• antidiabetic drugs;
  • bromocriptine-QR;
  • pramlintide
  • 降糖药物,溴隐亭-QR,普兰林肽


  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References

Several classes of antidiabetic agents have been introduced into the market place over the past dozen years. As our understanding of the underlying pathophysiology of type 2 diabetes has advanced, attempts have been made to address these defects specifically. This brief review focuses on our experience with two such pharmacological approaches: (i) a synthetic amylin analog addressing amylin deficiency; and (ii) a dopaminergic agonist, focused on enhancing the lowered dopaminergic tone in patients with type 2 diabetes. Importantly, the use of these agents is not associated with hypoglycemia or weight gain.




  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References

Initially, medical professionals only had insulin at their disposal when they wanted to lower glucose levels pharmacologically in their patients with diabetes. It took over three decades (from the early 1920s to the mid-1950s) before the next pharmaceuticals (sulfonylureas) appeared to help lower glucose levels. The advent of metformin represented a significant advance, with a different mode of action and so causing neither hypoglycemia nor weight gain, and effective in combination with sulfonylureas. Physicians and patients have seen the introduction of several new classes of agents in rapid succession over the past dozen years: thiazolidinediones (e.g. troglitazone, rosiglitazone, pioglitazone), α-glucosidase inhibitors (e.g. acarbose, voglibose, miglitol), and glinides (e.g. nateglinide, repaglinide). This short review summarizes our experience to date with two additional classes of drugs introduced into our therapeutic armamentarium in the past decade: pramlintide (a synthetic amylin analog) and the dopamine D2 receptor agonist bromocriptine-QR (a quick-release formulation of bromocriptine mesylate). Both drugs share the advantages of not inducing hypoglycemia and weight gain, two major concerns faced when trying to intensify glycemic control.

Pramlintide acetate

  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References

Cosecretion of amylin with insulin (in an approximate 1:100 molar ratio) from the β-cells of pancreatic islets has been recognized for a long time.[1] Thus, insulinopenic patients with type 1 diabetes mellitus (T1DM) do not secrete amylin after food ingestion. Secretion of amylin in those with type 2 diabetes mellitus (T2DM) mimics that of insulin: “too little, too late”. Clinicians had attempted to correct only hypoinsulinemia because the molecular structure of amylin and its mechanism of action (it exerts its effects by specific binding to its cognate receptor in the central nervous system) had not been elucidated until the late 1990s.[2] It was not until March 2005 that the administration of pramlintide (Symlin®; Amylin Pharmaceuticals Inc., San Diego, CA, USA) was approved by the US Food and Drug Administration (FDA) ( for use in the US in patients with T1DM and T2DM, in conjunction with administration of prandial insulin to improve postprandial glycemic control. Figure 1 shows the amino acid sequences of native human amylin and synthetic pramlintide, with three amino acid differences in their primary structure. Native human amylin is poorly soluble and self-aggregating, which make it unsuitable for clinical use. The amino acid modifications of pramlintide acetate make it a stable bioactive peptide analog useful for clinical purposes.


Figure 1. Amino acid sequences of native human amylin and pramlintide.

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Mechanism of action

Pramlintide, by acting as an amylino-mimetic agent, has several effects in humans: (i) modulation of gastric emptying; (ii) prevention of the postprandial rise in plasma glucagon; and (iii) satiety, leading to decreased caloric intake and potential weight loss. All of its effects are mediated by its binding to a specific receptor in the central nervous system with neural transmission to peripheral target organs. The specific amylin receptors have been located in the nucleus accumbens, the dorsal raphe, and the hindbrain area postrema. It is likely that the latter area is key in mediating the physiological effects of amylin because it is located outside the blood–brain barrier.[3] The story of the development of pramlintide as a useful adjunct for the treatment of both T1DM and T2DM has been well summarized in many reviews (see, for example, Ryan et al.[4]).

