Diabetes Management
Figure 4: Possible Mechanisms for the Liraglutide-mediated Improvements in Glycemic Control Suggested by Study Switching from Premixed Insulin 50/50 to Liraglutide
Pancreas
Reduce glucagon release (α−cells)
Stimulate insulin secretion (β−cells)
Adipocytes
Reduce fatty acids release
Insulin secretion Insulin sensitivity Liver
Reduce glucagon-mediated glycogenolysis Reduce glucagon-mediated gluconeogenesis
Liraglutide
Hepatic glucose output
Improve glucose metabolism Source: Yanai et al., 2011.86
and maintaining recommended levels of glycemic control.53
Appropriate targeting of plasma glucose may help patients and practitioners achieve
glycosylated hemoglobin (HbA1c) goals, reduce excessive self-testing, and minimize the occurrence of HEs.54
Subset analyses from the Action to control cardiovascular risk in diabetes (ACCORD) trial demonstrated that the lowest risk of mortality
was related to lower mean levels of HbA1c with the intensive therapy strategy. Risk of death increased steadily as mean levels increased from 6 % to 9 %. The minority subgroup of patients in the intensive therapy
group who had HbA1c levels higher than 7 % accounted for the excess risk associated with that therapy regimen. Therefore, trying to lower
the HbA1c level to less than 7 % with intensive treatment in therapy-resistant individuals may be detrimental.55–57
Basically, an HbA1c
goal of less than 7 % remains recommended, although goals should be individualized for selected patients. Unrecognized hypoglycemia and weight gain in the ACCORD study were also likely major contribuors to its adverse outcomes.58
Earlier and more intensive intervention when a patient is not
experiencing severe HEs, rather than waiting for an increase in HbA1c and then intensifying glucose control, may improve the glycemic profile by avoiding prolonged periods of hyperglycemia.59
Periods of glycemic exposure may be avoided by transitioning earlier to more
intensive glucose therapy, instead of waiting for a rise in HbA1c and then increasing glucose control. Intensive glucose control has demonstrated advantages, such as lowering the risk of non-fatal MI; however, it may also increase the risk of severe hypoglycemia.60–63
A meta-analysis of the
effect of intensive glucose control on cardiovascular outcomes in individuals with type 2 diabetes found that a higher proportion of patients on intensive therapy than standard treatment had a hypoglycemic episode. Severe hypoglycemia was much less frequent than non-severe hypoglycemia; however, nearly twice as many patients on intensive therapy compared with those on standard treatment had a severe HE. Additionally, patients receiving intensive therapy were a mean of 2.5 kg heavier than those on standard treatment by the end of the study.64
100
Insulin has traditionally been considered a last resort for patients who fail to maintain glycemic control with diet and OADs. A recent study compared insulin-based therapy with an oral therapy-based treatment regimen in patients with newly diagnosed type 2 diabetes. Insulin-based therapy was found to be equivalent to oral-based therapy in terms of efficacy, weight gain, frequency of HEs, compliance, treatment satisfaction, and QoL.69
Insulin is also thought to protect against the
decline in β-cell function, therefore conferring a disease-modifying effect.70
Recently developed insulin analogs have more predictable onsets and durations of action than human insulin formulations and more closely approximate the physiological action profile of endogenous insulin. Rapid-acting analogs have a more rapid onset
US ENDOCRINOLOGY
Metformin often fails to maintain glycemic control over the long term, because disease progression is accompanied by a progressive decline in insulin-secreting β-cell function, which begins early in the disease course, and an impaired incretin response. After five years, metformin has been shown to have a 21 % failure rate.67
The ADA and EASD recommend that
patients who fail to achieve glycemic control on metformin should consider alternative regimens, including concomitant treatment with a sulfonylurea or insulin.53,68
However, effective insulin treatment is often delayed because of perceived fear of hypoglycemia.
A major challenge in the management of HEs in patients with type 2 diabetes is hypoglycemic unawareness, which is caused by deficient epinephrine response and characterized by a progressive loss of the autonomic symptoms of hypoglycemia, such as sweating, tremor, and palpitations, together with a reduced response of glucagon and epinephrine to falling levels of blood glucose.15,16
As a result, patients are
unaware of the problem until they have central nervous system dysfunction and may not be able to appropriately respond to the hypoglycemia. Hypoglycemic unawareness is associated with a high risk of more severe HEs that may result in seizures and coma.65
However, the
condition is reversible to some extent and several strategies for managing hypoglycemic unawareness exist, such as strict avoidance of HEs for two to three weeks and optimizing insulin treatment (see Table 2).66
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