Hyperglycemia results from a failure of beta-cell insulin-secretion capacity to adequately compensate for insulin resistance in peripheral tissues. Results from the UK Prospective Diabetes Study (UKPDS) indicate that beta-cell failure is progressive, despite therapy with diet, insulin, sulfonylurea, or metformin.1 As beta-cell dysfunction is progressive, many type 2 diabetic patients eventually require insulin as primary therapy to achieve glycemic control goals.2 Glucose control in this population remains inadequate, as average hemoglobin A1C (HbA1C) values reported in most epidemiologic studies are well above 8% as compared with normal levels of <6%, despite the availability of a number of therapeutic agents. The reason is current diabetes therapies lower blood glucose but do not target underlying mechanisms of beta-cell dysfunction.3 Recent breakthroughs in understanding incretin-based therapies provide additional options for treating type 2 diabetes from a pathophysiological basis. Exenatide is the first glucagon like peptide-1 (GLP-1) receptor agonist available for the treatment of type 2 diabetes and serves as a promising anti-diabetic agents, since activation of GLP-1 receptor has been reported to preserve beta-cell mass by stimulating beta-cell proliferation, and inhibiting beta-cell apoptosis, in addition to enhancing glucose-induced insulin secretion.4-6 Exenatide is a 39-amino acid GLP-1 receptor agonist that has multiple glucose regulatory modes of action, similar to those of endogenous GLP-1. Exenatide treatment is currently available as adjunctive therapy in many countries for patients with type 2 diabetes who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea, but have not achieved adequate glycemic control.7,8
Both insulin resistance and insulin deficiency appear to occur early in the development of type 2 diabetes and may be present for an extended period prior to diagnosis. Early use of incretin may be effective in preventing diabetes in those at risk, or in halting or in slowing down disease progression in patients with diabetes. Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest. Questions arise such as, what is the most appropriate timing for exenatide introduction in type 2 diabetes? Is it safe enough to be used as an initial therapy among type 2 diabetes patients in China?
According to the latest consensus statement on the treatment of hyperglycemia by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), in addition to lifestyle interventions, metformin was the first choice, especially by overweight type 2 diabetes patients.9,10 To further evaluate the efficacy, tolerability and beta-cell function of exenatide monotherapy, we conducted the current 26-week study in obese type 2 diabetes patients with exenatide or metformin.
Fifty-nine new obese type 2 diabetes patients were randomly assigned to exenatide (n=33) and metformin (n=26) groups for 26 weeks of therapy using a computer-generated allocation schedule. This study was approved by the ethics committee of Peking University First Hospital (No. 2010231). Investigators obtained patients’ written informed consent. Patients were eligible for this study if they were greater than 18 years of age, had new type 2 diabetes (<1 month), HbA1C 7%–10%, and body mass index (BMI) >28 kg/m2 and <40 kg/m2 or waist circumstance >90 cm (male) or 85 cm (female) (inclusive). Patients were required to have been managing their type 2 diabetes with diet and exercise, prior to the study. Patients were excluded if they had ever been treated with anti-diabetic or lipid lowering agents, had blood pressure >150/100 mmHg, had a history or presence of clinically significant cardiac disease within the year prior to inclusion in the study, had renal or hepatic dysfunction, or had a history or clinically suspected hyper- or hypothyroid disease and Cushing syndrome.
Initial 5 µg exenatide injections were given twice daily before morning and evening meals for 4 weeks, and without hypoglycemia then increased to 10 µg twice daily thereafter. Metformin administrations were started at 500 mg twice daily for 4 weeks, and then increased to 500 mg three times a day during 4–12 weeks. If fast plasma glucose (FPG) >6.1 mmol/L at week 12, metformin administrations was increased to 1000 mg twice daily. One confirmed hypoglycemic event (documented blood glucose <3.3 mmol/L) and 2 unconfirmed hypoglycemic events allowed the exenatide or metformin dose to be decreased 50% (additional episodes allowed further decrease or discontinuation).
