The selection of an optimal agent for treatment of T2DM can pose a challenge given that many therapeutic options are effective in reducing HbA1c, an indicator of blood glucose control. However, not all therapies reduce HbA1c sufficiently to achieve therapeutic goals. The recent Standards in Medical Care in Diabetes from the ADA has outlined a set of target goals believed to favorably affect the health outcomes of patients with T2DM . The guidelines also suggest that individual preferences and comorbidities should be taken into consideration when choosing a therapy. Factors such as weight loss (or at least no weight gain) and the avoidance of hypoglycemia are important considerations. Indeed, in a patient survey conducted in patients with T2DM, more than half of the patients indicated that they would be willing to take an injectable once-weekly medication if the medication promoted weight loss or helped avoid weight gain . Hypertension and dyslipidemia are other major modifiable risk factors for CVD commonly associated with T2DM. As such, they contribute to the already increased risk of CVD. Beyond glycemic control, the improvement of such CV risk factors represents an added advantage to therapies providing such benefits.
Achievement of glycemic goals
This analysis compared the ability of exenatide QW vs metformin, sitagliptin, pioglitazone, or insulin glargine to assist patients in achieving ADA-recommended target goals. NNTs were calculated as a metric to assess how many patients would need to be treated with one therapy rather than another to allow one additional patient to reach a target. Compared to the other therapies examined, exenatide QW assisted a larger proportion of patients who were not already at HbA1c ≤6.5% or <7% at baseline in reaching the target goal after 26 weeks of treatment. The ABI for the goal of HbA1c ≤6.5% significantly favored exenatide QW over metformin, sitagliptin, pioglitazone, or insulin glargine in all studies except for DURATION-4 where the ABI for exenatide QW vs pioglitazone favored exenatide QW, but did not reach statistical significance. Contrary to the HbA1c goals, insulin was significantly favored over exenatide QW for the FBG goal. One reason for the discrepancy between the two glycemic endpoints is that the insulin was titrated according to a FBG target. Thus, the dosage of insulin glargine was raised until the FBG target was met, thereby contributing to bias. In addition, FBG is a short-term measure of blood glucose levels while HbA1c indirectly measures an average glucose concentration over a prolonged period of time. As insulin glargine is a titrated, long-acting basal insulin, it may function well to reduce fasting glucose levels but permit higher postprandial excursions leading to a larger average glucose concentration compared to the glucose-dependent activity of exenatide QW [32, 33].
The results of this analysis provide information to assist in personalization of therapy. The NNT for the HbA1c ≤6.5% goal was 8 when exenatide QW was compared to insulin glargine. However, for the alternate glycemic goal, FBG <6.99 mmol/L, the NNT was -8 for exenatide QW vs insulin glargine (favoring insulin glargine). This means that, in patients for whom FBG may be the more important clinical concern, treatment of 8 patients with insulin glargine rather than exenatide QW would allow one additional patient to reach a FBG goal. However, in patients wishing to achieve the HbA1c target (≤6.5%), 8 patients would need to be treated with exenatide QW rather than insulin to allow one additional patient to achieve the goal.
Control of cardiovascular risk factors
Although the main focus of treatment is a reduction in hyperglycemia, improved glycemic control is associated with weight gain and the risk of hypoglycemia for some medications, and these CV risk factors also reduce patients’ quality of life. Unlike medications that promote weight gain or increase the risk of hypoglycemia, GLP-1 receptor agonists are generally associated with weight loss and minimal risk of hypoglycemia. In the current analysis, examination of the weight and hypoglycemia effects of exenatide QW was assessed as a composite goal of HbA1c <7% with no weight gain and no hypoglycemia. Exenatide QW provided a significant ABI for achieving this composite goal compared to sitagliptin, pioglitazone, and insulin glargine, with NNTs as low as 3 (vs pioglitazone and insulin glargine). Across the three studies, exenatide QW assisted between 47 and 48% of patients who were not already at this composite goal in achieving the goal after 26 weeks. The comparators assisted between 10% (pioglitazone) and 48% (metformin) of patients in achieving this goal. These data are consistent with an analysis pooling 804 patients treated with exenatide QW during the DURATION trials, where 50% of patients treated with exenatide QW achieved the goal of HbA1c <7% with no weight gain and no hypoglycemia after 24-30 weeks . A recent meta-analysis study similarly showed that 1.8 mg liraglutide once daily assisted 40% of patients in achieving the goal of HbA1c <7% with no weight gain and no hypoglycemia . The meta-analysis additionally showed that the twice-daily formulation of exenatide assisted 25% of patients in achieving the composite goal, which was a higher percentage than sulfonylureas (8%), thiazolidinediones (6%), insulin glargine (15%), sitagliptin (11%), and placebo (8%) .
