to avoid weight gain. Sulphonylureas are used with basal insulin as they may minimise initial deterioration of glycaemic control, but they can usually be titrated down after this. They should be avoided when basal bolus regimens are used. TZDs should be reduced or stopped to avoid oedema and weight gain.^1,2

Interventions for risk factors

Patients with T2D are at high risk of CV events. Metformin is a useful drug in the setting of cardiovascular disease once contraindications have been satisfied. Such contraindications include renal disease, liver disease, alcohol abuse and heart failure. UTD pioglitazone has been shown to reduce adverse cardiovascular events in the setting of macrovascular disease; however, its potential link to bladder cancer makes it an unpopular choice. 

Conversely, sulphonylureas should be avoided as they may aggravate myocardial ischaemia through their effects on cardiac potassium channels. TZDs should be avoided in heart failure as they may precipitate oedema. Up to 30% of T2D patients develop renal failure and an eGFR of less than 60ml/min. US guidelines suggest stopping metformin when the creatinine rises above 133mmol/L in men and 124mmol/L in women; the UK guidelines rely on eGFR rather than absolute creatinine values, suggesting reducing doses at a GFR of 45ml/min and stopping at 30ml/min.^1,2

Conclusion

T2D is increasing in incidence and it behoves all clinicians to remain abreast of developments in the field. Most patients with T2D will require pharmacological intervention. Metformin is the first-line agent of choice. The inevitability of requiring insulin should be acknowledged and, again, the institution of this treatment should not be delayed.  

References 

1. Inzucchi SE, Bergenstal RM et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach position statement of the ADA and EASD. Diabetes Care June 2012; 35 (6): 1364-1379
2. UptoDate website: www.uptodate.com
3. Misra M. SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus. Journal of Pharmacy and Pharmacology, 9 AUG 2012
4. (doi: 10.1111/j.2042-7158.2012.01574.x)