DM Full Guideline (2010) - VA/DoD Clinical Practice Guidelines Home

Version 4.0
VA/DoD Clinical Practice Guideline
for the Management of Diabetes Mellitus
Two RCTs showed that adding exenatide versus insulin glargine (mean doses 25-29U/day) to metformin, SU or both
metformin +SU resulted in a similar reduction in HbA 1 c; however, reduction in fasting glucose was greater with
insulin glargine. Exenatide use resulted in mean weight loss (2-3kg) whereas insulin glargine use resulted in mean
weight gain (1.0-2.3kg). The results for overall hypoglycemia were inconsistent, where 1 study showed no
difference between glargine and exenatide and the other showed significantly fewer episodes with exenatide. The
rate of nocturnal hypoglycemia was lower with exenatide in both studies. In a subgroup of patients receiving SU as
background therapy, the rate of hypoglycemia was similar with exenatide and glargine. The exenatide group
reported a greater incidence of adverse GI effects and had more patients dropping out of the studies (Heine et al.,
2005; Barnett et al., 2007).
In patients with inadequate glycemic control on combination metformin + SU, the addition of exenatide versus
biphasic insulin aspart was compared in a 52-week and 24-week trial. The 52-week study showed no significant
difference in reduction in HbA 1 c between the 2 agents (mean insulin dose 24.4U) and in overall incidence of
hypoglycemia; however, exenatide was associated with less nocturnal hypoglycemia (0.6 vs.1.1 events/patient-year).
On the contrary, the 24-week treat-to-target study found that reduction in HbA1c with biphasic insulin aspart was
superior compared to exenatide and had significantly greater rate of hypoglycemia. Both studies showed exenatide
use resulted in mean weight loss (2-2.5kg) whereas biphasic aspart insulin use resulted in mean weight gain (2.9-
4kg). The exenatide group reported a greater incidence of adverse GI effects and had more patients dropping out of
the studies (Bergenstal et al., 2009; Nauck et al., 2007a)
Triple oral therapy
The long-term safety and efficacy of three oral hypoglycemic agents is unknown. For patients who have not
achieved their glycemic goal on a 2-drug oral regimen, addition of once daily or bedtime insulin is preferred.
However, addition of a third oral agent could be considered for those who are not good candidates for insulin or
decline insulin use and the target HbA1c is within the efficacy range of the oral agent. (Dailey et al., 2004;
Hermansen et al., 2007; Roberts et al., 2005; Rosenstock et al., 2006b).
Four drug oral therapy
The efficacy and safety of such a combination is not known and should be strongly discouraged. Such a trial might
rarely be considered in patients with inadequate glycemic control on 3-drug therapy and are not good candidates for
the addition of insulin.
Combination with Insulin
The data seems to suggest that patients receiving combination treatment with oral hypoglycemic agents (OHAs) plus
insulin have significantly lower HbA1c levels when compared to those treated with insulin monotherapy. However,
studies in this area have several limitations: 1.Fasting plasma glucose values were not consistently assessed by most
of the studies; 2. Many of the studies had small sample sizes and/or were of low quality, and several were openlabeled;
and 3. Direct comparison between studies is hampered by the number of different drug combinations and
comparisons, and dosing and titration regimens.
A Cochrane review (Goudswaard et al., 2004) of randomized controlled trials assessing the effects of insulin
monotherapy versus insulin-OHA combinations therapy found that bedtime NPH insulin combined with oral
hypoglycemic agents provided comparable glycemic control to insulin monotherapy and was associated with less
weight gain if metformin is used.
• Insulin-OHA combination therapy had statistically significant benefits on glycemic control (mean
difference 0.3% (95% CI 0.0 to 0.6, p=0.03)) over insulin monotherapy only when the latter was applied as
a once-daily injection of NPH insulin
• Conversely, twice-daily insulin monotherapy (NPH or mixed insulin) provided superior glycemic control
(mean difference 0.4% (95% CI 0.1 to 0.8, p=0.03)) to insulin-OHA combination therapy regimens where
insulin was administered as a single morning injection.
• Regimens utilizing OHAs with bedtime NPH insulin provided comparable glycemic control to insulin
monotherapy (administered as twice or more daily injections).
• Overall, insulin-OHA combination therapy was associated with a 43% reduction in total daily insulin
requirement compared to insulin monotherapy.
Module G: Glycemic Control Page 59