Gastric emptying

The gastric emptying rate is an important determinant of the postprandial rise in plasma glucose. Pramlintide slows the rate at which food is released from the stomach into the small intestine following a meal; it does not affect small bowel or colonic transit time. Thus, it reduces the initial postprandial increase in plasma glucose.[5-7] This effect lasts for approximately 3 h following its administration. Pramlintide does not alter the net absorption of ingested carbohydrates or other nutrients.[5-7]

Postprandial glucagon secretion

In patients with diabetes, glucagon concentrations are abnormally elevated during the postprandial period, contributing to hyperglycemia. Pramlintide decreases postprandial glucagon concentrations in insulin-using patients with diabetes.[8, 9]


Pramlintide administered prior to a meal has been shown to reduce total caloric intake.[10, 11] This effect appears to be independent of the nausea that can accompany pramlintide treatment.

Clinical studies

Preapproval studies of pramlintide in both T1DM and T2DM as an adjunct to meal-time insulin injections have been summarized in several review articles.[12, 13] The results of typical experiments in T1DM and T2DM patients from these studies are summarized in Tables 1 and 2.[14-22] It is evident that the major effect of pramlintide is on the reduction of postprandial glucose excursions.[18, 23-25] That short-term effect was amply demonstrated in the initial placebo-controlled studies in patients with both T1DM and T2DM. The critical question for practitioners is whether these acute effects will translate into long-term glycemic benefits. A brief overview of some of the clinical trials is given below.

Table 1. Selected studies of pramlintide in patients with type 1 diabetes
StudyNo. patientsStudy duration (weeks)Pramlintide (μg)ΔHbA1c (%)ΔWeight (kg)
Buse et al.[13]5862660, t.i.d.–0.20–1.6
90, b.i.d.–0.10 (ns)–0.7
90, t.i.d.–0.10 (ns)–1.6
Placebo+0.10+0.3 (NS)
Fineman et al.[14]4795260, t.i.d.–0.40–1.4
60, q.i.d.–0.30–1.7
Hollander et al.[21]4805230, q.i.d.–0.39–0.5
60, q.i.d.–0.12+1.0
Hollander et al.[22]4795260, t.i.d.–0.29–0.4
60, q.i.d.–0.34–0.4
Table 2. Studies of pramlintide in patients with type 2 diabetes
StudyNo. patientsStudy duration (weeks)Pramlintide (μg)ΔHbA1c (%)ΔWeight (kg)
Gottlieb et al.[19]203430, q.i.d.–0.53–0.36
60, t.i.d.–0.58–0.89
60, q.i.d.–0.51–0.72
Gottlieb et al.[15]4992690, b.i.d.–0.30–0.80
90, t.i.d.–0.40–1.30
120, b.i.d.–0.40–1.40
Kolterman et al.[24]5385230, t.i.d.–0.30–0.30
75, t.i.d.–0.50–0.40
150, t.i.d.–0.60–1.20
Hollander et al.[21]6565260, t.i.d.–0.35–0.50
90, b.i.d.–0.62–1.40
120, b.i.d.–0.41–1.80
Thompson et al.[25]49826120, b.i.d.–0.41–1.80

Patients with T2DM (baseline HbA1c 9.1 ± 1.2%) were enrolled in a 52-week double-blind placebo-controlled parallel-group study and were treated with insulin (alone or in combination with sulfonylureas and/or metformin) and randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 μg, t.i.d.; 90 μg, b.i.d.; or 120 μg, b.i.d.).[21] Treatment with pramlintide 120 μg, b.i.d., resulted in a reduction from the rather high baseline in HbA1c by 0.68% and 0.62% at Weeks 26 and 52, respectively, which was significantly greater than that seen with placebo. The glycemic improvement with pramlintide 120 μg, b.i.d., was accompanied by a mean weight loss of –1.4 kg (compared with a gain of +0.7 kg with placebo) at Week 52 (P < 0.05) and occurred without an overall increase in the rate of severe hypoglycemia.

