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Norris SL, Lee NJ, Severance S, et al. Drug Class Review: Newer Drugs for the Treatment of Diabetes Mellitus: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2008 Aug.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Results

Pramlintide

We identified 134 citations from our literature search (Figure 1). Six randomized controlled trials (with 1 companion paper) and 4 pooled analyses fulfilled inclusion criteria. No comparative cohort or case-control studies reporting long-term benefits or harms were identified. Details of included studies are found in Evidence Tables 13 and quality assessment in Evidence Table 4. Trials excluded upon review of the full text are listed in Appendix D. In the FDA Medical and Statistical Reviews, 6 relevant trials were identified, of which 4 were published and already included in our review. The remaining two trials could not be found in the published literature. No good quality systematic reviews of pramlintide were identified for inclusion.

Figure 1

Figure 1

Literature search results for pramlintide

Summary of Evidence for Pramlintide

Key Question 1. For children and adults with type 1 or type 2 diabetes, does pramlintide differ in efficacy, effectiveness, and in harms for achieving glycemic control when added to prandial insulin compared to conventional insulin therapy?

Type 1 diabetes
Evidence in children
  • No data on children were reported, although children were eligible for study enrollment in 2 included trials.
Long-term health outcomes and adverse events
  • No studies evaluated long-term health outcomes or adverse events and none were longer than 52 weeks in duration.
Efficacy and harms
  • A1c was either slightly improved or no different with the addition of pramlintide 30 or 60 mcg/meal to a flexible-dose insulin regimen compared with placebo plus flexible-dose insulin regimen over 29 weeks13 (between-group difference: 0.0%) and 52 weeks14 (between-group difference: 0.27%, P-value, not reported) of treatment.
  • When pramlintide 60 mcg 3 or 4 times a day was added to fixed-dose insulin therapy, A1c decreased from baseline by 0.29% to 0.34% (P<0.01), with no significant effect in the placebo group 0.04% at 52 weeks of follow-up.15
  • Patients randomized to receive pramlintide in addition to insulin lost slightly more weight from baseline (range: −0.4 to −1.3 kg) than compared with those receiving placebo plus insulin in a fixed- or flexible-dose setting, who experienced slight weight gain (range: +0.8 to +1.2 kg) over 29 and 52 weeks.
  • Groups receiving pramlintide in addition to fixed- or flexible-dose insulin therapy exhibited larger overall rates of withdrawal (range across studies: 20–42% compared with 10–33%) and withdrawals due to adverse events (range across studies: 5–20% compared with 2–8%) than groups receiving placebo plus insulin.
  • Adverse events including nausea, vomiting, anorexia, and reduced appetite were more commonly reported with the use of pramlintide plus insulin than with placebo plus insulin.
  • Severe hypoglycemia occurred more frequently with pramlintide plus insulin during the first 4 weeks of treatment compared with placebo plus insulin. Rates of severe hypoglycemia declined once pramlintide doses stabilized but continued to remain slightly higher than with placebo plus insulin at up to 52 weeks of follow-up.
Type 2 diabetes
Evidence in children
  • Children and adolescents ≤18 years were not included in any of the published studies on effectiveness, efficacy, or harms.
Long-term health outcomes and adverse events
  • No studies evaluated long-term health outcomes or adverse events and none were longer than 52 weeks in duration.
Efficacy and harms
  • Pramlintide 90 mcg or 120 mcg added to fixed- or stable doses of insulin decreased A1c by 0.13% to 0.4% and weight by 1.1 kg to 1.85 kg (placebo-corrected differences) at 52 weeks compared with placebo and insulin.16, 17
  • At 16 weeks the addition of pramlintide to glargine (without prandial insulin) reduced A1c by 0.34% and weight by 2.3 kg (placebo-corrected differences) relative to placebo plus glargine in a flexible-dose setting.18
  • Both pramlintide- and placebo-treated subjects exhibited similar rates of withdrawal and withdrawal due to adverse events.
  • The most commonly reported adverse event was nausea, which occurred more frequently with pramlintide plus insulin than with placebo plus insulin especially during the first 4 weeks of treatment and declined thereafter.
  • Severe hypoglycemia occurred more frequently with pramlintide 150 mcg 3 times a day added to insulin than with insulin plus placebo during the first 4 weeks of treatment. Rates of hypoglycemia after 4 weeks were similar among treatment groups.

Detailed Assessment of Pramlintide in Type 1 Diabetes

Key Question 1. For children and adults with type 1 diabetes, does pramlintide differ in efficacy, effectiveness, or harms in achieving glycemic control when added to prandial insulin compared with conventional insulin therapy?

Details of the three included placebo-controlled trials are presented in Table 3 and glycemic control results are presented in Table 4. None of these trials were similar enough for efficacy data to be pooled. This section reports key details of individual studies.

Table 3

Table 3

Characteristics of pramlintide placebo-controlled trials in adults with type 1 diabetes

Table 4

Table 4

Pramlintide in type 1 diabetes

Flexible-dose insulin

In a fair-quality trial the addition of pramlintide 30 mcg or 60 mcg 3 or 4 times a day with meals to a flexible-dose insulin regimen did not significantly improve A1c (−0.5% vs. −0.5%; Table 4). The comparison group was patients receiving a combination of short- and long-acting insulin plus placebo adjusted to achieve specified glycemic targets over 29 weeks.13 According to the study investigators, a greater percentage of pramlintide-treated patients who self-monitored blood glucose concentrations achieved post-prandial glucoses below the American Diabetes Association targets for all three meals compared with those on insulin plus placebo (breakfast: 68% compared with 51%; lunch: 71% compared with 61%; dinner: 70% compared with 58%, P<0.0001 for each meal compared with placebo). Pramlintide-treated patients lost slightly more weight than insulin-only patients (−1.3 kg compared with +1.2 kg). Pramlintide-treated patients also exhibited slightly larger reductions in total daily insulin doses (−12% of total daily dose from baseline) than patients using insulin plus placebo (+1% of total daily dose from baseline) by the end of 29 weeks. In the initial 4 weeks of treatment however, more pramlintide-treated patients decreased their prandial insulin doses than compared with patients on insulin plus placebo (−28% of prandial insulin dose vs. −8% of prandial insulin dose). During the remainder of the trial, patients in both treatment arms required dose increases to their basal insulin regimen (pramlintide, +3% of basal insulin dose vs. placebo, +10% of basal insulin dose).

All patients received stable doses (±10% change from baseline) of intensive insulin therapy using multiple daily injections or continuous insulin infusion before enrolling in the study. Patients were mainly middle-aged and white and had long-standing type 1 diabetes. Mean baseline A1c was 8.1%. A 30%–50% reduction in mealtime insulin was recommended before starting pramlintide to avoid hypoglycemic events.

A patient survey examined whether subjects in this study believed that pramlintide added to insulin provided marked benefits compared with placebo plus insulin.19 A significantly greater proportion of subjects receiving pramlintide believed their study medication provided them with more control over their blood sugar, weight, appetite, and ability to function than compared with those in the insulin plus placebo arm. However, more pramlintide-treated patients believed their study medication “had side effects that would keep me from using it on a long-term basis” relative to those randomized to the placebo plus insulin arm.

The authors of this study stratified the results by insulin delivery method (multiple injections or continuous infusion). Patients using placebo plus continuously infused insulin were more likely to have lower satisfaction than patients on pramlintide plus insulin delivered by either modality. Because baseline treatment satisfaction data were not presented, this study could not be used to determine whether significant changes in satisfaction occurred over the duration of the study. Also, the study does not explicitly state that patients participating in the survey remained blinded during the entire survey period.

In a second trial using flexible insulin dosing,14 the addition of pramlintide 30 mcg or 60 mcg 4 times a day to insulin with each meal was slightly more effective than insulin plus placebo in lowering A1c, weight, and total insulin requirement (Table 4). The change in A1c at week 52 was −0.39% with pramlintide plus insulin and −0.12% with insulin plus placebo (between-group difference: 0.27%, P-value, not reported). During the course of the trial, patients from both treatment groups required increases in their total daily insulin dose. The percent change in insulin dose adjustment were statistically significant between pramlintide-treated and insulin plus placebo-treated patients at the end of 52 weeks (+2.3% compared with +10.3%, P=0.018); however, the clinical significance of the between-group difference is yet to be determined. A higher proportion of pramlintide-treated patients achieved an A1c of <7% “at any time” at the end of the trial.

This trial was rated fair-poor quality: only 71% of patients completed the 52 weeks of therapy and data from only completers were examined. The total withdrawal rates of 28–29% were similar between the treatments, however, more pramlintide-treated patients discontinued due to adverse events than placebo-treated patients during the study (12.8% compared with 8.0%). Nausea was the most common reason for withdrawal. In addition, the authors reported no further details on insulin dose adjustments than that they were made according to “good medical practices.”

Stable insulin dosing

The addition of pramlintide 60 mcg 3 or 4 times a day with meals to fixed or stable background insulin therapy improved A1c by 0.25% and 0.34% compared with 0.04% improvement in the insulin plus placebo group over 52 weeks of therapy.15 A greater proportion of pramlintide-treated patients achieved the A1c goal of <7% at “any time” and exhibited small decline in total daily insulin doses over the study duration (3–6% decrease in total daily dose of insulin from baseline compared with 0% change). Pramlintide-treated subjects also demonstrated nominal weight loss from baseline (−0.5 kg at 52 weeks, P<0.05), which was not seen with placebo (+0.8 kg at 52 weeks, P>0.05). This trial was rated fair-poor quality because of high withdrawal rates (>35% in all treatment arms), however a greater proportion of pramlintide-treated patients discontinued due to adverse events (primarily nausea) compared with those in the placebo plus insulin arm (14–20% compared with 3% for adverse events).

This trial began with a 90 mcg dose arm, which was removed from efficacy analysis when another trial (identified as study #137–117 in FDA reviews) revealed an adverse tolerability profile associated with this 90 mcg dose. Specific reasons for “intolerability” with the 90 mcg dose could not be found in either study #137–117 in the FDA documents or from this trial by Ratner and colleagues. Only general sweeping statements were made by Ratner and colleagues: there was 2-fold increase in nausea, vomiting, anorexia and 4-fold increase in severe hypoglycemia event rates associated with pramlintide across the doses compared with placebo. Study #137–117 could not be found in a peer-reviewed publication.

Harms

Patients receiving pramlintide in addition to insulin had greater rates of withdrawal due to all causes and withdrawal due to adverse events than patients receiving placebo plus insulin. This was found with both fixed- and flexible-dose insulin (see Evidence Table 3). No included trial reported deaths or listed rare adverse events. There were no significant cardiac, hepatic, renal, or drug-related idiosyncratic adverse events observed in any treatment arm. Adverse events reported in the included studies are summarized in Table 5.

Table 5

Table 5

Adverse events with pramlintide in type 1 diabetes

Hypoglycemia

During the first 4 weeks of treatment severe hypoglycemia occurred more frequently with pramlintide plus insulin than with insulin plus placebo, with both fixed and flexible insulin regimens. The rate of severe hypoglycemia declined once pramlintide doses were stabilized and not being titrated; however, at weeks 26–5214, 15 and weeks 0–2913 the rate of severe hypoglycemia associated with pramlintide was still slightly higher than placebo (event rates 0.42 to 1.10 compared with 0.30 to 0.52) (Table 5). Only 1 trial13 reported that a 30–50% reduction in prandial insulin was allowed before the use of pramlintide. Even in this study, pramlintide-treated patients exhibited slightly higher rates of severe hypoglycemia than compared with insulin plus placebo-treated patients (Table 5). No trials reported the overall incidence of mild to moderate hypoglycemic episodes. All 3 trials predefined the term “severe hypoglycemia” to mean: those requiring either assistance of another person, the administration of glucagon, or the administration of intravenous glucose.

