E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
`O R I G I N A L
`A R T I C L E
`
`Twelve- and 52-Week Efficacy of the
`Dipeptidyl Peptidase IV Inhibitor
`LAF237 in Metformin-Treated Patients
`With Type 2 Diabetes
`
`1
`BO AHR´EN, MD
`2
`RAMON GOMIS, MD
`EBERHARD STANDL, MD
`
`3
`
`4
`DAVID MILLS, MSC
`ANJA SCHWEIZER, PHD
`
`4
`
`OBJECTIVE — To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhib-
`itor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment.
`
`RESEARCH DESIGN AND METHODS — We conducted a 12-week, randomized,
`double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week
`extension in those completing the core study and agreeing, together with the investigator, to
`extend treatment to 1 year. Placebo (n ⫽ 51) or LAF237 (50 mg once daily, n ⫽ 56) was added
`to ongoing metformin treatment (1,500 –3,000 mg/day). HbA1c and fasting plasma glucose
`(FPG) were measured periodically, and standardized meal tests were performed at baseline, week
`12, and week 52.
`
`RESULTS — In patients randomized to LAF237, baseline HbA1c averaged 7.7 ⫾ 0.1% and
`decreased at week 12 (⌬ ⫽ ⫺0.6 ⫾ 0.1%), whereas HbA1c did not change from a baseline of
`7.9 ⫾ 0.1% in patients given placebo (between-group difference in ⌬HbA1c
`⫽ ⫺0.7 ⫾ 0.1%,
`P ⬍ 0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving
`LAF237 versus placebo by 2.2 ⫾ 0.4 mmol/l (P ⬍ 0.0001) and 1.2 ⫾ 0.4 mmol/l (P ⫽ 0.0057),
`respectively, but plasma insulin levels were not affected. At end point of the extension, the
`between-group differences in change in mean prandial glucose, insulin, and FPG were ⫺2.4 ⫾
`0.6 mmol/l (P ⫽ 0.0001), 40 ⫾ 16 pmol/l (P ⫽ 0.0153), and ⫺1.1 ⫾ 0.5 mmol/l (P ⫽ 0.0312),
`respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n ⫽
`42) but increased in participants given placebo (n ⫽ 29). The between-group difference in
`⌬HbA1c after 1 year was ⫺1.1 ⫾ 0.2% (P ⬍ 0.0001).
`
`CONCLUSIONS — Data from this study demonstrate that LAF237 effectively prevents de-
`terioration of glycemic control when added to metformin monotherapy in type 2 diabetes.
`
`Diabetes Care 27:2874 –2880, 2004
`
`T he compound LAF237 is an agent
`
`tion (dipeptidyl peptidase IV [DPP-4]). In
`short-term studies, LAF237 inhibited
`that potentiates the effects of the in-
`plasma DPP-4 activity, increased circulat-
`cretin hormones glucagon-like pep-
`ing levels of intact GLP-1, and improved
`tide 1 (GLP-1) and glucose-dependent
`glucose tolerance in animal models of
`insulinotropic peptide (GIP) by inhibiting
`type 2 diabetes (1,2) and in diabetic pa-
`the enzyme responsible for their degrada-
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From 1Lund University, Lund, Sweden; 2Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona,
`Spain; the 3Diabetes Research Institute, Munich, Germany; and 4Novartis Pharma, Basel, Switzerland.
`Address correspondence and reprint requests to Dr. Bo Ahre´n, Department of Medicine, Lund University
`B11 BMC, SE-221 84 Lund, Sweden. E-mail: bo.ahren@med.lu.se.
`Received for publication 28 May 2004 and accepted in revised form 7 September 2004.
`Abbreviations: AM⌬, adjusted mean change; CIRGluPeak, corrected insulin response at peak glucose;
`DPP-4, dipeptidyl peptidase IV; ECG, electrocardiogram; FPG, fasting plasma glucose; GIP, glucose-
`dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; I/G, insulinogenic index at peak glucose;
`ITT, intent to treat; SAE, serious adverse event; SMBG, self-monitoring of blood glucose.
`A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
`factors for many substances.
`© 2004 by the American Diabetes Association.