Body weight, waist circumference, blood pressure, FPG, and side events were checked during monthly visits. HbA1C, liver and renal functions were tested at weeks 0, 12, and 26. Oral glucose tolerance test (OGTT) including insulin, and insulinogenic index (IGI30), homeostasis model assessment of beta-cell function (HOMA-B), and HOMA for insulin sensitivity (HOMA-S) were calculated at weeks 0 and 26.
Assays for insulin and HbA1C
Clinical blood samples were analyzed by clinical laboratories using standard methods. Serum insulin was quantitated by a chemiluminescent immunoassay (IMMULITE1000, Siemens, Germany). HbA1C was measured using high-performance liquid chromatography (Primus-Ultra2, Turkey). HOMA-B and HOMA-S measurements were determined based on FPG and fasting serum insulin values using HOMA 2 Calculator version 2.2.2 (Oxford Center for Diabetes). HOMA-B = 20 × fasting insulin (mU/ml)/fasting glucose (mmol/L) – 3.5. HOMA-S=1/(fasting insulin (mU/ml) × fasting glucose (mmol/L)).
All data were presented for the intent-to-treat (ITT) sample, which included all randomized patients who received more than one dose of the relevant drug. The analysis of covariance model was used to analyze variables measured only at baseline and the end of the study. The significance of the differences between means was assessed by Student’s t test. The HOMA-B data were logarithmically transformed to satisfy the normality assumption. Thus, geometric mean values are reported. Fisher’s exact test was used to analyze the following binary variables: proportion of participants achieving an HbA1C <6.5% (International Diabetes Federation) and <7% (American Association of Clinical American Diabetes Association) at study end (both using the last observation carried forward approach), incidence of hypoglycemia, and treatment elicited adverse events. Rates of hypoglycemia (episodes per year) were analyzed using an analysis of variance model. All tests of treatment differences were conducted at a 2-sided significance level of 0.05 with SSPS.13.0 software (SPSS Inc., USA). Unless otherwise stated, data were presented as means ± standard deviation (SD), and P values were presented for significant differences between exenatide and metformin.
Patient disposition and characteristics
Patient disposition is shown in Table 1. Of 59 randomized patients, 59 comprised an ITT sample and 58 completed the study. This is a treat to target study (FPG <6.1 mmol/L). Upon conclusion of the study, 31/33 patients treated with exenatide had 20 µg daily and 2/33 had 10 µg daily. According to FPG target level <6.1 mmol/L, 21/26 metformin patients had 1500 mg/d and 5/26 patients had 2000 mg/d. One patient enrolled with exenatide discontinued at week 4 due to severe nausea.
HbA1C and FPG values were comparable at baseline (Table 1). Significant differences in HbA1C and FPG from baseline were observed in both exenatide and metformin groups at 12 and 26 weeks (P <0.001). HbA1C endpoint data reduced from baseline, and were (–2.10±1.79)% in the exenatide group compared with (–1.66±1.38)% in the metformin group (P=0.045). The FPG changes from baseline were the same in both groups: (–1.8±2.0) mmol/L vs. (–1.6±1.7) mmol/L (P=0.80). The OGTT 2 hour glycemia reduction was greater with exenatide (–5.11±2.68) mmol/L than with metformin (–2.80±2.70) mmol/L (P=0.006). With exenatide, 97% and 79% of treated patients achieved HbA1C <7% and <6.5%, respectively, at end point, vs. 93% and 73% with metformin (P >0.05).
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Table 1. Baseline clinical data for exenatide and metformin groups
HOMA and insulinogenic index are shown in Table 2. HOMA-B values were comparable across treatment groups at baseline, with geometric means of 51.1% to 47.0%. These values did not significantly increase from baseline to end point in either group. HOMA-S values were comparable across treatment groups at baseline, with geometric means of 49.47% and 52.06%, and there was significant improvement in insulin sensitivity with exenatide, compared with metformin (P=0.042). The insulinogenic index, which reflects the acute insulin response, increased significantly with exenatide treatment (P=0.012).