Nausea and vomiting

A significant proportion of pramlintide-treated patients experienced nausea during the trials: Across trials overall rates of nausea for pramlintide groups ranged from 46% to 95%; for placebo groups, 12% to 36%. Specifically, patients who did not tolerate pramlintide 60 mcg also frequently experienced nausea with the 30 mcg dose, and the highest reported rates of nausea (95%) were in subjects who received 30 mcg 3 times a day.13 Higher rates of nausea were reported with pramlintide 90 mcg 3 times a day15 than with lower dosages in the same trial.

Severe nausea was much less common than nausea overall, ranging between 5.8% and 8.5% for pramlintide plus insulin and 0.7% to 1.7% for placebo plus insulin across studies.13–15

More than 10% of patients randomized to pramlintide plus insulin experienced vomiting, compared with rates of up to 8.0% with placebo plus insulin. Severe vomiting occurred in up to 2% of patients taking pramlintide compared with 0.4% to 0.7% taking placebo.13–15

Of note, 2 of 3 placebo-controlled trials 14, 15 reported that most cases of nausea and vomiting tended to occur within 2–4 weeks of treatment but no actual data were provided to verify these statements.

Anorexia or reduced appetite

Rate of anorexia was significantly more frequent with pramlintide plus insulin (11%–18% across trials) than with placebo plus insulin (approximately 2%). Severe anorexia occurred in <2% of pramlintide patients and no placebo patients.14,15

Other adverse events

One trial reported sinusitis at a rate of 14.0% with pramlintide and 8.8% with placebo (P>0.05).13 Two non-comparative observational studies20, 21 were also evaluated for rare adverse events and neither reported any additional information.

Key Question 3. Are there subgroups of patients with type 1 diabetes for which pramlintide is more or less suitable than other hypoglycemic agents?

There was insufficient evidence to perform subgroup analyses based on age, sex, race, ethnicity, or baseline A1c in individual studies.

One randomized controlled trial conducted subgroup analyses that were not all prespecified, and one post hoc pooled-analyses was identified.15, 22 Results from these hypothesis-generating analyses should be used with caution. Further prospective research with larger sample sizes will need to be conducted to verify these findings.

Total daily insulin dose

No studies conducted subgroup analysis evaluating whether pramlintide exhibited differential effects depending on total daily insulin dose.

Stable insulin dose

A1c outcomes were reported for a subgroup with stable insulin dosing (± 10% change in total insulin dose from baseline over 52 weeks).15 Change in A1c was −0.59% with pramlintide 60 mcg 3 times a day and −0.57% with dosing 4 times a day. These reductions were significantly larger than those noted in the entire study group of −0.29 to −0.34%; however, generalizability of using fixed doses of insulin is limited in clinical practice.

Baseline body mass index

Pramlintide appeared to inhibit weight gain in patients with baseline body mass index ≤23 kg/m2 while producing mild weight loss for patients with body mass index > 23 kg/m2 (baseline to week 26).15 Data at 52-week follow-up were not reported.

Baseline A1c < 8%

Data from 3 studies that included patients with baseline A1c between 7% and 8.5% receiving pramlintide 30 mcg or 60 mcg were pooled and reported in a separate publication.22 Two of the 3 studies were identified and included in our review.14, 15 The third study was in abstract form and was excluded. The pooled publication reported results up to 26 weeks. In this subgroup, the pooled change in A1c was −0.3% and the change in weight was −1.6 kg (both placebo-corrected; both P<0.0009). There was no overall increased risk in hypoglycemia. The improvement in A1c in this pooled subgroup analysis was similar to the change in A1c noted for all subjects (across a range of A1c) in the original studies. Thus, it appears that patients with good but not optimal baseline A1c of 7%–8.5% experienced similar degrees of A1c reduction as the populations included in the original trials, with no increased risk of hypoglycemia at 26 weeks.

Applicability to general populations with type 1 diabetes

The methods for recruiting study subjects were not reported in these trials, and subjects likely represent a highly selected population: Primarily white, middle-aged men and women with mean baseline A1c ranging from 8.1% to 9.0% and diabetes of 16 to 21 years duration. None of the patients had significant cardiovascular or renal disease or problems with gastrointestinal motility. Data regarding baseline comorbidities, disease severity, and existing microvascular disease such as retinopathy or neuropathy were not reported. The population included highly motivated subjects who were willing to add 2 to 4 injections to their daily regimen and who rigorously self-monitored blood glucose over the course of the study. Study settings were not reported, but they were likely to have been outpatient clinics.

Detailed Assessment of Pramlintide in Type 2 Diabetes

Key Question 2. For children and adults with type 2 diabetes, does pramlintide differ in efficacy, effectiveness, or harms in achieving glycemic control when added to prandial insulin compared with conventional insulin therapy?

Details of the three included placebo-controlled trials are presented in Table 6 and glycemic results in Table 7. None of the trials were pooled due to significant heterogeneity.

Table 6

Table 6

Characteristics of pramlintide placebo-controlled trials in adults with type 2 diabetes

Table 7

Table 7

Effect of pramlintide in type 2 diabetes

Dose-ranging study

The addition of pramlintide 75 mcg/meal or 150 mcg/meal to fixed-dose insulin, with or without oral hypoglycemic agents (metformin or sulfonylureas), improved A1c by 0.3% to 0.4% and weight loss by 1.5 to 2.4 kg (placebo-corrected values)17 in a population with poorly controlled (A1c 9.0–9.3%) type 2 diabetes over 52 weeks. No significant differences in A1c were observed between two pramlintide doses at the end of the trial: pramlintide 75 mcg (−0.5%) vs. 150 mcg (−0.6%). The largest reductions in A1c (almost 1%) occurred early on at week 13 for those on the 150 mcg dose. A greater percentage of patients taking pramlintide achieved an A1c goal of <7% at “any time” during the study than compared with patients taking placebo (Table 7). Both placebo- and pramlintide-treated patients required increases in their total daily insulin doses during the 52 weeks (change in total daily dose from baseline for pramlintide compared with placebo: pramlintide: +8 to +11% vs. placebo: +15%, P-value, not reported).

This trial was rated fair-poor quality based on a high withdrawal rate (~30%) which were similar for placebo, pramlintide 30 mcg and 75 mcg groups. Those randomized to pramlintide 150 mcg dose exhibited largest rates of total withdrawal and withdrawal due to adverse events (37.5% and 18%).

Stable insulin dosing

During the course of this one fair-quality trial,16 results from another study (identified as study #137-123 in the FDA reviews) found that pramlintide 60 mcg was less effective than compared with higher doses. As a result, efficacy and safety information from the 60 mcg arm were excluded from this trial, though safety results should have been reported.

The addition of pramlintide 90 mcg or 120 mcg to fixed or stable doses of insulin with or without oral hypoglycemic agents (metformin or sulfonylureas) gave slightly larger improvements in A1c and weight at 52 weeks than patients randomized to placebo plus fixed-dose insulin (placebo-corrected values for A1c: 90 mcg: −0.13%, 120 mcg: −0.4% and for weight: 90 mcg: −1.1 kg; 120 mcg: −1.85 kg).16 Effect on A1c was greatest at 26 weeks for both pramlintide groups (P<0.05 compared with placebo) and persisted only with the 120 mcg arm at 52 weeks (change in A1c from baseline −0.62%, P<0.05). No dose adjustments of baseline insulin or oral hyperglycemic agents were implemented during the study and no specific glycemic targets were reported. Approximately 20–27% of all randomized patients were taking oral hypoglycemic agents at baseline.

Flexible basal insulin dosing

In contrast to the previous study, this short-term fair-quality trial 18 evaluated pramlintide as a pre-meal medication in conjunction with glargine (without prandial insulin) with or without oral hypoglycemic agents (metformin, sulfonylureas, and/or thiazolidinediones). The comparison group was patients on flexible-dose glargine plus placebo. At 16 weeks, the addition of pramlintide to glargine reduced A1c by 0.36% and induced weight loss of 2.3 kg (placebo-corrected values) relative to placebo plus glargine. Pramlintide-treated patients also exhibited larger reductions in post-prandial glucose (change from baseline: −24.4 mg/dL ± 3.6 mg/dL compared with −0.4 mg/dL ± 3.0 mg/dL, P<0.0001). There were no significant differences between pramlintide-treated and placebo-treated groups for those achieving A1c <7% (54% compared with 45%) and no significant differences in changes in total daily insulin dose (change from baseline: +11.7 units compared with +13.1 units) following 16 weeks of treatment.

Glargine, a basal insulin without pronounced peak effects, was allowed to be adjusted during the study to achieve prespecified fasting glucose targets once pramlintide doses were stabilized. Patients had diabetes of 10 to 11 years’ duration. At baseline A1c was moderately elevated at 8.5%, and patients were using insulin glargine 48 to 54 units per day, with 50% of patients concomitantly taking ≥ 2 oral hypoglycemic agents and 89% taking at least 1 oral agent.

Harms

Pramlintide-plus-insulin and placebo-plus-insulin groups had similar rates of withdrawal due to all causes and withdrawal due to adverse events (see Evidence Table 3). There was no evidence of cardiac, hepatic, renal, or drug-related idiosyncratic adverse events in patients in any treatment arm of the three randomized controlled trials identified for this review and no deaths were reported. Adverse effects are summarized in Table 8.

Table 8

Table 8

Adverse effects reported with pramlintide

Hypoglycemia

Pramlintide-plus-insulin and placebo-plus-insulin groups experienced similar rates of mild-to-moderate hypoglycemia,17, 18 but pramlintide-treated patients experienced more episodes of severe hypoglycemia. Severe hypoglycemia occurred most with pramlintide 120 mcg during the first 4 weeks of therapy (0.9 events/patient-year compared with 0.3 events/patient-year with placebo).16 The incidence of severe symptoms declined with continued use of pramlintide, and rates were similar to placebo for weeks 4–26 and 26–52.16 All 3 trials predefined the term “severe hypoglycemia” to mean: those requiring either assistance of another person, the administration of glucagon, or the administration of intravenous glucose.

Nausea

The incidence of mild-to-moderate and severe nausea was significantly higher with pramlintide 75, 90, 120, and 150 mcg than with placebo plus insulin. Only 1 trial reported data showing that most events occurred within the first 4 weeks of treatment.16 When metformin use was stratified in one trial, its addition to pramlintide plus insulin appeared to have no significant effect on nausea compared with the larger study population.16 These trials did not report vomiting or anorexia.

Headache

Higher rates of headache were reported with pramlintide (15% and 17%) than with placebo (8%).16 In another trial17 rate of headache was similar among treatment groups, ranging from 13.2% in the placebo-plus-insulin group to 19.1% with pramlintide 75 mcg 3 times a day plus insulin. None of the studies provided enough information to determine whether there were any correlations between the incidence of headaches and hypoglycemic events.

Other adverse events

No trials reported any treatment-emergent adverse events occurring with a frequency of more than 2%–5%. Overall adverse events occurring with a frequency of ≥ 10% with a minimum 5 percentage point difference between pramlintide- and placebo-treated patients comprised sinusitis, retinal disorder, inflicted injury, and injection site reactions (Table 8).16, 17

Higher incidence of retinal disorder was reported with pramlintide 150 mcg than with lower pramlintide doses and placebo.17 The authors performed detailed medical reviews of these patients with reported retinal disorder and concluded that the increased incidence was likely attributable to preexisting conditions that were not documented at the time of screening.

Key Question 3. Are there subgroups of patients with type 2 diabetes for which pramlintide is more or less suitable than other hypoglycemic agents?