`
`tients (3). Similar findings were reported
`for a related compound NVP DPP728 (4),
`suggesting that DPP-4 inhibitors will be
`effective as monotherapy.
`Given the documented therapeutic
`effects of GLP-1 agonists, both alone (5)
`and in combination with metformin
`(6,7), we hypothesized that LAF237
`would also be effective in metformin-
`treated patients. In view of the potential
`disease-modifying effects of the incretins
`(8,9), we further hypothesized that the
`efficacy of LAF237 would be maintained
`with long-term treatment. The present
`study tested these hypotheses by assess-
`ing the effects of LAF237 added to an on-
`going stable dosage of metformin in
`patients with type 2 diabetes. In addition
`to providing “proof of concept” regarding
`the efficacy of a DPP-4 inhibitor com-
`bined with metformin, this study offers
`the first 52-week data on the efficacy and
`tolerability of a DPP-4 inhibitor.
`
`RESEARCH DESIGN AND
`METHODS — This was a multicenter,
`randomized, double-blind, placebo-
`controlled trial comparing the effects of
`12-week treatment with LAF237 (50 mg
`once daily, n ⫽ 56) and placebo (n ⫽ 51)
`in patients with type 2 diabetes continu-
`ing a stable dosage of metformin (1,500 –
`3,000 mg/day). The 12-week core study
`was followed by a 40-week extension in
`those patients completing the core study
`and agreeing, together with the investiga-
`tor, to participate (n ⫽ 42 for the LAF237/
`metformin group and n ⫽ 29 for the
`placebo/metformin group). Male or infer-
`tile female patients aged ⱖ30 years diag-
`nosed with type 2 diabetes at least 6
`months before enrollment and treated
`with a stable dosage of metformin for ⱖ3
`months were included. Prerandomization
`HbA1c while on metformin monotherapy
`was required to be between 7.0 and 9.5%
`(inclusive), and baseline BMI was re-
`quired to be between 20 and 35 kg/m2
`(inclusive).
`
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`
`Patients were excluded if they had a
`history of type 1 or secondary forms of
`diabetes, significant diabetes complica-
`tions, clinically significant cardiovascular
`abnormalities, liver disease, acromegaly,
`asthma, major skin allergies, or major gas-
`trointestinal surgery. Patients with fasting
`triglyceride levels ⬎5.1 mmol/l or fasting
`plasma glucose (FPG) ⬍6.1 or ⱖ13.3
`mmol/l were excluded, as were those
`treated with any drugs considered possibly
`able to affect results or their interpretation.
`Preceding randomization, there was a
`4-week run-in period in which patients
`received placebo while maintaining their
`previous metformin regimen. During this
`period, baseline assessments (HbA1c,
`FPG, lipids, standard biochemistry, he-
`matology and urinalysis, physical exam,
`and electrocardiogram [ECG]) were made
`to verify eligibility, and patients under-
`went a baseline standard meal test. Pa-
`tients were then randomized to LAF237
`plus metformin or placebo plus met-
`formin for 12 weeks of double-blind
`treatment. Fasting plasma levels of insulin
`and lipids and FPG were measured at
`weeks 1, 2, 4, 8, and 12. HbA1c was mea-
`sured at weeks 4, 8, and 12, and the stan-
`dard meal test was repeated at week 12 (or
`at end point). Forty-two and 29 patients
`receiving LAF237 plus metformin or pla-
`cebo plus metformin, respectively, partic-
`ipated in the extension, during which
`double-blind treatment continued;
`HbA1c and FPG were measured at weeks
`16, 24, 36, and 52. The standard meal test
`was repeated at week 52 (or at end point)
`of the extension.
`For standard meal tests, patients
`fasted overnight and study drug was ad-
`ministered 30 min before consumption of
`a standardized 465-kcal breakfast meal.
`The meal was consumed within 15 min,
`and samples for determination of glucose
`and insulin were obtained 35 and 5 min
`before and 5, 10, 15, 30, 60, 90, 120, 180,
`and 240 min after the start of the meal
`(time 0).
