Diabetes Management
Post-meal increases in endogenous GLP-1 are linked with increased blood supply to the prefrontal cortex and hypothalamus in humans, an indication of neuronal activity in areas controlling satiety and food intake.73
Clinical data also support reduced calorie intake during GLP-1 receptor agonist therapy.64,65
Potential Cardioprotection
GLP-1 receptor agonist therapy may exert a cardioprotective effect in type 2 diabetes. A database study of 39,275 patients treated with exenatide twice daily and 381,218 patients receiving other antihyperglycemic drugs linked GLP-1 therapy with reduced cardiovascular events (hazard ratio [HR]: 0.81, p=0.01), reduced hospital admissions for cardiovascular events (HR: 0.88, p=0.02), and reduced all-cause hospital admissions (HR: 0.94, p<0.001).74
raised serum creatinine, acute renal failure, or worsening of chronic renal failure.9
A meta-analysis of the six LEAD phase III RCTs concluded that the efficacy and safety profile of liraglutide was unaffected by mild renal impairment.77
Both GLP-1 receptor agonists and DPP-4 inhibitors are novel classes of drugs, and careful long-term monitoring and post-marketing surveillance for any unexpected AEs are required. Further data are required to confirm whether GLP-1 receptor agonists or DPP-4 inhibitors do increase pancreatitis risk. In the meantime, it seems prudent to assume that, if there is a causative link, it may be a class effect, and caution should be used when prescribing GLP-1 receptor agonists or DPP-4 inhibitors, particularly in patients with pre-existing pancreatitis.
Robust clinical trial data are required to confirm whether incretin-based therapies are cardioprotective in type 2 diabetes; several studies are under way (see Table 4).
Comparison of Incretin-based Therapies DPP-4 inhibitors have rapidly gained position among the oral antidiabetic treatments. This is due to their ease of use, lack of any increase in weight, minor hypoglycemia risk, apparently benign AE profile, and good tolerability. The GLP-1 receptor agonists exenatide twice daily and liraglutide also offer a low hypoglycemia risk and a good tolerability/safety profile. Unlike the DPP-4 inhibitors, the two approved GLP-1 receptor agonists are injected but, although this might appear to be less convenient or attractive for patients, they offer the added benefit of long-term sustained weight loss. Indeed, an assumed patient preference for oral treatments may reflect prescriber perceptions rather than actual patient preferences. RCT data revealed significantly higher overall treatment satisfaction with liraglutide than with sitagliptin, despite the latter having an oral mode of administration.62
Pharmacokinetic Considerations
Both sitagliptin and saxagliptin are primarily eliminated via the kidney; therefore, dose reductions are required in patients with moderate or severe renal impairment (saxagliptin has not been studied in patients receiving dialysis). This is highly relevant for the type 2 diabetes population, of whom about 40 % have chronic kidney disease (CKD) according to data from the Fourth National Health and Nutrition Examination Survey (NHANES IV); also, elderly patients may have normal serum creatinine levels but ‘concealed’ impaired glomerular filtration.75,76 In contrast, the kidney accounts for only 5 % of linagliptin excretion, so no dose adjustments are required in patients with renal impairment. Linagliptin clearance is via the liver, so drugs that induce cytochrome P450, isozyme CP3A4, or P-glycoprotein (P-gp) are likely to reduce linagliptin exposure to subtherapeutic levels.7
Linagliptin should not be used in patients who require CP3A4 or P-gp inducers such as rifampin.7
No dose adjustments in patients with renal impairment are required for either exenatide twice daily or liraglutide, although both drugs should be used with caution in this population.5,9
Exenatide is not
recommended in patients with severe renal impairment or end-stage renal disease (ESRD), and physicians should be cautious about giving exenatide twice daily doses of 5 µg or more to patients with moderate renal impairment.5
Discussion
Current advice is to use liraglutide with caution in patients with renal impairment, following post-marketing reports of
92
Type 2 diabetes is a complex disease that involves multiple, interrelated metabolic processes. Patients are often overweight and have other cardiovascular risk factors such as dyslipidemia. Tight glycemic control is achievable using maximized doses of
US ENDOCRINOLOGY Implications of Clinical Trial Data
Typical considerations for most patients with type 2 diabetes would be efficacy, hypoglycemia, impact on body weight, and common AEs. Incretin-based therapies have shown minimal risk of hypoglycemia when used as monotherapy. Combining DPP-4 inhibitors or GLP-1 receptor agonists with other antihyperglycemic agents such as sulfonylureas has been linked with increased hypoglycemia rates, but reducing sulfonylurea doses may mitigate this risk.
DPP-4 inhibitors appear to be weight neutral, while GLP-1 receptor agonists are linked with long-term weight loss, which is an attractive characteristic for both physicians and patients that could optimize treatment adherence. GI side effects such as nausea may prove limiting for some patients, but clinical trials have demonstrated that nausea declines rapidly during the first few weeks of liraglutide treatment. LEAD-6 study data suggest that nausea may subside earlier with liraglutide than with exenatide twice daily.53
Interestingly, 382 patients with type 2 diabetes who participated in an online survey ranked
efficacy (measured by HbA1c) as the most important of four factors determining preference for a hypothetical GLP-1 receptor agonist, ahead of nausea, hypoglycemia, and dosing schedule; 96 % of patients preferred the product profile of liraglutide to the product profile of exenatide twice daily, based on clinical trial data.78
Both liraglutide and exenatide twice daily have shown superior
efficacy (including HbA1c reductions) compared with sitagliptin in direct comparator trials.64–66
Within the GLP-1 receptor agonists
class, the phase III LEAD-6 trial revealed significantly greater HbA1c reduction and treatment satisfaction for liraglutide versus exenatide
twice daily.54
Results of a meta-analysis of seven trials (n=4,625) were consistent with the head-to-head comparator studies: 40 % and 32 % of patients receiving liraglutide 1.8 mg or 1.2 mg, respectively,
achieved a pre-specified composite endpoint of HbA1c <7.0 % without weight gain or hypoglycemia.79
The same composite endpoint
occurred in 6–25 % of comparators, including 25 % with exenatide twice daily and 11 % with sitagliptin.79
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