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Table 2. HOMA and insulinogenic index before and after therapy
Weight, BMI, and waist circumference were comparable at baseline, with means of 82 and 83 kg, 30.6 and 29.3 kg/m2, 99 and 98 cm in the exenatide and metformin groups, respectively. Significant differences in weight, BMI and waist circumference changes from baseline were observed for exenatide at week 12 and for metformin at week 26 (P <0.05). At week 26, weight, BMI, and waist circumference changes from baseline were (–5.80±1.66) kg, (–3.42±0.62) kg/m2 and (–8.20±2.92) cm for exenatide treatment compared with (–3.81±1.38) kg, (–2.01±0.89) kg/m2 and (–3.10±1.06) cm in the metformin group (P <0.01).
Side effects observed in both groups are shown in Table 3. Most patients reported more than one treatment related adverse event (64% (21/33) in exenatide, and 50% (13/26) in metformin). The event(s) were mild or moderate in intensity. No treatment-emergent adverse events were reported. The incidence of nausea was significantly greater in the exenatide group (30%) vs. metformin (8%) (P=0.010). Nausea occurred mainly in the first few weeks of therapy and tended to decline with continued treatment, impacting 12% (4/33) of exenatide patients and 3.4% (1/26) of metformin patients, respectively. Hypoglycemia events were often reported during the first 4 weeks, which were observed in 12% of exenatide patients and 3.2% of metformin patients (P <0.05). Hypoglycemia rates per patient per year were 0.46 and 0.18. No severe cases of hypoglycemia were reported during the study (severe hypoglycemia: patients with hypoglycemia and need someone to help or to the hospital for treatment). No other significant adverse events were observed between the exenatide and metformin groups.
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Table 3. Side effects observed in both groups
Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest.11 In animal studies, when plasma insulin was still elevated at the compensatory stage, exenatide reversed transitory hyperglycemia and maintained islet morphology similar to that in non-diabetic animals. In contrast, treatment when plasma insulin was declining did not prevent decline of beta-cell mass.2 This suggests that the timing is crucial for pancreatic function intervention. GLP-1 based therapy initiated after administeration of oral antidiabetic agents does not achieve desired glucose levels. There have been few studies regarding early intervention with GLP-1 in type 2 diabetes. Moretto’s exenatide mono-therapy study showed that HbA1C reductions were significantly greater with exenatide than placebo (–0.9% vs. –0.2%), as were FPG reductions (mg/dl) (–18.7 vs. –5.2). Changes in weight (kg) at 26 weeks were greater with exenatide than placebo (–3.1 vs. –1.4). HOMA-B values increased from baseline to end point by 28% with exenatide, versus 6% for placebo.12
We used metformin as the control in the present study closely to mimic clinical applications. There was substantial reduction of HbA1C with 26 weeks of exenatide use compared with metformin in newly diagnosed type 2 diabetes patients. The reduction of HbA1C in exenatide was greater than that observed in previous mono- and add-on studies (0.9%–1.0%).12-16 Compared with those in the previous study, the diabetic duration was shorter (<1 month vs. 2 years) and initial pancreatic function evaluated with HOMA-B was better and body weight was significantly reduced (5.8 kg vs. 3.1 kg). We hypothesized that early administration in obese type 2 patients with exenatide would yield more benefits, such as timely glucose control and weight reduction. A follow-up study with a longer follow up time is needed to evaluate these beneficial effects on pancreatic beta-cell function and chronic diabetic complications such as CVD.
Body weight and waist circumference were significantly reduced with exenatide (5.8 kg and 8.2 cm) compared with metformin (3.8 kg and 3.1 cm). There was a greater reduction in body weight for exenatide group than that observed in previous studies (2–3 kg).12-15 It is not clear whether the differences in timing of initiation could be an underlying factor. There was no association between weight loss and the duration of nausea, and weight loss was observed in patients who did not experience nausea.
Pancreatic function and insulin sensitivity were evaluated by HOMA-B, insulinogenic-index, and HOMA-S. There was no significant change of HOMA-B in either group. The insulinogenic index was significantly increased with exenatide treatment compared with metformin. Improved acute insulin response with exenatide treatment has been reported in several previous studies.16-18 Insulin sensitivity measured using HOMA-S improved with exenatide treatment. The improvement of insulin sensitivity was due to significant body weight reduction and incretin direct effects.