`All samples were analyzed at a central
`laboratory (Medical Research Laborato-
`ries International, Zaventem, Belgium)
`using standardized procedures. Insulin
`was measured by radioimmunoassay
`(Boehringer Mannheim, Mannheim, Ger-
`many), glucose was measured with a glu-
`cose oxidase technique, and HbA1c was
`measured using Tosoh ion-exchange
`high-performance liquid chromatogra-
`phy (normal range 4.0 – 6.0%).
`
`All adverse events were recorded and
`assessed as to their severity and possible
`relationship to study medication. Vital
`signs were measured and safety labora-
`tory assessments made at every visit. Pa-
`tients were provided with glucose
`monitoring devices and supplies and in-
`structed on their use. An episode of hypo-
`glycemia was defined as symptoms
`suggestive of hypoglycemia accompanied
`by a self-monitoring of blood glucose
`(SMBG) measurement of ⬍3.1 mmol/l
`plasma glucose equivalents.
`
`Data handling and statistical
`analysis
`The primary efficacy variable was the
`change from baseline (mean of week ⫺2
`and week 0) to the end point in HbA1c in
`the intent-to-treat (ITT) population, with
`the last observation carried forward in
`both the core study and the extension.
`The areas under the curve (AUCs) for glu-
`cose and insulin were calculated with the
`trapezoidal method. The insulinogenic
`index at peak glucose [I/G ⫽ ⌬ insulin
`(␮U/ml) at peak glucose/⌬ glucose (mg/
`dl) at peak) and the corrected insulin re-
`⫽
`sponse at peak glucose {CIRGluPeak
`insulin at peak glucose (␮U/ml) ⫻ 100/
`[peak glucose (mg/dl) ⫻ peak glucose
`(mg/dl) – 70]} (10,11) were calculated as
`measures of ␤-cell function. Secondary
`end points were change from baseline in
`FPG, lipids and body weight, the 4-h
`mean (AUC/time) prandial glucose, and
`insulin levels during standardized meal
`test, I/G and CIRGluPeak.
`Data were analyzed with an ANCOVA
`model including terms for treatment,
`baseline value, pooled center (or country
`for extension study), and treatment-by-
`baseline interaction. Analyses were con-
`ducted using two-sided tests and a signif-
`icance level of 0.05. The Cochran Mantel-
`Haenszel
`test was used to assess
`comparability of baseline characteristics
`for qualitative variables and the t test for
`quantitative variables. Unless otherwise
`specified, data are presented as means ⫾
`SEM.
`
`Ethics and good clinical practice
`Written informed consent was obtained
`from all patients and renewed before par-
`ticipation in the extension. The institu-
`tional review boards and independent
`ethics committees at each site approved
`the protocol. The study was conducted
`
`Ahre´n and Associates
`
`with good clinical practice in accordance
`with the Declaration of Helsinki.
`
`RESULTS
`
`Patient disposition and baseline
`characteristics
`In the core study, 56 and 51 patients were
`randomized to receive LAF237 plus met-
`formin or placebo plus metformin, re-
`spectively. Fifty (89%) of the LAF237
`plus metformin–treated patients and 47
`(92%) of the placebo plus metformin–
`treated patients completed the core study
`and were eligible to participate in the ex-
`tension. Participation in the 40-week ex-
`tension required agreement by patient
`and investigator: 42 and 29 LAF237 plus
`metformin– and placebo plus metform-
`in–treated patients, respectively, were in-
`cluded in the extension. Thirty-two (76%)
`and 26 (90%) of LAF237 plus metformin–
`and placebo plus metformin–treated exten-
`sion study participants, respectively, com-
`pleted the 1-year treatment.
`Table 1 reports the baseline charac-
`teristics of the ITT populations in the core
`study and extension and reasons for dis-
`continuations. The patients were predomi-
`nantly overweight, male, and Caucasian,
`with a mean age of ⬃57 years. Approxi-
`mately 50% were hypertensive. There were
`no significant differences among the groups
`in any baseline characteristic.