Age, sex, total daily insulin dose, and prior use of oral hypoglycemic agents

None of the randomized controlled trials conducted subgroup analyses evaluating whether pramlintide had differential effects in these populations.

Race and ethnicity

A post hoc analysis23 of two 52-week trials16, 17 pooled subjects of various ethnic groups. Black and Hispanic patients tended to have higher baseline A1c (9.2%–9.7%) than white patients (8.9%–9.1%). Pramlintide produced larger reductions in A1c and weight from baseline in black patients (0.7%, 4.1 kg) than white patients (0.5%, 2.4 kg) and Hispanic patients (0.3%, 2.3 kg). Changes in total daily insulin requirement and baseline oral hyperglycemic use were not different among the different races and ethnicities.

Nausea and weight loss and effects of weight on A1c

Weight loss experienced with pramlintide 90 or 120 mcg appeared to be independent of nausea, as weight loss was similar in patients never experiencing nausea (90 or 150 mcg, −1.1 to −1.5 kg) and patients experiencing nausea at anytime (90 or 150 mcg, −0.3 to −2.0 kg).16 In addition, improvements in A1c observed with pramlintide appeared to be independent of weight lost or gained during the trial (subjects who gained weight, change in A1c −0.29% to −0.53%; subjects who lost weight, change in A1c −0.22% to −0.58%).

A pooled analysis24 of overweight and obese patients also evaluated whether weight loss associated with pramlintide 120 mcg was influenced by nausea. Like the other, this post hoc subgroup analysis suggested that weight loss was independent of nausea (change in weight in group reporting “never nausea,” −1.3 kg; “nausea at anytime,” −1.9 kg). None of the studies explored to see if there were any correlations between anorexia and weight loss.

Overweight and obese patients

A post hoc analysis24 pooled data from two randomized controlled trials comparing pramlintide 120 mcg with placebo when both were added to insulin. At 26-week follow-up overweight and obese (body mass index > 25 kg/m2) patients receiving pramlintide showed greater reductions in A1c and weight than similar patients receiving placebo. Approximately 2% of overweight and obese patients on pramlintide plus insulin achieved weight loss of ≥ 10% change from baseline compared with 0% in those on placebo plus insulin. Markedly obese patients (baseline body mass index 35–40 kg/m2 and >40 kg/m2) had the greatest weight loss (−2.4 kg and −3.2 kg, respectively).

Baseline A1c

When patients were stratified by baseline A1c,18 at 16 weeks patients with baseline A1c > 8.5% who received pramlintide plus insulin glargine showed larger improvements in A1c, fasting plasma glucose, and postprandial glucose than patients receiving placebo plus glargine (pramlintide change in A1c −1.19%, fasting plasma glucose −44.4 mg/dL, postprandial glucose −23 mg/dL, and weight −1.0 kg compared with placebo plus glargine A1c −0.69%, fasting plasma glucose −18.4 mg/dL, postprandial glucose +3.2 mg/dL, weight +1.1 kg). Among subjects with lower baseline A1c (≤8.5%), improvements in A1c (−0.36%) and weight (−2.0 kg) were also larger in pramlintide-treated patients than those who took placebo plus glargine. Overall, reductions in A1c were greatest in those with baseline A1c >8.5%.

Another post hoc analysis25 pooled data from two trials at 26-week follow-up and examined patients with baseline A1c of 7.0% to 8.5%. Pramlintide plus insulin was better than placebo plus insulin for A1c (placebo-corrected change in A1c −0.43, P<0.0009) and weight (placebo-corrected change in weight −2.0 kg, P<0.0003).

Applicability to general populations with type 2 diabetes

No included trial evaluated the effects of pramlintide in patients whose type 2 diabetes was inadequately managed on combination prandial and basal insulin therapy with or without oral agents. Two studies evaluated pramlintide in patients using fixed-dose insulin. One trial used flexible dosing for insulin glargine only. Hence, results have limited applicability to the broader population using more commonly prescribed insulin regimens.

FDA-approved dosage of pramlintide for type 2 diabetes includes initial therapy of 60 mcg/meal and maintenance therapy of 120 mcg/meal. Only 2 trials examined the 120 mcg dosage.16, 18 The third included trial was a dose-ranging study that did not use a 120 mcg dose but did include a 75 mcg dose which may be used in clinical practice.17

Overall, patients included in these 3 trials represent a highly selected population: mainly white, middle-aged men and women with mean baseline A1c between 8.5% and 9.3% and diabetes of 11–13 years’ duration. None of the patients had significant pulmonary, cardiovascular, renal, neurologic, or hematologic diseases or problems with gastrointestinal motility. The study populations probably included highly motivated subjects who desired to achieve optimal glycemic control through the additional 2–4 injections added to their usual regimens of insulin and oral hypoglycemic agent over 16–52 weeks of participation in a trial. Study setting also was not reported in any of the included trials; subjects likely were evaluated in outpatient clinics.

Table 9

Summary evidence table

Type 1 Diabetes
Type 1 DiabetesQuality of evidenceConclusion
Key Question 1. For children and adults with type 1 diabetes, does pramlintide differ in efficacy, effectiveness, and in harms for achieving glycemic control when added to prandial insulin compared to conventional insulin therapy?Evidence in children is lacking.
EffectivenessNo available data-Data are insufficient to determine long- term effectiveness of pramlintide.
-No studies assessed long-term health outcomes and none were >52 weeks in duration.
EfficacyPramlintide with titratable insulin (flexible schedule)-Fair, 2 RCTs




Pramlintide with fixed or stable doses of insulin
-Fair-Poor, 1 RCT (relevance: Low)
Pramlintide with titratable insulin-Evidence on FPG and time to treatment failure is lacking.
-One trial showed no significant differences in A1c lowering between those receiving pramlintide+insulin and placebo+insulin (in a setting where insulin was titrated to achieve prespecified glycemic targets) at the end of 29 weeks.
-In contrast, one trial showed a small improvement in A1c by 0.27% (placebo- corrected) with pramlintide + insulin compared with placebo + insulin over 52 weeks.
-Two trials showed small reductions in total daily insulin dose with those on pramlintide+insulin than compared with those on placebo+insulin (range: 3–12% decrease compared with 0–1% increase). Clinical significance is yet to be determined.
-Pramlintide-treated subjects showed more weight loss than insulin-treated subjects, but this was not clinically significant (range: −0.4 kg to −1.3 kg compared with +0.8 kg to + 1.2 kg) at 29 or 52 weeks.

Pramlintide with fixed or stable insulin
-Pramlintide produced small reductions in A1c (placebo-corrected: 0.21% to 0.30%) and weight (−1.3 kg) compared with a fixed doses of placebo plus insulin over 52 weeks.
Harms-Fair-PoorFor both groups:-Studies beyond 52 weeks in duration evaluating harms are lacking.
-More pramlintide-treated patients withdrew due to adverse effects than insulin-treated patients (5–20% compared with 2–8%).
-In general, adjunctive therapy with pramlintide was associated with higher rates of severe hypoglycemia during the initial 4 weeks than insulin alone (event rate: 0.46 to 3.78 compared with 0.42 to 1.04). In one trial where patients were allowed to decrease prandial insulin by 30–50%, rates of severe hypoglycemia were still slightly higher for those on pramlintide+insulin than compared with those receiving placebo+insulin.
-There was significantly greater incidence of nausea, vomiting, and anorexia associated with pramlintide therapy than insulin therapy. Two trials mentioned that most of these events occurred within 4 weeks of therapy, however, no actual data were available to verify the statement.
Key Question 2. Are there subgroups of patients for which pramlintide is more or less suitable than other hypoglycemic agents?-Poor (post hoc analyses and selective outcome reporting)-No subgroup analyses were conducted on age, sex, race, or total daily insulin usage.
-One study showed patients with baseline A1c<8% exhibited similar reductions in A1c than the total population.
-One study showed the use of pramlintide prevented weight gain in normal weight populations (BMI< 23 kg/m2) and assisted weight loss in overweight and obese patients (BMI >23 kg/m2).
Type 2 Diabetes
Type 2 DiabetesQuality of evidenceConclusions
Key Question 1. For children and adults with type 2 diabetes, does pramlintide differ in efficacy, effectiveness, and in harms for achieving glycemic control when added to prandial insulin compared to conventional insulin therapy?No evidence in children.
EffectivenessNo available data-Data were insufficient to determine long-term effectiveness of pramlintide.
-No studies assessed long-term health outcomes and none were >52 weeks in duration.
EfficacyPramlintide added to titratable doses of insulin glargine with or without oral agents-Fair, 1 RCT




Added to fixed or stable doses of insulin with or without oral agents
-Fair-Poor, 2 RCTs (relevance: Low)
-Evidence on FPG and time to treatment failure was lacking.
Added to titratable insulin glargine with or without oral agents)
-Addition of pramlintide to a glargine-only regimen lowered A1c by 0.36% (placebo-corrected values) more than those receiving placebo+glargine over 16 weeks.
-Small weight loss was observed with pramlintide, while minimal weight gain was seen with glargine. The results were not clinically significant (−1.6 kg compared with +0.7 kg) over 16 weeks.
-Patients in both treatment groups required dose increases to their insulin regiments. There was no significant differences between the groups at the end of 16 weeks (change from baseline: +11.7 units compared with +13.1 units).

Added to fixed or stable doses of insulin with or without oral agents
- Pramlintide lowered A1c by 0.13%–0.4% compared with placebo (placebo- corrected) over 52 weeks.
-Pramlintide-treated patients had larger weight loss than patients not on pramlintide, but these results were not clinically significant (−0.5 to −1.25 kg compared with +0.6 kg) over 52 weeks.
Harms-Fair-Poor-Studies beyond 52 weeks in duration evaluating harms are lacking.
-There were no significant differences in withdrawal rates between pramlintide+insulin and placebo+insulin treated patients.
-Both pramlintide+insulin and placebo+insulin groups exhibited similar rates of mild-moderate hypoglycemia.
-More pramlintide+insulin treated patients had greater incidence of severe hypoglycemic events during the first 4 weeks of treatment than those receiving placebo+insulin.
-Incidence of nausea was significantly greater for pramlintide + insulin than placebo+insulin treated patients. One trial reported data that showed most events occurring within 4 weeks of therapy.
-Headache was reported at a slightly higher rate in patients receiving pramlintide+insulin compared with those receiving placebo+ insulin. It is unknown whether these events were associated with hypoglycemia.
-Neither vomiting nor anorexia was reported.
Key Question 2. Are there subgroups of patients for which pramlintide is more or less suitable than other hypoglycemic agents?-Poor (post hoc analyses with selective outcome reporting)-No subgroup analyses were conducted on age, sex, race, or total daily insulin usage.
- Black patients may have slightly larger treatment effects with pramlintide than White or Hispanic patients.
-The incidence of nausea had no impact on observed weight loss with pramlintide.
- Markedly obese subjects (BMI ≥ 35 kg/m2) had the largest reduction in weight (2–3 kg) but only 1%–2% achieved clinically significant weight loss of ≥ 10% of body weight.
-Patients with higher baseline A1c (>8.5%) had larger treatment effects than patients with baseline A1c ≤ 8.5%.

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; PPG, postprandial glucose; RCT, randomized controlled trial.

Exenatide

We identified 4 RCTs that compared exenatide with conventional insulin therapy, with both groups receiving oral diabetes agents (Table 10 and Evidence Table 13).26–30 In addition we identified 4 placebo-controlled trials (Table 11 and Evidence Table 13),31–34 5 single-arm open-label extension studies of exenatide,35–39 one single-arm retrospective cohort study40 (Table 12 and Evidence Tables 14), and two relevant systematic reviews (Evidence Tables 56).41, 42 No studies that met our inclusion criteria compared exenatide to oral diabetes agents used as either monotherapy or combined therapy in adults. We found no studies of exenatide in children. The literature search results are provided in Figure 2, and studies excluded upon review of the full text are listed in Appendix D.