Reductions in postprandial glucose excursions by pramlintide also translated into sustained reductions in HbA1c in patients with T1DM. In a study of subjects with T1DM,[16] pramlintide treatment led to a mean reduction in HbA1c of 0.67% from baseline (mean 8.7%) to Week 13, which was significantly greater than the reduction in HbA1c in patients randomized to receive placebo (0.16%). A significant placebo-corrected treatment difference was sustained through Week 52.[16] The rate of severe hypoglycemia was not increased by pramlintide. In another study of patients with T1DM,[17] the addition of pramlintide 60 μg, t.i.d. or q.i.d., to insulin led to a small but significant reduction in HbA1c (from the high baseline of 8.9 ± 1.0%) of 0.29% and 0.34%, respectively, over 52 weeks. This was seen without an increase in insulin doses in the pramlintide-treated subjects. Within the subset of patients with an entry HbA1c between 7.0% and 8.5% (∼28% of all patients enrolled in three long-term studies), 196 were treated with placebo + insulin (baseline HbA1c 7.9 ± 0.4%, body weight 76.0 ± 14.3 kg) and 281 were treated with pramlintide + insulin (baseline HbA1c 7.9 ± 0.4%, body weight 75.4 ± 13.1 kg).[20] The addition of pramlintide resulted in significant reductions in HbA1c and body weight from baseline to Week 26 (0.3% and 1.8 kg, placebo-corrected treatment differences, respectively; both P ≤ 0.0009). These changes occurred without an increase in the overall risk of severe hypoglycemia.

In summary, the 26–52-week trials in patients with T1DM showed HbA1c lowering in the range 0.3%–0.6% from the rather high baseline of approximately 8.9%. The doses tested ranged from 30 to 90 μg, t.i.d. There was a mean weight loss of 0.9–1.4 kg. Hypoglycemia was rare and its incidence decreased with time. Similarly, studies of pramlintide in patients with T2DM lasted 26 or 52 weeks and resulted in a decline in HbA1c of 0.4%–0.7% from a baseline of approximately 9.1%. In general, weight loss was in the range 0.9–1.4 kg.

After approval of pramlintide in the US, several potentially relevant insights came from results of studies of subcutaneous continuous infusion of pramlintide in patients with T1DM and in combination with basal insulin in subjects with T2DM. For example, in a 24-h study, 13 adolescents with T1DM participated in a randomized, controlled crossover design trial that compared subcutaneous insulin therapy with insulin and pramlintide infusion.[26] Pramlintide was delivered by a separate pump. The addition of pramlintide led to a 26% reduction in postprandial hyperglycemia and reduced postprandial glucagon concentrations. In a longer 16-week open-label study in which 11 patients with T1DM were enrolled (mean age 39 years, baseline HbA1c 8.2%, body mass index [BMI] 29.7 kg/m2), pramlintide was delivered in a continuous basal-bolus subcutaneous infusion.[27] Subjects continued on their long-standing subcutaneous continuous insulin infusion therapy via a different pump. After 16 weeks HbA1c declined to a mean value of 7.8%, fasting plasma glucose (FPG) had decreased from 198 to 136 mg/dL, and weight was reduced by 0.5 kg. On average, patients reduced their bolus insulin by 20% by the end of the study while basal insulin was unchanged. There were no episodes of severe hypoglycemia documented.

Among patients with T2DM, three studies will be singled out. First, 212 patients with poorly controlled diabetes (baseline mean HbA1c 8.5%) on treatment with insulin glargine with or without concomitant oral hypoglycemic agents (OHA) were randomized in a double-blind fashion to either pramlintide (60 or 120 μg, b.i.d. or t.i.d.) or placebo for 16 weeks.[28] The primary endpoint was a composite score of achieving HbA1c ≤7%, HbA1c reduction of ≥0.5%, mean daily postprandial glucose increments of ≤40 mg/dL, no increase in body weight, and no severe hypoglycemia. This composite endpoint was achieved by more patients in the pramlintide group (25% vs 7%); HbA1c was reduced by 0.7% and the subjects lost, on average, 1.6 kg. All these parameters were significantly better than those achieved by patients randomized to the placebo arm of the study.[28] Second, 113 patients with uncontrolled T2DM (baseline HbA1c 8.2%) on basal insulin and OHA were randomized for 24 weeks to either meal-time pramlintide (120 μg, t.i.d.) or to titrated rapid-acting insulin analogs.[29] The primary endpoint of that study was the proportion of subjects reaching HbA1c ≤7% without weight gain or severe hypoglycemia, and occurred in more patients on pramlintide than on prandial insulin (30% vs 11%, respectively). Both therapies achieved the same improvements in HbA1c and FPG, but patients on insulin gained weight and had more mild-to-moderate hypoglycemia, whereas more patients in the pramlintide group complained of nausea (21%). Third, a retrospective chart review of clinical and laboratory data over 24 weeks of pramlintide therapy of 92 insulin-treated patients with T2DM was conducted and showed significant declines in HbA1c (from 8.3% to 7.9%), weight (from 104.4 to 103.2 kg) and low-density lipoprotein–cholesterol levels.[30] This improvement occurred despite reduced prandial insulin and adjustment of basal insulin and OHA.