`
`Efficacy
`Figure 1 depicts HbA1c levels during the
`12-week core study and during the 52-
`week treatment in extension study partic-
`ipants. During the 12-week core study, in
`patients randomized to placebo plus met-
`formin, HbA1c did not change from a
`mean baseline of 7.9 ⫾ 0.1% (adjusted
`mean change [AM⌬] 0.1 ⫾ 0.1%). In pa-
`tients receiving LAF237 plus metformin,
`HbA1c decreased from a mean baseline of
`7.7 ⫾ 0.1% (AM⌬ – 0.6 ⫾ 0.1%). The
`between-group difference in the AM⌬
`HbA1c was ⫺0.7 ⫾ 0.1% (P ⬍ 0.0001).
`Baseline HbA1c averaged 7.6 ⫾ 0.1 and
`7.8 ⫾ 0.1% in the extension study partic-
`ipants receiving LAF237 plus metformin
`and placebo plus metformin, respec-
`tively. In the placebo plus metformin–
`treated patients, HbA1c increased from
`week 12 to week 52 at a rate of 0.0656%
`per month, whereas the rate of ⌬HbA1c in
`patients taking LAF237 plus metformin
`was less (0.0128% per month) than that
`in patients taking placebo plus metformin
`
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`LAF237 efficacy in metformin-treated patients
`
`Table 1—Baseline characteristics and patient disposition of the ITT populations for the 12-week core and extension studies*
`
`Randomized for 12-week study
`
`Extension population
`
`LAF/MET
`
`PBO/MET
`
`LAF/MET
`
`PBO/MET
`
`29
`42
`51
`56
`n
`54.3 ⫾ 12.2
`58.4 ⫾ 9.2
`55.7 ⫾ 11.0
`57.9 ⫾ 10.0
`Age (years)
`22 (75.9)
`26 (61.9)
`34 (66.7)
`39 (69.6)
`Sex (male)
`29.9 ⫾ 3.6
`29.6 ⫾ 3.7
`30.2 ⫾ 3.6
`29.4 ⫾ 3.6
`BMI (kg/m2)
`4.6 ⫾ 3.6
`5.8 ⫾ 4.2
`5.5 ⫾ 3.7
`5.6 ⫾ 4.2
`Duration of diabetes (years)
`23.7 ⫾ 25.1
`28.7 ⫾ 24.0
`29.8 ⫾ 36.1
`28.2 ⫾ 25.6
`Duration of previous MET treatment (months)
`7.8 ⫾ 0.6
`7.6 ⫾ 0.6
`7.8 ⫾ 0.7
`7.7 ⫾ 0.6
`HbA1c (%)
`10.1 ⫾ 1.8
`9.6 ⫾ 1.6
`10.3 ⫾ 2.0
`9.9 ⫾ 2.0
`FPG (mmol/l)
`13 (44.8)
`25 (59.5)
`27 (52.9)
`28 (50.0)
`Hypertension
`3 (10.3)
`10 (23.8)
`4 (7.8)
`6 (10.7)
`Discontinued
`0
`3 (7.1)†
`0
`0
`Adverse event
`0
`1 (2.4)
`0
`1 (1.8)
`Abnormal laboratory value
`2 (6.9)
`3 (7.1)
`1 (2.0)
`1 (1.8)
`Unsatisfactory therapeutic effect‡
`1 (3.4)
`2 (4.8)
`1 (2.0)
`1 (1.8)
`Protocol violation
`0
`0
`1 (2.0)
`1 (1.8)
`Withdrew consent
`0
`0
`0
`1 (1.8)
`Lost to follow-up
`0
`1 (2.4)
`0
`1 (1.8)
`Administrative problems
`0
`0
`1 (2.0)
`0
`Abnormal test procedure results
`Data are means ⫾ SD and n (%). *One patient in the randomized LAF/MET group was Asian, all other participants were Caucasian. †Adverse events leading to
`discontinuation were worsening of hypertension, moderate, not suspected to be related to study medication; first-degree atrioventricular block, mild, suspected to
`be related to study medication; and moderate peripheral edema suspected to be related to study medication. ‡As judged by the investigator. LAF/MET, LAF237 plus
`metformin group; PBO/MET, placebo plus metformin group.
`
`(P ⫽ 0.0243) and not significantly differ-
`ent from zero. In the extension popula-
`tion, the between-group difference in the
`AM⌬ HbA1c was ⫺1.1 ⫾ 0.2% (P ⬍
`0.0001). An end point HbA1c of ⬍7.0%
`was achieved by 41.7% of patients taking
`LAF237 plus metformin and by 10.7% of
`those taking placebo plus metformin.
