Research: Treatment Efficacy and safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes S. Duran-Garcia1, J. Lee2, H. Yki-J€ arvinen3, J. Rosenstock4, U. Hehnke2, S. Thiemann2, S. Patel5 2 and H.-J. Woerle 1 Valme University Hospital Medical School, Seville, Spain, 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, 3Department of Medicine, University of Helsinki, Helsinki, Finland, 4Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA and 5Boehringer Ingelheim Ltd, Bracknell, UK
Accepted 18 November 2015
Abstract Aim To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin. Methods This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks.
A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (SE) change from baseline in HbA1c with linagliptin was –7 (1) mmol/mol [–0.7 (0.1) %; 95% CI –0.8, –0.6; P < 0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (SD) body weight were noted in either group [week 52: linagliptin, –0.5 (3.2) kg; placebo, 0.0 (3.1) kg]. Results
Conclusions Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.
Diabet. Med. 33, 926–933 (2016)
Introduction Guidelines for the treatment of Type 2 diabetes mellitus collectively recommend metformin as initial therapy [1–3]; however, because of the progressive decline in pancreatic bcell function in Type 2 diabetes, many patients will eventually fail to maintain glycaemic control with metformin alone . Failure of monotherapy alone is also attributed to the inability to act on the multiple pathophysiological mechanisms involved in the deterioration in glucose control ; therefore, most patients will eventually require the addition of one or more oral antidiabetic drugs or insulin replacement therapy to help achieve and maintain treatment glycaemic targets. Correspondence to: S. Duran-Garcia. E-mail: [email protected]
Although patients and physicians are often reluctant to initiate insulin therapy, patients with worsening or very high levels of hyperglycaemia may need daily subcutaneous insulin to achieve glycaemic targets. When insulin is initiated, metformin is typically continued—the rationale being that combining insulin with an insulin-sensitizing drug will reduce the need for high daily doses of insulin, thereby minimizing the risk of hypoglycaemia and body weight gain . Compared with insulin alone, this combination has been shown to provide better glycaemic control with less risk of hypoglycaemia and minimal increase in body weight [7–10]. As a consequence, combining basal insulin with metformin represents a common treatment option for patients with Type 2 diabetes in clinical practice .
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What’s new? • In people with Type 2 diabetes who are receiving metformin and are required to transition to basal insulin therapy, metformin is often continued as an effective adjunct therapy to mitigate the need for high doses of insulin, and thereby minimize the risk of hypoglycaemia and body weight gain. • In those who fail to achieve or maintain glycaemic targets with this combination, the addition of a dipeptidyl peptidase-4 inhibitor may further improve glycaemic control. • The results of the present analysis suggest that the addition of linagliptin to a background of basal insulin and metformin improves glycaemic control, with low additional risk of hypoglycaemia or body weight gain.
As a result of disease progression, the combination of basal insulin and metformin may also eventually be insufficient to achieve glycaemic targets; however, patients and physicians are often reluctant to further titrate the dose of basal insulin or add prandial insulin because of concerns about the increased risk of hypoglycaemia and body weight gain, as well as the complexity of insulin therapy. The addition of a dipeptidyl peptidase (DPP)-4 inhibitor to a regimen of insulin and metformin could be a simple option to improve glucose control without the deleterious effects associated with insulin uptitration. Furthermore, the combination of a DPP-4 inhibitor and basal insulin provides complementary mechanisms of action because DPP-4 inhibitors lower postprandial glucose and basal insulin reduces fasting plasma glucose (FPG). Linagliptin is an oral DPP-4 inhibitor which is available for the treatment of Type 2 diabetes in a 5-mg once-daily dose as monotherapy or in combination with various oral antidiabetic drugs and also insulin . A phase III study evaluated the efficacy and long-term safety of linagliptin added to basal insulin, alone or in combination with metformin and/or pioglitazone . The addition of linagliptin significantly improved glycaemic control compared with placebo without increasing hypoglycaemia or body weight. In the present subanalysis we investigated the efficacy and safety of linagliptin in combination with basal insulin and specifically in participants also on metformin, the most common background treatment in the aforementioned phase III study .