In a interesting post-hoc analysis presented at the 2012 Scientific Session of the American Diabetes Association (ADA),[31] data were gathered from seven-point glucose profiles in patients with T2DM on pramlintide. The proportion of pre- and postprandial readings that fell above, below, or within glycemic targets in an open-label, 6-mont clinical practice trial showed a shift to more favorable glycemia (more euglycemia, less hyperglycemia) by Week 4 and was sustained through the end of the study. The percentage of measurements within the ADA-defined “euglycemic” range (i.e. preprandial 70–130 mg/dL, postprandial 70–180 mg/dL) increased from 37.2 ± 2.6% at baseline to 54.6 ± 3.1% during the final time period (4–6 months; P < 0.0001).[31]

Adverse events seen most commonly in patients with T1DM and T2DM injected with pramlintide have been gastrointestinal in nature. Specifically, for those with T1DM, the adverse events were nausea (initially reported by 37%–48% patients in different studies), anorexia (0%–17%) and vomiting (7%–11%).[14-22] In patients with T2DM, nausea was reported initially by approximately 30% patients, headache by 5%–13%, anorexia by 0%–9%, and vomiting by 7%–8%.[14-22] These events were usually mild-to-moderate in nature, dose dependent, and dissipated over time.

Clinical recommendation for use of pramlintide in T1DM and T2DM is to use it (subcutaneously via a pen device) only alongside prandial injections of rapid-acting insulin for meals containing at least 30 g carbohydrates ( Given the propensity to cause nausea, the dose of pramlintide is titrated gradually. Patients with T1DM are more sensitive to its action and start at a dose of 15 μg, t.i.d., pramlintide and increase it every 3 days (provided there is no nausea) by increments of 15 μg until they reach the maximum recommended dose of 60 μg, t.i.d. Patients with T2DM start at a dose of 60 μg, t.i.d., pramlintide and increase the dose to 120 μg, t.i.d., after 3 days. It is also recommended to initially decrease the dose of prandial insulin (not basal insulin) by 25–50% to minimize chances of hypoglycemia when pramlintide is added. This recommendation is usually relevant for those insulin-sensitive patients with T1DM who are relatively closer to glycemic targets. Patients with T2DM who are poorly controlled typically do not need prandial insulin decreases. Of course, the dose of insulin is uptitrated once a stable dose of pramlintide is reached.


  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References

Dopaminergic transmission affects glucose and lipid metabolism. It has been reported that patients with diabetes have lower hypothalamic dopaminergic tone early in the morning.[32] Activation of the hypothalamic–pituitary–adrenal axis resulting from this decline has been postulated to increase insulin resistance.[33, 39] This hypothesis could explain the increased free fatty acid and triglyceride concentrations, inflammation, and hypercoagulability seen in T2DM.[33]

The mechanism of action of bromocriptine-QR has been explored in a small number of patients. For example, in non-diabetic obese hyperinsulinemic subjects (n = 12) bromocriptine (1.6 mg/day for 2 weeks) reduced fasting and post-meal plasma glucose levels, accompanied by a decline in fasting and postprandial plasma insulin concentrations of approximately 50%.[34] There was no weight change observed in these subjects.