`During the core study, in patients re-
`ceiving placebo plus metformin, mean
`baseline FPG was 10.2 ⫾ 0.3 mmol/l and
`increased slightly at the end point (AM⌬
`0.2 ⫾ 0.3 mmol/l). In patients receiving
`LAF237 plus metformin, FPG decreased
`from a mean baseline of 9.8 ⫾ 0.3 mmol/l
`(AM⌬ ⫺1.0 ⫾ 0.3 mmol/l). Thus, the be-
`tween-group difference in AM⌬ FPG was
`⫺1.2 ⫾ 0.4 mmol/l (P ⫽ 0.0057). In the
`extension, in patients receiving LAF237
`plus metformin, FPG decreased from an
`average baseline of 9.6 ⫾ 0.2 mmol/l to
`the end point (AM⌬ ⫺0.6 ⫾ 0.3 mmol/l),
`whereas in placebo plus metformin–
`treated patients, FPG increased from a
`baseline of 10.2 ⫾ 0.3 mmol/l (AM⌬
`0.5 ⫾ 0.4 mmol/l). The between-group
`difference was ⫺1.1 ⫾ 0.5 mmol/l (P ⫽
`0.0312).
`Figure 2 depicts plasma glucose and
`insulin profiles during standard meal tests
`performed at baseline and at the end point
`
`Figure 1—Time course of HbA1c in core study (open symbols) and extension (closed symbols). In
`the core study, the ITT populations consisted of 56 patients in the LAF237 plus metformin group
`(LAF/MET, ‚) (50 mg once daily) and 51 patients in the placebo plus metformin group (PBO/
`MET, E). Forty-two patients receiving LAF237 plus metformin (LAF/MET) participated in the
`extension (Œ) and 29 patients receiving placebo plus metformin (PBO/MET) participated in the
`extension (F). Data are means ⫾ SEM. Due to discontinuations or missing values, the number of
`measurements depicted for LAF237 plus metformin in the core study was 51 at weeks 4, 8, and 12
`and for placebo plus metformin in the core study was 50 at weeks 4 and 8 and 48 at week 12. Due
`to discontinuations or missing values, the number of determinations depicted for LAF237 plus
`metformin in the extension was 40 at week 24, 36 at week 36, and 33 at week 52 and for placebo
`plus metformin in the extension was 28 at weeks 16 and 36 and 26 at week 52.
`
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`Ahre´n and Associates
`
`Figure 2— Glucose (A and C) and immunoreactive insulin (IRI) (B and D) profiles during standardized meal tests performed at baseline (BL) (open
`symbols) and end point (EP) (closed symbols) of the 12-week core study (A and B) and the extension (C and D) in patients randomized to LAF237
`plus metformin (LAF/MET) (50 mg once daily, triangles) or placebo plus metformin (PBO/MET, circles). Data are means ⫾ SEM of ITT populations.
`In the core study, n ⫽ 56 for LAF237 plus metformin and n ⫽ 51 for placebo plus metformin. In the extension, n ⫽ 42 for LAF237 plus metformin
`and n ⫽ 29 for placebo plus metformin.
`
`of the core study and the extension. As
`illustrated in Fig. 2A, in the core study
`plasma glucose profiles were superimpos-
`able in the two groups at baseline and did
`not change during the 12-week treatment
`with placebo plus metformin. However,
`at week 12 or at the end point, plasma
`glucose levels were substantially lower in
`patients receiving LAF237 plus met-
`formin than in those receiving placebo
`plus metformin at all time points. The be-
`tween-group difference in the AM⌬ 4-h
`mean glucose level was ⫺2.2 ⫾ 0.4
`mmol/l (P ⬍ 0.0001).
`As shown in Fig. 2B, in the core study
`the plasma insulin profiles were essen-
`tially indistinguishable at baseline and at
`the end point in both groups of patients.