Table 10

Table 10

Characteristics of exenatide active-controlled trials in adults with type 2 diabetes

Table 11

Table 11

Characteristics of exenatide placebo-controlled trials in adults with type 2 diabetes

Table 12

Table 12

Placebo-control trials of exenatide: Meta-analysis

Figure 2

Figure 2

Literature search results for exenatide

Systematic Reviews

Two systematic reviews of exenatide met our inclusion criteria.41,42 Amori and colleagues41 published a high-quality review of published and unpublished English-language studies of FDA-approved and unapproved DPP-4 inhibitors (sitagliptin and vildagliptin) and GLP-1 analogs including exenatide. These reviewers derived the following pooled estimates of change from baseline for exenatide compared with placebo (both groups combined with various oral diabetes agents): A1c −1.01% (95% CI −1.18% to −0.84%), fasting plasma glucose −27 mg/dL (95% CI −34 to −20 mg/dL), and weight −1.44 kg (95% CI −2.13 to −0.75 kg). When exenatide was compared with various insulin regimens, the following pooled estimates of change from baseline for exenatide compared with insulin were noted: A1c −0.06% (95% CI −0.22% to 0.10%), fasting blood glucose 13 mg/dL (95% CI −16 to 41 mg/dL), and weight −4.8 kg (95% CI −6.0 to −3.5 kg). Weight loss was dose-dependent and progressive, with no apparent plateau by week 30. Severe hypoglycemia was rare (5/2781 patients who used exenatide) and occurred only when combined with sulfonylurea use. The risk ratio for mild to moderate hypoglycemia with exenatide compared with placebo was 2.3 (95% CI 1.1 to 4.9). Dose-dependent nausea and vomiting were the most frequently reported adverse events with exenatide (risk ratio nausea compared with any other treatment 2.9 (95% CI 2.0 to 4.2). Withdrawal rates due to gastrointestinal effects were higher with exenatide (4%) than with placebo.

The second review42 was poor quality (Score ≤ 4 using the Oxman and Guyatt criteria43) (see Evidence Table 4) and so was not included in our review.

Summary of Evidence for Exenatide

Key Question 1 and 2. For children and adults with type 2 diabetes, does exenatide differ in efficacy, effectiveness, and in harms for achieving glycemic control when compared to other hypoglycemic agents as monotherapy or combined therapy? or when added to other hypoglycemic agents compared to conventional insulin therapy?

Are there subgroups of patients for which exenatide is more or less suitable than other hypoglycemic agents?

Efficacy
  • Active-control trials compared exenatide to insulin, with both groups receiving oral diabetes agents, and demonstrated improved A1c in both treatment groups (range change in A1c exenatide 10 mcg twice daily −1.0% to −1.4%; range insulin −0.9% to −1.4%), with no significant differences between treatments.27, 28 The substitution of exenatide for insulin did not improve A1c in either group.26
  • A1c improved more with exenatide than with placebo, both added to various oral agents: between-group difference (exenatide minus placebo): 5 mcg twice daily: −0.6% (95% CI −0.8 to −0.4%); 10 mcg twice daily −1.0% (95% CI, −1.2 to −0.8%)
  • Active-control studies demonstrated significant weight loss in exenatide groups compared to weight gain with insulin (between-group difference 4.0 to 5.5 kg). Weight decreased progressively with exenatide combined with oral agents, compared with placebo, but weight change was small (pooled between group difference exenatide 5 mcg twice daily, −0.51 kg, 95% CI −0.89 to −0.13; exenatide 10 mcg twice daily, −1.25 kg, 95% CI −1.90 to −0.61).
  • No study examined children or adolescents with type 2 diabetes.
Effectiveness
  • Quality of life was examined in only one study. No significant differences were seen between exenatide dosed twice a day and insulin glargine, despite higher rates of gastrointestinal adverse effects with exenatide.
Adverse effects
  • Total withdrawals were less with exenatide 5 mcg twice daily than with placebo (relative risk 0.67, 95% CI 0.53–0.85); there was no significant difference between placebo and exenatide 10 mcg twice daily.
  • Withdrawal rates due to adverse events were higher with exenatide 10 mcg twice a day than with placebo; there were no differences between treatment groups at the 5 mcg twice daily dosing.
  • The incidence of hypoglycemia was elevated with exenatide 5 and 10 mcg twice a day compared with placebo but was significant only for the higher dosage (relative risk 2.44, 95% CI 1.09 to 5.49). Rates of hypoglycemia were greatest in subjects taking a sulfonylurea and exenatide compared with placebo plus exenatide. Rates of hypoglycemia were similar between insulin-treated and exenatide groups.
  • Nausea and vomiting were the most frequent adverse events among exenatide-treated patients, and rates of these symptoms were significantly higher in the exenatide group than the insulin or placebo groups. Nausea declined after the first 8 weeks of therapy
  • There was no evidence of cardiovascular, pulmonary, hepatic, or renal adverse effects across studies, and rates of serious events were similar between treatment groups.
Subgroups
  • In one pooled analysis, exenatide was equally efficacious in reducing A1c in patients over and under 65 years of age, and rates of hypoglycemia were similar between these two age groups. There were no other data on subgroups defined by demographic or other characteristics.

Detailed Assessment of Exenatide

Key Question 1 and 2. For children and adults with type 2 diabetes, does exenatide differ in efficacy, effectiveness, and in harms for achieving glycemic control when compared to other hypoglycemic agents as monotherapy or combined therapy? Or when added to other hypoglycemic agents compared to conventional insulin therapy?

Active-control trials

Four open label studies compared exenatide 10 mcg twice a day to insulin therapy (various regimens). All studies used concurrent sulfonylurea and/or metformin in addition to the study treatment regimes (Table 10, Evidence Tables 13). Three of these trials were fair-quality noninferiority studies,27, 28, 30 and one was a fair-to-poor-quality exploratory substitution study.26 The outcomes in these four trials were too heterogeneous to estimate meaningful pooled effect sizes.

Efficacy and effectiveness

Heine and colleagues27 compared once-daily glargine to exenatide twice daily over 26 weeks of follow-up in a noninferiority study, with both groups receiving metformin and a sulfonylurea. Reductions in A1c were 1.11% in both groups (between-group difference 0.017%, 95% CI −0.123 to 0.157%). Fasting plasma glucose decreased in both treatment groups, with a greater reduction with insulin glargine (change in the insulin glargine group − 51.5 md/dL and in the exenatide group −25.7 md/dL; between-group P<0.001). Weight increased in the insulin glargine group throughout the trial, with progressive reduction in the exenatide group (weight change −2.3 kg with exenatide, +1.8 kg with insulin glargine; between-group difference −4.1 kg, 95% CI −4.6 to −3.5 kg).

Quality of life was assessed in this trial.27, 29 A per protocol analysis of 455 of 549 original trial patients revealed no significant differences between the two treatments for measures of symptoms, quality of life, vitality, and treatment satisfaction. These similar outcomes occurred despite an additional injection daily and gastrointestinal adverse events with exenatide.

Another noninferiority study 30 also compared exenatide 10mcg twice daily to insulin glargine, with both groups continuing pre-study single oral agents. Change in A1c at 16 weeks was identical in the two treatment arms (−1.36%, SE 0.09%, within group P<0.001). Both exenatide and insulin glargine reduced A1c by a similar amount in patients with baseline A1c ≥ 9% (approximate change −1.8%) and< 9% (change −0.9%).30

A third non-inferiority study28 compared exenatide twice daily with biphasic insulin aspart in patients poorly controlled on sulfonylurea and metformin. The change in A1c was similar between groups (change with exenatide −1.04%, change with insulin aspart −0.89%; between group difference −0.15%, 95% CI −0.32 to 0.01%). Exenatide patients lost weight while insulin-treated patients gained weight (between-group difference −5.4 kg, 95% CI −5.9 to −5.0 kg). Fasting serum glucose decreased in both groups (insulin aspart −1.7 mmol/L; exenatide −1.8 mmol/L).

The fourth active-control trial26 examined persons with type 2 diabetes who were already using insulin and sulfonylurea and/or metformin. In this small (N=51), exploratory RCT, exenatide 5 and then 10 mcg twice daily was substituted for insulin, while oral agents were continued. Specific glycemic goals were not set. A1c did not change significantly in either group (P>0.05) and there was no significant between-group difference in A1c at 12-week follow-up. Exenatide patients noted a decrease in weight (mean weight change −4.2 kg, SD 3.0 kg, P<0.001), in contrast to the insulin group (mean weight change +0.5 kg, SD 1.7, P<0.001). This study was rated fair-poor quality because of its high and differential withdrawal rate and lack of reporting methods for randomization and allocation.

Adverse effects

Total withdrawals in the exenatide group ranged from 12.0% to 21.3% and in the comparison group from 0% to 10.1% in the four active-controlled trials. 26–28, 30 Withdrawals due to adverse events for the exenatide group ranged from 8% to 15% and were less than 1% in the comparison groups. Nausea and vomiting were the most frequent adverse events among exenatide-treated subjects, and rates of these symptoms were significantly higher in the exenatide group than in groups using insulin glargine27, 30 or other insulin routines,26,28 with rates of nausea ranging from 33% to 57% in the exenatide groups compared with<1 to 9% with the comparison group receiving insulin.

Overall hypoglycemia rates were similar between groups treated with insulin and with exenatide. 27, 28, 30 Hypoglycemia was particularly common when exenatide (39%) or insulin (38%) was combined with sulfonylurea and/or metformin;26 79% of hypoglycemia cases were associated with sulfonylurea. In a study comparing exenatide and titrated insulin glargine,30 the overall rate of hypoglycemia with exenatide (14.7%) was not statistically different than that with insulin glargine (25.2%). In subgroup analysis of this study, however, the rate of hypoglycemia in patients who received metformin and exenatide was 2.6% as compared with 17.4% in those receiving insulin glargine (P=0.010), whereas the rates of hypoglycemia in patients taking sulfonylureas was similar with exenatide (30.0%) and insulin glargine (34.5%).

Placebo-controlled trials

We identified 4 large, multicenter, fair-quality placebo-controlled trials31–34 of exenatide as combination therapy (Table 11, Evidence Tables 13). Overall, study subjects were fairly homogeneous. Subjects were similar in age (mean 53 to 57 years) and sex (52 to 60% male) with some variation in race and ethnicity. Mean baseline A1c ranged from 7.9% to 8.6% and mean duration of diabetes from 4.9 to 9.4 years.

Efficacy and effectiveness

Three very similar studies with overlapping authors compared exenatide to placebo, with both treatment groups taking oral hypoglycemic agents.31–33 Kendall and colleagues33 randomized patients to exenatide 5 mcg or 10 mcg or placebo twice daily over 30 weeks. Patients continued their pre-study metformin and a sulfonylurea. A1c decreased in the exenatide arms and steadily increased with placebo (placebo-adjusted change in A1c for exenatide 5 mcg, −0.8%; 10 mcg, −1.0%; P<0.001 for both treatment groups versus placebo). Weight decreased progressively in both exenatide arms, more so than in the placebo arm (weight change −1.6 kg, SE 0.2 kg in both exenatide groups; −0.9 kg, SE 0.2 kg with placebo).