The magnitudes of the NNT values obtained for some goals reflect key differences between therapies. To put NNT values into better perspective, an NNT of 1 would mean that every patient treated would reach the specified goal. The significant NNTs for the composite goal of HbA1c <7% with no weight gain and no hypoglycemia ranged from 3 when exenatide QW was compared to insulin glargine and pioglitazone (in DURATION-2) to 8 when exenatide QW was compared to sitagliptin in DURATION-4. However, an NNT of 250 was observed for exenatide QW compared to metformin suggesting no greater benefit of either treatment in achieving this composite goal. As commonly used, an NNT of 20 or less is generally sufficient to justify the choice of a clinical intervention in the absence of a more significant clinical harm [30, 36].
A second composite goal, based on findings from the Steno-2 study, highlighted the importance of HbA1c, blood pressure, and lipids in the reduction of CV risk in patients with T2DM . The Steno-2 study identified the benefits of a multifactorial intervention strategy by demonstrating an approximately 50% reduction in risk of CV and microvascular events by targeting multiple risk factors with intensified treatment . Despite the importance of such a multi-targeted therapeutic approach, the NHANES analysis reported that between 1999 and 2004, only 13% of surveyed diabetes patients achieved a composite goal of HbA1c <7.0%, blood pressure <130/80 mm Hg, and total cholesterol <5.17 mmol/L (<200 mg/dL) . The current analysis used the individual ADA-suggested goals to define a composite goal of HbA1c <7%, SBP <130 mm Hg, and LDL <2.59 mmol/L (<100 mg/dL). The results showed that across the three studies, between 23% and 15% of patients who were not already at the goal at baseline reached the composite goal using exenatide QW, slightly more than observed in the NHANES report. Comparators assisted between 15% (pioglitazone, DURATION-2) and 5% (sitagliptin, DURATION-4) of patients in reaching the composite goal which is in line with NHANES estimates for this composite. The ABI for this goal significantly favored exenatide QW compared to sitagliptin or insulin glargine with NNTs of 10 and 14, respectively.
Limitations and additional studies
Limitations of the current analysis include its retrospective, post hoc design and the small sample size. Common NNT analyses generally examine larger populations over a longer time period to observe a particular rare but clinically important outcome in a significant number of patients [28, 38, 39]. A study of the attainment of therapeutic goals and ABI calculations in a large, real-world population would be a useful follow-up to this study. Since exenatide QW was approved in 2011 in Europe and in 2012 in the United States, substantive real-world data are not yet available. Furthermore, the second composite goal (HbA1c <7%, SBP <130 mm Hg, and LDL <2.59 mmol/L) focused on a single lipid parameter, whereas other lipid parameters (eg, triglycerides, high-density lipoprotein cholesterol, lipoprotein subfractions) and endothelial function also influence CV risk and have been shown to be affected by treatment with exenatide QW, but evaluation of these variables were beyond the scope of the current investigation [40–42]. In addition, NNTs were calculated in the absence of a number needed to harm as the common adverse events associated with each of the therapies examined here were therapy-specific.
The current analysis comparing glucose-lowering therapies does not take into account differential cost or convenience factors; nor does it consider patient or physician perception of the different routes of administration. In addition, although the composite goals examined provide a clinically relevant combination of treatment targets, a single component of the composite could drive the result. For example, pioglitazone and insulin glargine are often associated with weight gain and therefore would not be favored in achieving composite goals containing a weight neutral component. Likewise, since insulin glargine is a glucose-independent, titrated medication, there is a greater risk for hypoglycemia which would lead to an unfavorable comparison with a glucose-dependent therapy (such as exenatide QW) in a composite goal including no hypoglycemia.
Although surrogate endpoints are not typically used in NNT assessments, the ability to achieve therapeutic goals is clinically important and relevant for short-term treatment decisions. Indeed, in a recent 1-year study with liraglutide, the NNT to achieve a loss of 10% of total body weight was calculated as 2 with liraglutide compared to 7 for placebo . While the NNTs calculated in the current analysis reflect the attainment of a glycemic goal over a relatively short period of time (26 weeks), data has suggested that early intensive glucose control, even for a short period of time, might have a significant effect on CV events later in life, the so called legacy effect [44–46]. The ongoing EXSCEL (Exenatide Study of Cardiovascular Event Lowering, clinical trial number NCT01144338) trial will measure the time to the first confirmed CV event. In addition, the results of the trial are expected to further clarify the ability of exenatide QW to assist patients in reaching ADA-recommended goals and examine the presumption that reaching these goals correlates with a reduction of CV risk.