`The between-group difference in the
`AM⌬ 4-h mean insulin was 2.1 ⫾ 10.2
`pmol/l (P ⫽ 0.8415). However, the
`CIRGluPeak was significantly increased,
`and the I/G tended to be improved in pa-
`tients receiving LAF237 plus metformin
`
`relative to those receiving placebo plus
`metformin. The between-group differ-
`ence in the AM⌬ CIRGluPeak was 0.05 ⫾
`0.01 (P ⫽ 0.0007), and the between-
`group difference in the AM⌬ I/G was
`0.13 ⫾ 0.07 (P ⫽ 0.0565).
`As illustrated in Fig. 2C, although the
`glucose profiles in the extension partici-
`pants randomized to LAF237 plus met-
`formin and placebo plus metformin were
`very similar at baseline, prandial glucose
`control worsened in patients taking pla-
`cebo plus metformin and clearly im-
`proved during the 52-week treatment
`with LAF237 plus metformin. The be-
`tween-group difference in the AM⌬ 4-h
`mean glucose was ⫺2.4 ⫾ 0.6 mmol/l
`(P ⫽ 0.0001).
`As depicted in Fig. 2D, during the 52-
`week treatment in the extension popula-
`tion, prandial insulin levels decreased in
`patients randomized to placebo plus met-
`formin and increased in those receiving
`LAF237 plus metformin. The between-
`
`group difference in AM⌬ 4-h mean im-
`munoreactive insulin level was 40 ⫾ 16
`pmol/l (P ⫽ 0.0153). The CIRGluPeak and
`I/G were also significantly increased in pa-
`tients receiving LAF237 plus metformin
`relative to those receiving placebo plus
`metformin. The between-group differ-
`ence in the AM⌬ CIRGluPeak was 0.05 ⫾
`0.01 (P ⫽ 0.0005), and the between-
`group difference in the AM⌬ I/G was
`0.17 ⫾ 0.07 (P ⫽ 0.0160).
`During the core study, there was no
`significant change in any lipid parameter
`(fasting triglycerides and total, HDL, and
`LDL cholesterol) or body weight. In the
`extension study, there was no significant
`effect of LAF237 on HDL cholesterol,
`LDL cholesterol, or triglycerides. How-
`ever, there was a modest decrease in total
`cholesterol in LAF237 plus metformin–
`treated patients relative to those receiving
`placebo plus metformin (between-group
`difference in AM⌬ ⫺0.30 ⫾ 0.14 mmol/l,
`P ⫽ 0.034). Body weight decreased by
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`LAF237 efficacy in metformin-treated patients
`
`Table 2—Adverse events occurring in >5% of patients in any treatment group
`
`Safety population
`
`12-week study
`
`Extension
`
`LAF/MET
`
`PBO/MET
`
`LAF/MET
`
`PBO/MET
`
`29
`42
`51
`56
`n
`0
`1 (2.4)
`0
`3 (5.4)
`Cough
`4 (13.8)
`6 (14.3)
`6 (11.8)
`2 (3.6)
`Nasopharyngitis
`0
`3 (7.1)
`0
`0
`Worsening hypertension
`2 (6.9)
`1 (2.4)
`3 (5.9)
`1 (1.8)
`Urinary tract infection
`2 (6.9)
`0
`0
`0
`Gastroenteritis
`2 (6.9)
`1 (2.4)
`0
`0
`Bursitis
`Data are n (%). LAF/MET, LAF237 plus metformin group; PBO/MET, placebo plus metformin group.
`
`0.4 ⫾ 0.2 kg in patients receiving LAF237
`plus metformin and by 0.5 ⫾ 0.2 kg in
`patients receiving placebo plus met-
`formin during the 12-week core study. In
`extension study participants, the body
`weight change from baseline to end point
`was ⫺0.2 kg in both groups.
`
`Safety and tolerability
`During the core study, the overall inci-
`dence of any adverse event was similar in
`patients randomized to LAF237 plus met-
`formin (29 patients, 51.8%) and placebo
`plus metformin (28 patients, 54.9%). In
`the extension population, 29 (69.0%) and
`17 (58.6%) of LAF237 plus metformin–
`treated and placebo plus metformin–
`treated participants, respectively,
`experienced an adverse event. Table 2 de-
`tails the incidence of adverse events oc-
`curring in ⱖ5% of patients in any group.