In a similarly designed study Buse and colleagues31 compared exenatide to placebo in patients taking a sulfonylurea. A1c improved in both treatment groups (A1c change with exenatide 5 mcg, −0.46%; 10 mcg, −0.86%) while increasing slightly in the placebo group (between-group P≤ 0.0002). Weight decreased more in the exenatide groups (weight change −1.6 kg, SE 0.3) than in the placebo group (weight change −0.6 kg, SE 0.3 kg). DeFronzo and colleagues32 performed a similar study except that all subjects were taking metformin. The researchers noted very similar improvements in A1c with exenatide 10 mcg (A1c change −0.78%, SE 0.1%) compared with placebo (A1c change 0.08%, SE 0.10%) and also a similar decrease in weight with exenatide.

In a fourth placebo-controlled trial, subjects who were inadequately controlled with a thiazolidinedione (with or without metformin), were randomized to exenatide 10 mcg twice daily or placebo.34 Exenatide improved A1c (mean between-group difference −0.98, 95% CI −1.21 to −0.74%) and fasting glucose (mean between-group difference −30.5 mg/dL, 95% CI −40.0 to −21.1 md/dL). Exenatide reduced weight but placebo did not (between-group difference −1.51 kg, 95% CI −2.15 to −0.88).

In several placebo-controlled trials of exenatide combined with oral agents, patients with a baseline A1c more than 9.0% achieved greater reductions in A1c than subjects with baseline less than 9.0%.31, 33, 36 Weight reductions were greater in persons who had higher body mass index at baseline.35, 38

These studies were sufficiently homogeneous to obtain pooled estimates of effect (Table 12, Figures 3 and 4) When compared with placebo, exenatide 5 mcg twice daily produced a significant decrease in A1c (pooled effect −0.59, 95% CI −0.79 to −0.40, P<0.00001, Figure 3).31–33 A larger improvement in A1c was noted with exenatide 10 mcg twice daily (pooled effect versus placebo −0.97, 95% CI −1.16 to −0.79, P<0.00001).31–33 Significant improvements were also noted in fasting plasma glucose with exenatide 10 mcg twice daily compared with placebo (pooled effect −1.50 mmol/L, 95% CI −1.85 to −1.15, P<0.00001, Table 12, Appendix B).31–33 Available data were insufficient to conduct meta-analyses on postprandial glucose.

Figure 3

Figure 3

Change in A1c in placebo-controlled studies of exenatide

Figure 4

Figure 4

Weight change in placebo-control exenatide studies

When compared with placebo, exenatide produced a significant decrease in weight (pooled effect exenatide 5 mcg twice daily, −0.51 kg, 95% CI −0.89 to −0.13, P=0.009; exenatide 10 mcg twice daily, −1.25 kg, 95% CI −1.90 to −0.61, P=0.0001).31–34 Statistical tests for heterogeneity were not significant (P>0.05) for all glycemic control and weight outcomes.

Adverse effects

Based on pooled estimates across the four placebo-controlled trials, total withdrawals were less with exenatide 5 mcg twice daily than with placebo (relative risk 0.67, 95% CI 0.53 to 0.85); there was no significant difference between placebo and exenatide 10 mcg twice daily. Withdrawals due to adverse effects were greater with exenatide 10 mcg twice daily than with placebo, however, with no significant difference between exenatide 5 mcg twice daily and placebo (See Table 12).

There was no evidence of cardiovascular, pulmonary, hepatic, or renal adverse effects across studies, and rates of serious events were similar between treatment groups. One study reported one subject who withdrew from the exenatide group because of chest pain and a second subject because of an injection site reaction.34 Two additional treatment-group patients in this study had serious adverse events (chest pain and allergic alveolitis) which did not necessitate study withdrawal.

Nausea, vomiting, and diarrhea were significantly more frequent with treatment at both dosages than in the placebo group (Table 12). Nausea declined after 8 weeks of treatment, although the statistical significance of the trend was not reported.31–34 There was no correlation between change in body weight and duration32, 33 or severity35 of nausea. When the incidence of nausea remained stable, body weight continued to decrease.39

The incidence of hypoglycemia was elevated in both dosage groups but was significant only for the higher dosage (relative risk 2.44, 95% CI 1.09 to 5.49). Hypoglycemia and nausea were much more common in the exenatide groups in a study by Buse and colleagues,31 where all subjects received a sulfonylurea, than in the other three placebo-controlled studies. Rates were particularly high with 10 mcg twice daily dosing. These high rates lead to heterogeneity of the data across studies. Excluding this study from the pooled effect still produced statistically a significant increase in hypoglycemia (RR 1.88, 95% CI 1.29 to 2.75) and nausea (RR 2.28, 95% CI 1.86 to 2.80), but with statistically homogeneous data (chi-square for heterogeneity P<0.05) (Table 12). In this trial which reported higher rates of nausea and hypoglycemia 31, no episodes of severe hypoglycemia (requiring third party assistance) were noted. Rates of mild-to-moderate hypoglycemia were reported in 36% of subjects who received exenatide 10 mcg twice daily, 14% with 5 mcg twice daily, and 3% with placebo. All subjects were taking a sulfonylurea titrated to maximum effect dosage during the lead-in period and dosages were reduced if hypoglycemia occurred. High rates of hypoglycemia were also noted in a placebo-controlled trial where all subjects received metformin plus a sulfonylurea.33 The risk of hypoglycemia was not increased compared with placebo when all subjects received a thiazolidinedione34 or metformin. 32

None of these studies included in this report noted cases of acute pancreatitis, however, from the date of the drug’s approval through December 2006, the FDA received 30 domestic reports of acute pancreatitis in patients who received exenatide.44 Median age of patients was 60 years and daily doses ranged from 10–20 mcg. The median time to onset of the symptoms was 34 days (range 4 to 300 days). Median amylase value was 384 IU/L and median lipase value 545 IU/L. Seventy percent of patients required hospitalization. A majority of affected patients (90%) had other risk factors for pancreatitis, including alcohol use or hypertriglyceridemia.

Cohort studies

We examined adverse events in cohort studies of exenatide and identified six single-arm open-label extension studies35–39, 45and one single-arm retrospective cohort40 study (Table 13). All of the open label extension studies assessed exenatide 10 mcg twice daily. In these studies, investigators included only subjects who had previously completed a prior study and several studies35, 38, 39 excluded patients who had received placebo.

Table 13

Table 13

Characteristics of exenatide observational studies in adults with type 2 diabetes

Table 14

Exenatide summary evidence table

Type 2 DiabetesQuality of evidenceConclusion
Key Question 1. For children and adults with type 2 diabetes, does exenatide differ in:No study examined children or adolescents with type 2 diabetes.

No study examined exenatide as monotherapy.
Efficacy and effectiveness for achieving glycemic control when compared to other hypoglycemic agents as monotherapy or combined therapy?Placebo-controlled trials, both groups receiving oral diabetes agents
Glycemic control: Fair quality, 4 RCTs

Weight change: Fair quality, 4 RCTs


Health outcomes: No data
A1c improved more with exenatide than with placebo, both added to various oral agents: between-group difference(exenatide minus placebo): 5 mcg BID: −0.6% (95% CI −0.8 to −0.4%); 10 mcg BID −1.0% (95% CI, −1.2 to −0.8%)

Weight decreased progressively with exenatide combined with oral agents and compared with placebo, but weight change was small (pooled between group difference: exenatide 5 mcg twice daily, −0.51 kg, 95% CI −0.89 to −0.13; exenatide 10 mcg twice daily, −1.25 kg, 95% CI −1.90 to −0.61).

No study examined health or quality-of-life outcomes.

Exenatide was not compared with other active drugs except insulin.
Efficacy and effectiveness for achieving glycemic control when added to other hypoglycemic agents compared to conventional insulin therapy?Active-controlled trials, both groups receiving oral diabetes agents
Glycemic control: Fair quality, 3 RCTs

Weight change: Fair quality, 3 RCTs

Health outcomes: Poor quality, 1 RCT
A1c improved in both treatment groups with no significant differences between treatments. The substitution of exenatide for insulin did not improve A1c in either group.

Exenatide produced significant weight loss compared to weight gain with insulin(difference 4–5.5 kg).

Quality of life was examined in only one study, with no significant differences between exenatide and insulin glargine despite higher rates of gastrointestinal adverse effects with exenatide.
Harms for achieving glycemic control when compared to other hypoglycemic agents as monotherapy or combined therapy?

Harms for achieving glycemic control when added to other hypoglycemic agents compared to conventional insulin therapy?
Nausea: Good quality, 7 RCTs

Hypoglycemia: Good quality, 7 RCTs

Severe, long-term, or idiosyncratic adverse events: Fair, most data from less than 30-week follow-up.
Total withdrawal rates were higher with exenatide than with insulin treatment or placebo.

Withdrawal rates due to adverse events were higher with exenatide 10 mcg BID than with placebo; there was no difference between treatment groups for 5 mcg BID.

Nausea and vomiting were the most frequent adverse events and rates were significantly higher in the exenatide group than with insulin or with placebo. Nausea persisted in 8% of subjects after 2 years (1 study).

The incidence of hypoglycemia was elevated with exenatide 5 and 10 mcg BID compared with placebo (both groups received oral agents), but was significant only for the higher dosage. Hypoglycemia rates were similar between insulin-treated and exenatide groups.

There was no evidence of cardiovascular, pulmonary, hepatic, or renal adverse effects across studies, and rates of serious events were similar between treatment groups.
Key Question 2. Are there subgroups of patients for which exenatide is more or less suitable than other hypoglycemic agents?Poor quality, 1 subgroup analysisOne study showed exenatide improved A1c to a similar degree in persons over and under 65 years of age. There were no other data on subgroups of interest.

Abbreviations: BID, twice daily; RCT, randomized controlled trial.

An open-label extension study of three of the placebo-controlled primary trials31–33 included in this report was published in multiple publications with overlapping or identical populations.35, 36, 38, 39, 45 These publications represented a pooled synthesis of patients continuing in an open-label extension beyond the original 30-week trial comparing exenatide 5 mcg or 10 mcg twice daily to placebo. Subjects from both the placebo and treatment groups were invited to continue on 10 mcg twice daily along with their existing metformin and/or sulfonylurea regimens for a 2-year36 and then 3-year45 period. Mild-to-moderate nausea was the most frequently reported adverse event, and 3% of subjects withdrew over the extension period (30 weeks to 2 years) because of nausea. Eight percent of subjects continued to complain of nausea after 2-years of follow-up. Hypoglycemia (of any severity) occurred at a rate of 1 case in 1010 person-years of exenatide treatment. There were no cardiovascular, pulmonary, hepatic, or renal effects attributed to treatment.

Adverse events in subjects completing 3-year follow-up of the open label extension of these three placebo-controlled trials45 included mild-to-moderate nausea (59%) (5% of subjects withdrew due to nausea over the 3 years), and hypoglycemia (40%) with 2 of 527 subjects withdrawing because of hypoglycemia. Weight progressively decreased over the follow-up period (change from baseline −5.3kg, SE 0.4). A1c reductions seen at 12 weeks were sustained at 3 years (A1c change −1.0%, SE 0.1%). This study population was a select group: only approximately half (46%) of subjects originally enrolled in the three primary trials enrolled in the open-label extension. Of subjects enrolled, only 54% completed the 2-year follow-up and 41% the 3-year follow-up.

An unrelated open-label, extension study37 (“Study B”) of a 28-day trial reported that nausea and vomiting were the most common adverse effects with exenatide 10 mcg twice daily for 26 weeks, but incidence rates were not reported. Approximately ¾ of subjects also received metformin; the other ¼ received diet and exercise only. A retrospective chart review40 of 200 patients who had used exenatide noted that 13% discontinued treatment due to side effects, including nausea (8%), urticaria (2%), and hypoglycemia (0.5%).