GLP-1 is known to cause gastrointestinal side effects. The incidence of nausea (30%) and vomiting (3%) observed with exenatide monotherapy was the same as that in previous placebo-controlled and open-label comparator (insulin) studies of exenatide. In combination with oral antidiabetic agents, nausea was reported in 33%–57% of patients treated with exenatide, and vomiting in 10%–17%.12,14-17 Nausea occurred mainly in the first few weeks of therapy and tended to decline with continued treatment.
Because exenatide would ideally enhance insulin secretion with glucose dependence and not inhibit glucagon at low levels of glucose, there should be little hypoglycemia with exenatide monotherapy. Hypoglycemia incidence increased when exenatide was combined with oral antidiabetic drugs.13 We observed more hypoglycemia events with monotherapy of exenatide than observed in the Moretto studies (12% vs. 4%).The reason for this difference may be that there is more of a reduction in HbA1C with more hypoglycemia attacks. A higher percentage of patients achieved a reduction in HbA1C (<7%) in our study. Second, the residual beta-cell function remained before therapy because of shorter duration. Finally, insulin sensitivity was greatly improved. We suggest that hypoglycemia in exenatide monotherapy, would be caution especially in newly diagnosed patients and during the first 4 weeks of treatment. To reduce the risk of hypoglycemia attacks, the initial regimen started with 5 µg exenatide daily followed by a stepwise titration.
Exenatide monotherapy greatly improved HbAlC levels, postprandial glucose control and weight reduction. The major side effects were mild hypoglycemia and nausea. These data suggest that exenatide may provide a viable treatment option in obese Chinese with new type 2 diabetes.
The study’s limitation was that it was single center and had a small sample size because of economic reason.
1. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus - Progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281: 2005-2012.
2. Ferrannini E. The stunned beta cell: a brief history. Cell Metab 2010; 11: 349-352.
3. Turner RC, Cull CA, Stratton IM, Manley SE, Kohner EM, Matthews DR, et al. UK Prospective Diabetes Study 16-overview of 6 years therapy of type-II diabetes: A progressive disease. Diabetes 1995; 44: 1269-1258.
4. Nauck MA. Unraveling the science of incretin biology. Am J Med 2009; 122: S3-S10.
5. Nauck MA, Niedereichholz U, Ettler R. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997; 273(5 Pt 1): E981-E988.
6. Vilsboll T, Toft-Nielsen MB, Krarup T. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1. Diabetes Care 2000; 23: 807-812.
7. Heine RJ, Diamant M, Mbanya JC, Nathan DM. Management of hyperglycaemia in type 2 diabetes. BMJ 2006; 333: 1200-1204.
8. Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med 2011; 124: S3-S18.
9. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32: 193-203.
10. Nolan JJ. Consensus guidelines, algorithms and care of the individual patient with type 2 diabetes. Diabetologia 2010; 53: 1247-1249.
11. Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 2011; 60: 1-23.
12. Moretto TJ, Milton DR, Ridge TD, Okerson T, Wolka AM, Brodows RG. Efficacy and tolerability of exenatide monotherapy over weeks in antidiabetic drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo controlled, parallel-group study. Clin Ther 2008; 30: 1448-1460.
13. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007; 298: 194-206.
14. Nelson P, Poon T, Guan X, Schnabel C, Wintle M, Fineman M. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Diabetes Tecknol Tker 2007; 9: 317-326.
15. DeFronzo IRA, Ratner RE, Han J. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092-1100.
16. Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, et al. Effects of exenatide (exendin-4) on glycemic control over 52 weeks in patients with type 2 diabetes. J Clin Endocrinol Metab 2005; 90: 5991-5997.
17. Kendall DM, Riddle MC, Rosenstock J. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083-1091.
18. Zinman B, Hoogwerf BJ, Durán García S, Milton DR, Giaconia JM, Kim DD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: A randomized trial. Ann lntem Med 2007; 146: 477-485.