`Three patients in the extension popula-
`tion receiving LAF237 plus metformin
`were observed to have worsening of hy-
`pertension, requiring additional antihy-
`pertensive treatment. One of these
`patients discontinued, but none of these
`adverse events were suspected to be drug
`related.
`One hypoglycemic episode (symp-
`toms of hypoglycemia confirmed by
`SMBG ⬍3.1 mmol/l plasma glucose
`equivalents) was experienced by each of
`two patients receiving LAF237 plus met-
`formin during the core study, and there
`were no hypoglycemic episodes during
`the extension. Additionally, one patient in
`the core study and one patient in the ex-
`tension study receiving LAF237 plus met-
`formin each reported three instances of
`asymptomatic SMBG ⱕ3.7 mmol/l (3.4,
`2.7, and 3.3 mmol/l and 2.1, 3.6, and 3.4
`mmol/l, respectively) plasma glucose
`
`equivalents. There were three additional
`patients receiving LAF237 plus met-
`formin with symptoms suggestive of low
`glucose: one patient in the core study with
`an SMBG of 3.5 mmol/l plasma glucose
`equivalents, one patient in the extension
`with an SMBG of 3.8 mmol/l plasma glu-
`cose equivalents, and one patient in the
`extension with no glucose measurement
`obtained.
`Notable laboratory abnormalities
`were uncommon and occurred in a simi-
`lar percentage of patients in each group.
`There were no consistent changes in ECG
`parameters or between-group differences
`in the change from baseline to end point
`in ECG parameters.
`During the core study, there were five
`serious adverse events (SAEs), one in the
`LAF237 plus metformin group and four
`in the placebo plus metformin group, but
`none were thought to be drug related.
`During the extension study there were
`seven SAEs, five events in four patients in
`the LAF237 plus metformin group and
`two events in one patient in the placebo
`plus metformin group. The only SAE
`thought to be drug related was an episode
`of peripheral edema in a patient receiving
`LAF237 plus metformin. No deaths oc-
`curred during this study.
`
`CONCLUSIONS —This study showed
`that when added to metformin treatment,
`LAF237 was effective at improving glyce-
`mic control for at least 1 year in patients
`with type 2 diabetes and appeared to be
`well tolerated. This represents the first
`data available on combination therapy
`with a DPP-4 inhibitor and attests to the
`durability of efficacy of LAF237. Two pre-
`vious 4-week studies of drug-naı¨ve pa-
`tients with type 2 diabetes confirmed that
`
`a DPP-4 inhibitor reduces both fasting
`and postprandial glucose levels and sug-
`gested that this approach will be effective
`as monotherapy (3,4), but questions
`about longer-term effects of DPP-4 inhib-
`itors and their potential efficacy in com-
`bination therapy remained unanswered.
`The 12-week treatment with LAF237
`produced a placebo-subtracted reduction
`in HbA1c of 0.7% in patients with baseline
`HbA1c levels of ⬃7.7% while on a stable
`dosage of metformin. After 52 weeks, the
`between-group difference in HbA1c was
`⫺1.1%, reflecting deterioration of glyce-
`mic control in placebo plus metformin–
`treated patients and a stable HbA1c of
`⬃7.1% from week 12 to week 52 in pa-
`tients treated with LAF237 plus met-
`formin. The magnitude of the effect of
`LAF237 is notable for at least two reasons.
`First, HbA1c reductions are invariably
`found to be proportional to baseline lev-
`els, and the patients in this study had only
`moderately elevated baseline HbA1c while
`on metformin monotherapy. Second, the
`essentially flat HbA1c profile seen in
`LAF237 plus metformin–treated patients
`from week 12 to week 52 raises the in-
`triguing question of whether LAF237 may
`influence mechanisms underlying the
`progression of the disease. This, of course,
`would need to be addressed in larger and
`longer studies with a different trial design.