Key Question 3. Are there subgroups of patients for which exenatide is more or less suitable than other hypoglycemic agents?

Only one publication examined subgroups based on demographic characteristics. A pooled analysis36 of three placebo-controlled trials reported that reductions in A1c were not related to age and that hypoglycemia was not more frequent in subjects ≥65 years of age. No primary study examined the efficacy or effectiveness of exenatide in subgroups defined by age or other characteristics.

Applicability of efficacy, effectiveness, and safety data to general diabetes populations

The studies identified for this review are rather homogeneous, relatively small, and may be rather selected, thus applicability to broader diabetes populations may be limited. Study subjects were homogeneous across studies for age, sex, and baseline A1c in both the In the placebo- and active-controlled trials. Significant comorbidities were excluded in the three placebo-controlled studies reporting that characteristic31–33 and comorbidities were not mentioned in three of the four active-controlled trials.26, 28, 30

Most studies reported only the number of subjects randomized, and randomization occurred in all placebo-controlled trials after a run-in of injected placebo. In other words, the number of potential study subjects who did not tolerate twice daily injections and who were therefore not included in the study was usually not reported. Open label extension studies were of highly selected populations who completed the primary study and who volunteered to continue (or start if on placebo) exenatide.

Sitagliptin

We identified 166 citations by various methods of literature searching (Figure 5). Eleven randomized controlled trials and 2 systematic reviews fulfilled inclusion criteria. No comparative cohort or case-control studies were identified reporting either long-term benefits or adverse events. In the FDA Medical and Statistical Reviews we identified 10 relevant trials, of which 7 were published in peer-reviewed journals. One of the trials46 identified from the FDA Reviews was not included because it did not meet inclusion criteria; the 3 remaining trials (study #P10X1, P014, and P014X1) could not be found in the medical literature. Details of included studies are found in Table 15 with their quality assessment in Evidence Tables 16. Trials excluded upon review of the full text are listed in Appendix D.

Figure 5

Figure 5

Literature search results for sitagliptin

Table 15

Table 15

Characteristics of sitagliptin placebo-controlled trials in adults with type 2 diabetes

Systematic Reviews

Amori and colleagues41 published a high-quality systematic review of FDA approved and unapproved GLP-1 analogues (exenatide, linaclotide) and DPP-4 inhibitors (sitagliptin [8 studies] and vildagliptin [12 studies]). Sitagliptin and vildagliptin (examined together) lowered A1c, fasting plasma glucose, and postprandial glucose when used as either monotherapy or add-on therapy compared with placebo, with or without additional oral hypoglycemic agents. When sitagliptin and vildagliptin were compared with other active oral hypoglycemic agents, the DPP-4 inhibitors were slightly less effective in reducing A1c (pooled weighted mean difference in A1c: 0.21%, 95% CI 0.02 to 0.39; I2= 66%). The results were pooled from 4 trials, 3 of which evaluated vildagliptin and included patients with baseline A1c of 8.7%. Small increases in weight were also observed with sitagliptin when compared with placebo. When compared with glipizide or pioglitazone, sitagliptin had a more favorable weight profile. Metformin was the only comparator medication that exhibited weight loss. Both DPP-4 inhibitors were generally well tolerated; severe hypoglycemia was reported in only two patients receiving DPP-4 inhibitors across the included studies. No differences in risk of mild-to-moderate hypoglycemia or gastrointestinal adverse events were reported when sitagliptin and vildagliptin were compared to placebo. Results for sitagliptin and vildagliptin were not examined individually; vildagliptin is also not yet approved in the United States.

Barnett and colleagues42 reviewed the effects on weight of hypoglycemic agents, including GLP-1 analogs and DPP-4 inhibitors. This systematic review was considered low quality, as there was insufficient information about study selection criteria and individual study quality assessment. Thus, the study did not meet our inclusion criteria and we did not further evaluate its findings.

Summary of Evidence

Key Question 1 and 2. For children and adults with type 2 diabetes, does sitagliptin differ in effectiveness, efficacy, and in harms for achieving glycemic control when compared to other hypoglycemic agents as monotherapy, combined therapy, or when compared to placebo? or when added to other hypoglycemic agents as second-or third-line therapy?

Evidence in children
  • Children and adolescents ≤18 years were not included in any of the published studies on effectiveness, efficacy, or harms.
Evidence on long-term health outcomes and harms
  • No studies provided data on benefits or harms for follow-up periods longer than 52 weeks.
Evidence on efficacy
  • When compared with placebo, sitagliptin 100 mg/d monotherapy significantly lowered A1c (pooled effect, between-group change −0.81%, 95% CI −0.94% to −0.67%) in patients inadequately controlled on diet and exercise over 12–24 weeks.
  • Though formal statistical analyses were not conducted for glipizide-or metformin monotherapy compared with sitagliptin monotherapy, it appears that sitagliptin may be comparable to glipizide and metformin 1 g/d in lowering A1c based on estimated magnitude of difference between groups. Additional trials are needed to verify the findings.
  • Overall, in patients inadequately managed on metformin, the addition of sitagliptin was as effective as the addition of glipizide or rosiglitazone in lowering A1c at the end of 18 and 52 weeks. Patients receiving glipizide or rosiglitazone gained weight compared with patients on sitagliptin who lost weight during the course of the trial.
  • In patients inadequately managed on 2 oral hypoglycemic agents, the addition of sitagliptin lowered A1c by about 0.6% compared with an increase in A1c of 0.3% with placebo plus 2 oral hypoglycemic agents over 24 weeks.
  • Using the initial combination of sitagliptin and metformin 1–2 g/d lowered A1c by about 1.4% to 1.9% from baseline compared with sitagliptin (−0.66%) or metformin 1–2 g/d (−0.82 to −1.13%) monotherapy in patients inadequately controlled on diet and exercise over 24 weeks.
  • Sitagliptin’s effects on fasting plasma glucose and postprandial glucose were moderate compared with placebo whether used as monotherapy (pooled estimates of fasting plasma glucose −24.4 mg/dL, 95% CI−1.6 to −1.1 mg/dL; postprandial glucose −54.5 mg/dL, 95% CI −3.6 to −2.4 mg/dL) or as adjunctive therapy (range of between-group difference for fasting plasma glucose −18 to −35 mg/dL; postprandial glucose −35 to −50 mg/dL).
Harms
  • Weight generally decreased for both sitagliptin-treated and placebo-treated patients (range for change in weight from baseline: sitagliptin −0.1 to −0.6 kg vs. placebo −0.7 to −1.1 kg); however, subjects randomized to sitagliptin lost less weight than compared with placebo. Adjunctive therapy with sitagliptin also did not negatively affect weight, particularly in persons taking metformin; however, small increases in weight were seen when sitagliptin was added to sulfonylureas, pioglitazone, or rosiglitazone.
  • Overall, sitagliptin appeared to be well-tolerated. There were 20 reports of severe hypoglycemia in 2 of 9 trials, mostly in patients taking glipizide (90%). The rates for total withdrawal were slightly lower with sitagliptin than compared with placebo (pooled RR 0.69, 95% CI 0.55–0.88) and withdrawal due to adverse events were not significantly different between the treatment groups (pooled RR 0.76, 95% CI 0.33–1.73).
  • The more commonly reported adverse events across treatment groups were hypoglycemia, nausea, vomiting, diarrhea, and abdominal pain.

Detailed Assessment

Key Question 1 and 2. For children and adults with type 2 diabetes, does sitagliptin differ in efficacy, effectiveness, and in harms for achieving glycemic control when compared to placebo, when compared to other hypoglycemic agents as monotherapy or combined therapy, or when added to other hypoglycemic agents?

Eight randomized controlled trials were rated fair-quality and 1 fair-poor. This review is organized by how sitagliptin was used (mono- or combined therapy compared with placebo or active control).

Sitagliptin monotherapy
Sitagliptin compared with placebo

Five fair-quality trials ranging from 12–24 weeks in duration compared sitagliptin 100 mg/d to placebo (Table 15).47, 48, 53, 54, 56 Patients randomized to receive sitagliptin 100 mg/d showed significant reductions in A1c (placebo-corrected change 0.81%, 95% CI −0.94% to −0.67%) and fasting plasma glucose (placebo-corrected change 24.4 mg/dL, 95% CI −29.5 to −19.3 mg/dL), while placebo-treated patients generally showed worsening glycemic control (Table 17, Figures 6 and 7). For patients who volunteered to participate in a meal-tolerance test, sitagliptin lowered postprandial glucose relative to placebo (placebo-corrected change 54.5 mg/dL, 95% CI −65.5 to −43.5 mg/dL). A greater proportion of patients receiving sitagliptin than placebo reached the A1c goal of <7%, although 9%–21% of subjects on sitagliptin required the use of a second medication.

Table 17

Table 17

Sitagliptin monotherapy compared with placebo

Figure 6

Figure 6

Meta-analysis of sitagliptin studies for A1c

Figure 7

Figure 7

Meta-analysis of sitagliptin studies for weight loss

Weight generally decreased in both treatment arms (range for change from baseline: sitagliptin −0.1 to −0.6 kg compared with placebo −0.7 to −1.1 kg). Overall, however, subjects randomized to sitagliptin lost slightly less weight than subjects randomized to placebo (weighted mean difference: 0.62, 95% CI 0.36–0.89; see Figure 7).

Approximately 50% of subjects were on 1 or more oral hypoglycemic agents at screening. These agents were discontinued before diet and exercise run-in periods. Patients not responding to diet and exercise were eligible for study inclusion but were required to participate in a 2-week single-blind, placebo run-in period prior to randomization. Three trials allowed use of prespecified rescue medications based on certain glycemic criteria. Mean baseline A1c was 7.6%–8.9% and mean duration of diabetes was 4–5 years.

Sitagliptin compared with an active agent

In 2 fair-quality trials that evaluated sitagliptin 100 mg/d, active treatment arms of glipizide 5–20 mg/d or metformin 1000–2000 mg/d were included in the studies (Table 16).53, 54 Patients had baseline A1c of 7.9%–8.9% with 4–5 years duration of diabetes. Overall, patients on glipizide and metformin 1–2g/d monotherapy showed numerically larger reductions in A1c, fasting plasma glucose, and postprandial glucose than compared with sitagliptin monotherapy (Table 18). However, based on the estimated magnitude of difference between groups, it appears that sitagliptin may be comparable to glipizide and metformin 1 g/day for lowering A1c (sitagliptin-glipizide difference: +0.22% and sitagliptin-metformin 1g difference: +0.16%; Table 18). The estimated magnitude of difference between sitagliptin and metformin 2 g/d was greater (+0.47%); it is unclear whether this larger difference between treatments would have statistical significance if analyses were conducted. Hence, these results should be considered with caution since neither trial performed statistical analyses for these comparisons and power may not have been adequate to detect the between-group differences in A1c, fasting plasma glucose, or postprandial glucose.

Table 16

Table 16

Characteristics of sitagliptin active-controlled trials with or without placebo study arms in adults with type 2 diabetes

Table 18

Table 18

Sitagliptin compared with an active agent

With regard to changes in weight, patients randomized to glipizide gained about 1 kg from baseline compared with a nominal increase in weight for those on sitagliptin (0.4 kg).53 In another trial54 patients on metformin observed slightly larger reductions in weight by about 1 kg from baseline than no change in weight experienced by those receiving sitagliptin.