Eight-week treatment of insulin-resistant obese women (n = 13) by bromocriptine-QR resulted in lower plasma glucose, triglyceride, and free fatty acid concentrations and decreased plasma insulin levels.[35] Insulin-stimulated glucose disposal, measured with the insulin suppression test, was not altered. The improved postprandial plasma glucose[34] may result from decreased hepatic gluconeogenesis, as was documented previously in seasonally obese hamsters.[36] This speculation has not been yet confirmed in human studies. The decline in postprandial plasma free fatty acid and triglyceride concentrations[34] is similar to observations in animals.[36, 37]

In obese patients with T2DM (n = 22) given bromocriptine-QR for 16 weeks in a double-blind placebo-controlled fashion, glucose control improved (HbA1c decreased by 1.2%, FPG by 54 mg/dL, and mean plasma glucose during oral glucose tolerance test by 46 mg/dL).[38] Neither body weight, body fat, nor plasma insulin levels were changed in that study. Insulin sensitivity did not change during the first insulin clamp step (80 μU/mL) in a euglycemic–hyperinsulinemic clamp experiment, but maximally insulin-stimulated (377 μU/mL) glucose disposal was enhanced.[38] DeFronzo interpreted these findings as being consistent with those observed with the insulin suppression test,[39] demonstrating that, within the physiologic range of hyperinsulinemia, bromocriptine-QR does not improve insulin action in muscle. It remains unclear from these studies whether hepatic insulin sensitivity was enhanced by insulin.

In insulin-treated patients with T2DM randomized to 4.8 mg/day bromocriptine-QR (n = 21) or placebo (n = 11) for 12 weeks, bromocriptine-QR reduced HbA1c by 0.7% (from a baseline of 9.5%), mean diurnal glucose concentration by 29 mg/dL, and insulin dose by 8% without changing body weight.[40] These results are consistent with an improvement in insulin sensitivity in humans. The precise mechanism of this decrease in insulin resistance needs to be elucidated.

The quick-release formulation of bromocriptine (different from the one used for the treatment of prolactinoma for years) then addresses the central nervous system defect among patients with insulin resistance and T2DM. Its administration after awakening has been shown to normalize the dysfunctional circadian clock among insulin-resistant patients.[34] As a result, measures of insulin resistance have been shown to improve and result in improved glycemic control, mainly due to amelioration of postprandial hyperglycemia. Timing of the once-daily oral dose is critical with this preparation. It has to be given within the first 2 h in the morning after waking. Currently, only a single 0.8-mg dose is available; the drug is titrated once weekly, by increasing the dose by one pill, up to maximum of six pills (4.8 mg) or until the desired glucose effect or intolerance is achieved.

Bromocriptine-QR is approved for use in patients with T2DM uncontrolled by diet and exercise. It has been used as monotherapy as well in addition to patients’ customary antidiabetic therapy (including one or more oral agents or insulin). In Phase 3 studies, bromocriptine-QR was compared to placebo.[38, 41, 43] Obese T2DM subjects randomized in a double-blind placebo-controlled study of bromocriptine-QR as adjunct therapy to sulfonylurea (baseline HbA1c 9.4%) were held on a weight-maintaining diet.[41] The addition of bromocriptine-QR to sulfonylurea reduced HbA1c by a mean of 0.5% (∼1% for responders, 65% of patients), fasting and postprandial glucose by 23 and 26 mg/dL, respectively, fasting and postprandial triglycerides by 72 and 63 mg/dL, respectively, and fasting and postprandial free fatty acids by 150 and 165 μEq/L, respectively, relative to placebo (all statistically significant). However, 12% of all subjects receiving bromocriptine-QR withdrew from the study because of adverse events, compared with 3% of those receiving placebo. The most common events causing withdrawal were nausea, dizziness, asthenia, and rhinitis. Overall, among all reported adverse events during bromocriptine-QR studies, nausea (32% vs 8% in placebo) was the most common, followed by dizziness (15% vs 9%), fatigue (14% vs 7%) and headache (11 vs 8%). Bromocriptine-QR as monotherapy also improved glycemic control, with a 0.56% decrease in HbA1c compared with placebo after 24 weeks.[41]