`The mechanism by which LAF237
`improved glycemic control in these met-
`formin-treated patients was not directly
`addressed; however, it is likely attribut-
`able to inhibition of DPP-4 and resultant
`increases of circulating levels of the intact,
`biologically active incretins. Although
`plasma DPP-4 activity, GLP-1, and GIP
`were not measured here, earlier studies
`have shown that LAF237 profoundly sup-
`presses DPP-4 activity and increases
`plasma levels of intact GLP-1 (3) and GIP
`(12).
`In the core study, addition of LAF237
`to ongoing metformin therapy decreased
`fasting and postmeal glucose levels by 1.2
`and 2.2 mmol/l, respectively, but did not
`significantly affect plasma insulin levels.
`In light of the consistently reported effects
`of GLP-1 to augment insulin secretion in
`the presence of hyperglycemia (13–17),
`this finding may be initially surprising.
`However, insulin secretion can improve
`without changes in circulating insulin lev-
`els, and when assessing ␤-cell function it
`is appropriate to consider insulin levels in
`the context of the glucose concentration
`
`2878
`
`DIABETES CARE, VOLUME 27, NUMBER 12, DECEMBER 2004
`
`MYLAN Ex. 1005, Page 5
`
`

`
`(18,19). Thus, unchanged or even de-
`creased insulin levels in the face of de-
`creased glucose may reflect improvement
`of ␤-cell function. Indeed, in this study
`the insulin response to meals corrected
`for glucose (CIRGluPeak) (see RESEARCH DE-
`SIGN AND METHODS for details) was signifi-
`cantly increased relative to placebo in
`both the core and extension study popu-
`lations, and the insulinogenic index at
`peak glucose was also significantly im-
`proved in the extension. Further, in the
`extension, the 4-h mean prandial insulin
`levels were significantly increased relative
`to placebo. Taken together, these findings
`suggest that LAF237 improves ␤-cell
`function, although more sophisticated
`tests will be required to characterize the ef-
`fects of LAF237 on insulin secretion per se.
`Whether slowing of gastric emptying
`or suppression of glucagon secretion con-
`tributed to the antidiabetic actions of the
`DPP-4 inhibitor cannot be determined
`from the data obtained here; however, it
`may be of interest to note that in the
`4-week monotherapy study of LAF237, it
`was concluded that reduced glucagon se-
`cretion is an important factor in the glu-
`cose-lowering effects of this compound
`(3).
`
`The present study also provides infor-
`mation regarding the safety/tolerability of
`LAF237. The overall incidence of adverse
`events was similar in the two groups of
`patients, and only one serious adverse
`event (peripheral edema in a patient re-
`ceiving LAF237 plus metformin during
`the extension) was suspected to be drug
`related. Although none of the three ad-
`verse events reported as worsening hyper-
`tension (occurring in LAF237 plus
`metformin–treated patients in the exten-
`sion) were suspected to be drug related,
`the influence of DPP-4 inhibition and/or
`GLP-1 on blood pressure merits further
`clinical study. There were no notable
`changes in hematology, biochemistry, or
`ECG suspected to be drug related, and the
`frequency of any specific adverse event
`was low. Overall, DPP-4 inhibition in
`general and LAF237 in particular appear
`to be well tolerated, although this needs
`to be confirmed when a larger database is
`available.
`In summary, 1-year treatment with
`once-daily LAF237 (50 mg) reduced fast-
`ing and postprandial plasma glucose lev-
`els and produced a sustained reduction in
`HbA1c in metformin-treated patients with
`type 2 diabetes having a baseline HbA1c of
`
`⬃7.7% with a favorable tolerability pro-
`file. Although larger and longer-term
`studies in a variety of patient populations
`will be required to fully establish the effi-
`cacy and safety of LAF237, inhibition of
`DPP-4 is a promising new approach for
`the treatment of type 2 diabetes and may
`be useful in a broad spectrum of patients.
`
`Acknowledgments— B.A. is grateful for sup-
`port from the Swedish Research Council.
`The authors gratefully acknowledge Mona
`Landin-Olsson, Lund; Per-Anders Jansson,
`Go¨ teborg; Maria Svensson, Umeå; Suad Efen-
`dic, Stockholm; Per Olof Ohlsson, Karlstad;
`and Ibe Lager, Kristianstad, Sweden, and other
`physicians, research nurses, and patients who
`participated in the study.
`
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