Add-on therapy
Sitagliptin or placebo added to one oral hypoglycemic agent

Three fair-quality randomized controlled trials50, 57, 58 assessed the effects of sitagliptin added to background therapy of “failed” treatment with metformin, pioglitazone, or glimepiride. Mean baseline A1c ranged from 8.0% to 8.4% with 6.1–8.0 years’ duration of diabetes. Approximately 60% of patients were on more than 1 oral hypoglycemic agent, while 30% were on more than 2 oral agents (Table 15). Patients were considered to have “failed” therapy with metformin, pioglitazone, or glimepiride at screening or after 10–19 weeks of dose stabilization and if A1c was between 7–10% or 7.5–10.5%. Patients also entered 2-week single-blind, placebo run-in periods prior to randomization.

The addition of sitagliptin to metformin, pioglitazone, or glimepiride appears to show larger reductions in A1c and fasting plasma glucose compared with the addition of placebo over 24 weeks (Table 19). A larger proportion of sitagliptin-treated patients also achieved the A1c goal of <7% than placebo-treated patients (approximately 11%–47.0% compared with 9%–23.0%). Subjects who received placebo plus glimepiride showed worsening glycemic control, while subjects on placebo plus metformin or placebo plus pioglitazone had slight improvements or no change in A1c from baseline. Weight gain was generally seen in patients taking pioglitazone or glimepiride, with or without the addition of sitagliptin. Patients randomized to metformin lost weight by 0.6 kg to 0.7 kg (P<0.017 and P<0.0001 compared with baseline) (Table 19).

Table 19

Table 19

Sitagliptin or placebo added to one oral hypoglycemic agent

Another fair quality randomized trial52 studied the effects of sitagliptin or placebo added to ongoing metformin therapy. Unlike the other studies50, 57, 58, this trial evaluated the effects of sitagliptin in patients with worse glycemic control (baseline A1c between 8–11%). Of the 544 patients screened, 190 patients were randomized to treatment. These patients were on metformin and diet and exercise for 6 weeks, had baseline A1c between 8–11%, and had ≥85% adherence to their regimens during a 2-week, placebo run-in period. No patients were naïve to oral hypoglycemic agents and approximately 50% were already taking metformin monotherapy or combination oral therapy at baseline.

The addition of sitagliptin to ongoing metformin therapy was more effective than placebo plus metformin at lowering A1c (placebo-corrected difference: −1.0%, 95% CI −1.4 to −0.6%) and fasting plasma glucose (placebo-corrected difference: −25.2 mg/dL, 95% CI −37.8 to −12.6 mg/dL) over 30 weeks. Further evaluation of the data showed that the largest magnitude of A1c lowering was present in patients with the highest baseline A1c between 10–11%. Postprandial glucose levels at 18 weeks were also lower with sitagliptin plus metformin than placebo plus metformin (placebo-corrected difference: −54 mg/dL, 95% CI −75.6 to −34.2 mg/dL)—measurements at 30 weeks however, were not determined by the investigators. Overall, a significantly larger proportion of sitagliptin-treated patients achieved A1c <7% than placebo-treated patients (P<0.001) and also needed less rescue therapy over the study duration (P<0.001). Both treatment groups exhibited weight loss of −0.5 kg over 30 weeks.

Sitagliptin or glipizide added to metformin

One fair-to-poor-quality trial compared the effects of adding either sitagliptin 100 mg/d or glipizide 5–20 mg/d in patients with inadequate glycemic control on metformin (Table 16).55 Glycemic control was considered inadequate if the metformin dose was ≥1500 mg/d with baseline A1c 6.5–10% at initial screening or after several weeks of stabilizing the metformin dose prior to a 2-week single-blind, placebo run-in period before randomization.

Over 52 weeks the 2 study groups showed no significant differences in treatment effects for A1c, fasting plasma glucose, or proportion of patients achieving A1c <7% from one another (Table 20). The only significant difference between treatment groups was in the change in weight. Sitagliptin-treated subjects experienced slightly more weight loss (−1.5 kg) compared with a small weight gain (+1.1 kg) seen in glipizide-treated subjects. Most patients had low baseline A1c (mean 7.5%) and an average of 5.8 years’ duration of diabetes. More than 70% of patients were on oral monotherapy while approximately 30% were on two oral agents at baseline.

Table 20

Table 20

Sitagliptin or glipizide added to metformin

This trial was rated fair-poor mainly because the withdrawal rate exceeded 30%. Of the 374 patients who withdrew, more sitagliptin-treated patients withdrew due to lack of efficacy than glipizide-treated patients (86 patients vs. 58 patients). Main reason for withdrawal due to lack of efficacy was because of prespecified fasting plasma glucose and/or A1c criteria per study protocol. Also, patients who withdrew due to lack of efficacy had more severe hyperglycemia at baseline (A1c 8.6%) than those who completed the trial (7.5%). Analyses of per-protocol populations were used to show noninferiority and analyses of all-patients-treated population were also reported.

Sitagliptin, rosiglitazone, or placebo added to metformin monotherapy

Another fair quality trial51 assessed the effects of sitagliptin, rosiglitazone, or placebo added to regimens of metformin monotherapy over 18 weeks. Prior to randomization patients had to have inadequate glycemic control (A1c 7–11%) and had to be taking metformin at stable doses 1500 mg/d for at least 10 weeks before entering a 2-week run-in period. The mean duration of diabetes for included patients was 4.9 years with mean baseline A1c of 7.7%.

In these patients, the addition of sitagliptin or rosiglitazone to metformin was significantly more effective than the addition of placebo to metformin at lowering A1c (P≤0.001). The placebo-corrected LS mean change from baseline was −0.51% (95% CI, −0.70 to −0.32%) for sitagliptin, and was −0.57% (95% CI, −0.76 to −0.37%) for rosiglitazone. Also, comparisons between sitagliptin and rosiglitazone were conducted and showed no statistically significant differences in lowering A1c (between-group difference: −0.06%, 95% CI −0.25 to 0.14). Similarly, there were no significant differences between sitagliptin-treated and rosiglitazone-treated patients in the proportion achieving A1c <7% (55% compared with 63%; between-group difference 8%, 95% CI, −6 to 22%). Slightly larger reductions in fasting plasma glucose (between-group difference: −12.8 mg/dL, 95% CI, −22.6 to −3.0 mg/dL) and 2-hour postprandial glucose measurements (between-group difference: −15.9 mg/dL, 95% CI, −31.6 to −0.3) were observed with those randomized to rosiglitazone than compared with those on sitagliptin. Patients randomized to sitagliptin or placebo exhibited slight weight loss from baseline (sitagliptin, −0.4 kg, 95% CI −0.8 to 0.0 vs. placebo, −0.8 kg, 95% CI −1.2 to −0.4) while patients on rosiglitazone gained weight (from baseline: +1.5 kg, 95% CI 1.0 to 1.9) over 18 weeks of therapy.

Sitagliptin or placebo added to two existing oral hypoglycemic agents

One fair-quality trial evaluated the addition of sitagliptin or placebo in patients whose glycemia was inadequately controlled on glimepiride 4–8 mg/d alone or glimepiride plus metformin 1500–3000 mg/d.50 Results of sitagliptin or placebo added to glimepiride alone have already been reviewed. In patients already on glimepiride plus metformin, the addition of sitagliptin improved A1c by 0.89% (95% CI −1.1 to −0.68%), fasting plasma glucose by 20.7 mg/dL (95% CI −31.7 to −9.7 mg/dL), and postprandial glucose by 37.1 mg/dL (95% CI −62.7 to −11.6 mg/dL) over 24 weeks of treatment. More sitagliptin-treated patients than placebo-treated patients also achieved the A1c goal of <7% (P<0.001). Weight, however, increased slightly (+0.4 kg, 95% CI −0.1 to 0.9 kg) with sitagliptin relative to placebo; whereas, placebo-treated patients showed more weight loss (−0.7 kg, 95% CI −1.4 to −0.1 kg) (Table 21).

Table 21

Table 21

Sitagliptin or placebo added to two oral hypoglycemic agents

In this trial, mean baseline A1c was 8.3%, average duration of diabetes was 8.8 years, and approximately 65% of subjects had an A1c >8%. More than 95% of patients were also taking combination oral hypoglycemic agents at baseline and were considered to have failed this regimen either at screening or after several weeks of dose-stabilization of glimepiride and metformin before participating in a 2-week placebo run-in phase prior to randomization.

Initial treatment with a combination of sitagliptin plus metformin compared with placebo

Unlike other trials, this study compared initial combination therapy of sitagliptin plus metformin to placebo, sitagliptin monotherapy, and metformin monotherapy in subjects who were inadequately controlled only on diet and exercise.54 As in the placebo-controlled monotherapy trials, patients in this study were taken off prior oral hypoglycemic agents and put through a diet and exercise run-in phase in addition to a 2-week single-blind placebo run-in period before enrollment. Approximately 50% of patients were taking oral hypoglycemic agents at baseline, implying that the remainder was medication naive. Mean A1c was close to 9% and duration of diabetes was less than 5 years (Table 22). In all treatment arms metformin was titrated to increase tolerability.

Table 22

Table 22

Initial combination of sitagliptin plus metformin compared with placebo and individual agents

The initial use of sitagliptin 100 mg/d plus metformin 2000 mg/d significantly improved A1c, fasting plasma glucose, postprandial glucose, weight, and proportion of patients achieving A1c <7% compared with sitagliptin plus metformin 1000 mg/d, placebo alone, sitagliptin monotherapy, or metformin monotherapy over 24 weeks (Table 22). In general, patients in all but 1 treatment arm showed weight loss (−0.6 kg to −1.3 kg, P=0.01 and P<0.001 from baseline). Weight was unchanged for patients on sitagliptin monotherapy (0 kg) (weight data obtained from manufacturer).

Harms

In 5 trials with data suitable for meta-analysis, total withdrawals and withdrawals due to adverse events were lower among patients randomized to sitagliptin monotherapy than patients receiving only placebo (relative risk for total withdrawals 0.69, 95% CI 0.55–0.88; relative risk for withdrawal due to adverse events 0.76, 95% CI 0.33–1.73). Patients on sitagliptin monotherapy also had lower rates of total withdrawal relative to patients on glipizide, who experienced more hypoglycemic events. When compared with metformin, however, sitagliptin was associated with a greater attrition rate, mainly due to withdrawal of consent, violations of protocol, and abnormalities in laboratory. The rate of total withdrawals was also higher in patients whose add-on therapy was sitagliptin than in patients using monotherapy metformin, pioglitazone, or glimepiride.

The most commonly reported adverse events were hypoglycemia, abdominal pain, nausea, vomiting, and diarrhea.

A total of 5 deaths occurred in 3 trials over 24–52 weeks. None was considered to be related to study interventions; 3 were sudden cardiac deaths, 1 was secondary to trauma, and 1 was related to chronic obstructive pulmonary disease and interstitial lung disease.

Rare adverse events

Five of the 10 randomized controlled trials reported adverse events. In those 5 trials adverse events occurring in at least 4% of study subjects included: upper respiratory tract infections, headache, influenza, nasopharyngitis, and urinary tract infection. Four studies47, 50, 55, 58 reported small increases (≤10% from baseline) in mean white blood cell count, mainly an increase in absolute neutrophil count, in regimens with sitagliptin compared to regimens without. These increases appeared early and remained stable throughout the duration of the studies. No other trials provided data on changes in white blood cell count with sitagliptin.

Hypoglycemia

Two studies53, 55 documented 20 cases of severe hypoglycemia, mostly associated with glipizide (90%) rather than with sitagliptin. In 1 trial 3 patients on glipizide monotherapy discontinued treatment. In the other trial 8 patients receiving glipizide plus metformin required non-medical, third-party assistance compared with 1 patient taking sitagliptin added to metformin. Seven patients taking glipizide plus metformin experienced severe symptoms requiring medical assistance compared with 1 patient receiving sitagliptin plus metformin. The remaining six studies reported no cases of severe hypoglycemia.