In another 24-week study, bromocriptine-QR reduced HbA1c by approximately 0.7% (from a baseline of 8.3%) compared with placebo as monotherapy, and as addition to sulfonylurea compared with sulfonylurea alone.[42] In an intriguing 52-week safety trial with 3095 patients in which bromocriptine-QR was added to whatever therapy patients were receiving at the time (oral agents or insulin),[43] 42% relative risk reduction in composite cardiovascular endpoints (myocardial infarction, coronary revascularization, hospitalization for unstable angina, hospitalization for congestive heart failure) was seen among patients placed on bromocriptine-QR compared with placebo. In two additional post hoc analyses (n = 3070) that included only “hard” endpoints (death from cardiovascular causes, myocardial infarction, stroke),[44] the initially reported findings were confirmed: there was a 39% reduction in relative risk in the cardiovascular death-inclusive composite endpoint and a 52% reduction in the relative risk of major adverse cardiovascular events (Table 3).

Table 3. Effects of bromocriptine-QR versus placebo on major adverse cardiovascular events composite endpoint (myocardial infarction, stroke, cardiovascular death) in a 52-week randomized, double-blind study[43]
 Bromocriptine-QR (n = 2054)Placebo (n = 1016)HR (95% CI)
  1. Unless indicated otherwise, data show the number of patients in each group with percentages in parentheses.

  2. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction.

CV death4 (0.2%)2 (0.2%)0.48 (0.07–3.43)
MI7 (0.3%)9 (0.9%)0.41 (0.15–1.11)
Stroke5 (0.2%)6 (0.6%)0.44 (0.13–1.43)
MACE composite14 (0.7%)15 (1.5%)0.48 (0.23–1.00)

In a subset of patients enrolled in the 52-week safety study, among those with HbA1c ≥7.5% on thiazolidinedione therapy (n = 122; 73 evaluable per protocol at 52 weeks), HbA1c was reduced by a mean of 0.9% (from a baseline of 8.2%) compared with placebo.[45] Further, for the entire subset of 515 patients starting at HbA1c ≥7.5% and evaluable per protocol at 24 weeks, addition of bromocriptine-QR to the various antidiabetic therapies resulted in 32% of subjects reaching the target of HbA1c ≤7% (from an average baseline of 8.3%), compared with 6% of patients in the placebo group.[46] Specifically, HbA1c was reduced by 0.47% (vs +0.22% for placebo) for the entire group (n = 341 randomized to bromocriptine-QR; 33% discontinued prior to 24 weeks), by 0.55% (vs +0.26% for placebo) for those on metformin ± another antidiabetic agent (n = 237 on bromocriptine-QR; 33% discontinued), and by 0.63% (vs +0.20% for placebo) in an analysis that assessed only those on metformin and sulfonylurea therapy (n = 160 randomized to bromocriptine-QR; 41% discontinued).[45] The major reasons given for discontinuing bromocriptine-QR in that study were gastrointestinal in nature, with nausea being the most common. There was no adverse effect of bromocriptine-QR on weight or the risk of hypoglycemia.


  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References

It is apparent that results of basic scientific studies into the nature of pathophysiological defects in patients with T2DM are being gradually translated into the clinical arena. The present brief review highlights initial clinical results with two agents addressing two of the defects: (i) relative amylin deficit; and (ii) lower hypothalamic dopaminergic tone. As with all agents used to optimize glycemic control in patients with T2DM, it will be up to individual physicians to decide on the choice of specific agents and the sequence of their addition in order to achieve glucose targets in as safe a manner as possible.


  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References

The author has received research funding from Amylin and served on a speakers bureau for Amylin and Santarus over the past 12 months.


  1. Top of page
  2. Abstract摘要
  3. Introduction
  4. Pramlintide acetate
  5. Bromocriptine-QR
  6. Conclusions
  7. Disclosure
  8. References
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