There was no statistically significant difference in the overall risk of mild to moderate hypoglycemia between sitagliptin and placebo (pooled relative risk 1.21, 95% CI 0.42 to 3.5) (see Table 23). The rate of mild-to-moderate hypoglycemia increased slightly when sitagliptin was added to glimepiride (7.6% compared with 2.8%) or pioglitazone (1.1% compared with 0%).

Table 23

Table 23

Adverse events of sitagliptin compared with oral hypoglycemic agents

Abdominal pain, nausea, vomiting, and diarrhea

There were no statistically significant differences between sitagliptin monotherapy and placebo in the risk of abdominal pain (pooled RR 1.17, 95% CI 0.54–2.52) 47, 48, 54, nausea (pooled RR 1.56, 95% CI 0.53–4.57) 47, 48, 54, diarrhea (pooled RR 1.26, 95% CI 0.64–2.25) 47, 48, 54, and vomiting (pooled RR 0.65, 95% CI 0.18–2.4). 47, 48, 54 However, based on the elevated relative risks, there appears to be a trend for greater risk of experiencing abdominal pain, and nausea with sitagliptin monotherapy compared with placebo.

Compared with metformin monotherapy, sitagliptin was associated with lower incidence of abdominal pain, nausea, vomiting, and diarrhea (Table 23). Combination therapy of sitagliptin plus glimepiride, metformin, or pioglitazone had <6% incidence of abdominal pain, nausea, vomiting, and diarrhea; these results were not significantly different from their comparisons (Table 23).

Key Question 3. Are there subgroups of patients for which sitagliptin is more or less suitable than other hypoglycemic agents?

There was insufficient evidence to perform subgroup analyses based on age, sex, race, ethnicity, baseline A1c, or other characteristics at the study level. Subgroup data not available in publications were supplemented by data provided by the manufacturer. The results from this section should be considered with caution until larger prospective trials evaluating these populations verify the findings.

Age, sex, race, body mass index, and prior use of oral hypoglycemic agents

Four published trials48, 49, 51, 52 reported no significant differences in changes in A1c based on subgroups defined by age, sex, race, and BMI. Data on file from 3 additional trials (Rosenstock 2006, Aschner 2006, Hermansen 2007)59 also showed similar findings.

Data on file from one trial (Charbonnel 2006)59 showed a significant interaction between treatment effect and race for those on sitagliptin monotherapy and placebo. Hispanic patients experienced the largest decline in A1c (placebo-corrected difference in A1c from baseline: −1.04%, 95% CI −1.38 to −0.70%) followed by White patients (placebo-corrected difference: in A1c from baseline: −0.69%, 95% CI −0.84 to 0.55%), and Other patients (placebo-corrected difference in A1c from baseline: −0.44%, 95% CI, −0.82 to −0.07%).

Of the 5 studies (Scott 2007, Hermansen 2007, Nonaka 2008, Charbonnel 2006, Goldstein 2007)59 that stratified groups by prior oral hypoglycemic agent use, only 1 trial (Goldstein 2007)59 showed a large numerical difference in treatment effect. Patients who were not taking an oral hypoglycemic agent prior to this trial experienced greater decline in A1c across all treatment arms compared with patients who were using oral agents before enrolling into the study. For instance, the change in A1c from baseline for “no prior oral agent use” for sitagliptin versus placebo was −1.11% vs. −0.13% compared with −0.26% vs. +0.52% for those “treated with prior oral agents.” Between-group difference calculations were not conducted.

Baseline A1c

Subgroup information stratified by baseline A1c were found in 10 of 11 trials. Some data were available from the 9 published studies47–52, 54, 55, 57 and additional information from 4 of these trials (Scott 2007, Charbonnel 2006, Nauck 2006, Scott 2008) were obtained from data on file.59

Four trials (Charbonnel 2006, Hermansen 2006, Nonaka 2008, Raz 2006) found no significant differences in the change in baseline A1c among those in the following subgroups: <7.5%, <8%, 8–8.9%, >7.5%, ≥8.5%, and ≥9%. One trial47showed significant interaction (P<0.001) in the change in A1c stratified by baseline A1c <8% and ≥9%. In patients with baseline A1c ≥9%, placebo-corrected reductions of −1.52% were observed for sitagliptin 100 mg/d compared with about −0.6% decrease in those with baseline A1c <8%. Data from Goldstein, et al.59 also showed consistent findings for sitagliptin 100 mg/d compared with placebo. For this study, interaction analyses were not conducted (change in A1c from baseline for those with A1c <8%: sitagliptin, −0.37% vs. placebo, +0.15% compared with those with A1c ≥9%: sitagliptin, −0.88% vs. placebo, +0.08%).

Duration of diabetes

One trial48 reported a potential interaction between median baseline duration of diabetes and A1c effects in patients randomized to sitagliptin 100 mg compared with placebo. Patients with diabetes of ≤ 3 years’ duration had significantly greater reductions in A1c than patients who had diabetes for > 3 years (placebo-corrected mean change A1c for ≤ 3years −0.90%, 95% CI −1.21% to −0.60% compared with mean change A1c for > 3years −0.28%, 95% CI −0.59 to +0.20).

Applicability to general diabetes populations

Patients enrolled in the 11 trials represented a highly selected population: primarily white, middle-aged, obese adults with moderately elevated baseline A1c (< 9%) and diabetes for less than 10 years. These populations were further selected during long dose-stabilization and run-in periods, where only persons with > 75% adherence to placebo went on to randomization. Moreover, these trials did not provide sufficient baseline information on comorbidities and other characteristics and laboratory values that would enable inference about the applicability of study findings to general diabetic populations. The available data appear to be limited to persons with diabetes without related comorbidities and who are highly motivated.

Table 24

Summary evidence table for sitagliptin

Type 2 DiabetesQuality of evidenceConclusion
Key Question 1. For children and adults with type 2 diabetes, does sitagliptin differ in efficacy, effectiveness, and in harms when compared to placebo, when compared to other hypoglycemic agents as monotherapy, or when added to other hypoglycemic agents?Evidence in children is lacking.
EffectivenessNo available data-No studies assessed long-term health outcomes and none were > 52 weeks in duration.
EfficacyMonotherapy compared with placebo
-Fair, 5 RCTs



Monotherapy compared with an oral hypoglycemic agent
-Fair, 2 RCTs



Combined therapy compared with placebo
-Fair, 4 RCTs



Combined therapy compared with oral hypoglycemic agents
-Fair-Poor, 1 RCT
-Evidence on time-to-treatment-failure is lacking.

Monotherapy compared with placebo
-Sitagliptin significantly improved A1c, FPG, and PPG relative to placebo.

Pooled data for the above:
A1c: −0.81% (95% CI, −0.94 to −0.67)
FPG: −24.4 mg/dL (95% CI, −29.5 to −19.3)
PPG: −54.5 mg/dL (95% CI, −65.5 to −43.5)


-Sitagliptin-treated patients lost slightly less weight compared with placebo-treated patients (range: −0.1 to −0.6 kg compared with −0.7 to −1.1 kg; pooled: +0.62 kg (95% CI, +0.36 to+0.89)

Monotherapy compared with an oral hypoglycemic agent-Though formal statistical analyses were not conducted for glipizide-or metformin monotherapy compared with sitagliptin monotherapy, it appears that sitagliptin may be comparable to glipizide and metformin 1 g/d in lowering A1c based on qualitative evaluation of the magnitude of difference between groups. Additional trials are needed to verify the findings.

Ranges for sitagliptin monotherapy compared with glipizide and metformin monotherapies:
A1c: −0.54% to −0.66% compared with −0.8% to −1.1%
FPG: −18 mg/dL compared with −25 to −29 mg/dL
PPG: −48 to −59 mg/dL compared with −53 to −78 mg/dL


-Weight remained unchanged for sitagliptin while weight gain (+0.9 kg) occurred for those on glipizide. Weight loss occurred with metformin by about 1 kg.

Combined therapy compared with placebo
-The addition of sitagliptin to one or two oral hypoglycemic agents was more effective for glycemic control than the addition of placebo.

Combined therapy compared with oral hypoglycemic agents
-There was no difference in A1c between regimens that included the addition of sitagliptin or glipizide to metformin. Sitagliptin- treated patients experienced slightly more weight loss (−1.5 kg) than compared with weight gain seen in glipizide-treated patients (+1.5 kg).
-There were no significant differences in the reduction in A1c for those on sitagliptin or rosiglitazone added to metformin monotherapy (between-group difference: −0.06%, 95% CI −0.25 to +0.14%) at 18 weeks.
HarmsMonotherapy compared with placebo
-Fair, 5 RCTs



Monotherapy compared with an oral hypoglycemic agent
-Fair, 2 RCTs



Combined therapy compared with placebo
-Fair, 4 RCTs



Combined therapy compared with oral hypoglycemic agents
-Fair-Poor, 1 RCT
- Studies beyond 52 weeks in duration evaluating harms are lacking.

Monotherapy compared with placebo
-Fewer sitagliptin-treated patients than placebo-treated patients withdrew due to adverse events.
-There was no statistically significant difference in the risk of hypoglycemia between sitagliptin and placebo groups (pooled relative risk 1.21, 95% CI 0.42 to 3.5).
- There were no statistically significant differences between sitagliptin monotherapy and placebo in the risk of abdominal pain, nausea, vomiting, or diarrhea.

Pooled relative risks:
Abdominal pain: RR 1.17, 95% CI 0.54–2.52
Nausea: RR 1.56, 95% CI 0.53–4.57
Vomiting: pooled RR 0.65, 95% CI 0.18–2.4
Diarrhea: RR 1.26, 95% CI 0.64–2.25

Monotherapy compared with an oral hypoglycemic agent
-Sitagliptin and metformin had a lower incidence of hypoglycemia than glipizide.
-Sitagliptin had lower rates of abdominal pain, nausea, vomiting, and diarrhea than metformin.

Combined therapy compared with placebo
- Regimens that included sulfonylurea ± sitagliptin exhibited greater risk of hypoglycemia than therapies without sulfonylurea.
-Combination therapies of sitagliptin with sulfonylurea, thiazolidinedione, and metformin had slightly greater rates of abdominal pain, nausea, vomiting, and diarrhea than the individual oral hypoglycemic agents as monotherapy.

Combined therapy compared with oral hypoglycemic agents
-Sitagliptin added to metformin had lower rates of hypoglycemia than glipizide added to metformin.
- Sitagliptin + metformin versus glipizide + metformin showed minimal difference in the incidence of abdominal pain, nausea, vomiting, and diarrhea.
Key Question 2. Are there subgroups of patients for which sitagliptin is more or less suitable than other hypoglycemic agents?-Fair-Poor-In general, it appears that there are no significant differences in treatment effect based on age, sex, BMI, race. Data on file from 1 trial showed that Hispanic patients showed slightly larger reductions in A1c than White or “Other” patients.
- Patients with higher baseline A1c ≥9% tended to exhibit larger treatment effects than patients with baseline A1c <8%.
-Patients with <3 years’ duration of diabetes tended to exhibit larger treatment effects than those with > 3 years’ duration of diabetes.

Abbreviations: CI, confidence interval; FPG, fasting plasma glucose; PPG, postprandial glucose; RCT, randomized controlled trial.

Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Cover of Drug Class Review: Newer Drugs for the Treatment of Diabetes Mellitus
Drug Class Review: Newer Drugs for the Treatment of Diabetes Mellitus: Final Report [Internet].
Norris SL, Lee NJ, Severance S, et al.
Portland (OR): Oregon Health & Science University; 2008 Aug.

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