Participants and methods
Type 2 diabetes (NCT00954447). The design and methodology of this trial have been described previously in detail . Briefly, eligible study participants were aged ≥18 years with a diagnosis of Type 2 diabetes and inadequate glycaemic control [glycated haemoglobin (HbA1c) ≥53 to ≤86 mmol/mol (≥7.0 to ≤10.0%)], had a body mass index (BMI) of ≤45 kg/m2, and were being treated with basal insulin alone or in combination with metformin and/or pioglitazone for ≥12 weeks. The main exclusion criteria were: uncontrolled fasting hyperglycaemia (glucose >13.3 mmol/l); myocardial infarction, stroke or transient ischaemic attack < 6 months before informed consent; impaired hepatic function; previous gastric bypass surgery; or any medical history of cancer in the 5 years before screening . The protocol of the original study  was reviewed and approved by the independent ethics committees or institutional review boards of each participating site. The study was conducted in compliance with the principles of the Declaration of Helsinki (1996), and in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. All participants gave written informed consent before participation. Eligible participants were randomized (1:1) to receive double-blind treatment with linagliptin 5 mg or placebo for ≥52 weeks as add-on therapy to basal insulin, alone or in combination with metformin and/or pioglitazone. The background basal insulin dose was kept stable for the first 24 weeks (within 10% of baseline dose), but could then be titrated according to the clinical judgement of the investigator with a FPG target of 6.1 mmol/l. The dose of metformin was to remain stable throughout the study. This subanalysis included data from all participants who were receiving basal insulin in combination with metformin in the original parent trial . The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. Secondary endpoints were the change from baseline in HbA1c over time, the proportion of participants achieving HbA1c <53 mmol/mol (<7.0%) after 52 weeks, the change in FPG after 24 weeks and over time, and the change from baseline in basal insulin dose over time. The change from baseline in body weight to the end of treatment was assessed. Safety endpoints included the frequency and intensity of adverse events, including hypoglycaemia. Adverse events were also analysed according to renal impairment status. Other safety endpoints included adjudicated cardiovascular events (cardiovascular death, myocardial infarction, stroke, or hospitalization as a result of unstable angina), and changes in laboratory variables including amylase levels.
This subanalysis further evaluated data from a global placebo-controlled, phase III trial in participants with
This subanalysis was a post hoc analysis using the prespecified statistical methods from the main study report . The
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Linagliptin as add-on to basal insulin and metformin in Type 2 diabetes S. Duran-Garcia et al.
primary and secondary efficacy endpoints were evaluated on the full analysis set, which comprised all randomized participants who received at least one dose of study medication and who had a baseline measurement and at least one on-treatment HbA1c measurement within the first 24 weeks of treatment. The primary efficacy endpoint was the change in HbA1c from baseline to week 24, which was analysed using ANCOVA at the two-sided level of a=0.05. The model included ‘treatment’ and ‘baseline renal impairment category’ as fixed classification effects, and ‘baseline HbA1c’ as a covariate. A last observation carried forward (LOCF) approach was used to impute missing data. The same method was used to evaluate change in HbA1c over time. Change in FPG from baseline to week 24 was analysed using ANCOVA similar to the primary analysis with the addition of ‘baseline FPG’ as another covariate. The change in FPG over time was analysed using descriptive statistics based on observed cases (missing data values were excluded; data obtained after the use of rescue medication were set to missing). For analysis of participants achieving a HbA1c of <53 mmol/mol (<7.0%), missing values were imputed using the non-completers considered failure approach. Change in insulin dose from baseline to week 52 was analysed using ANCOVA with ‘treatment’, ‘continuous baseline HbA1c’, ‘continuous baseline weight’, ‘continuous baseline insulin’ and ‘baseline renal impairment category’ as covariates; change in insulin dose over time was analysed descriptively using either a last observation carried forward approach or original results (all observed data were analysed including values
obtained after rescue therapy; no imputation for missing data). Changes in laboratory variables and body weight were analysed using descriptive statistics. All randomized participants treated with at least one dose of study drug (treated set) were included in the safety evaluation. Safety endpoints were summarized using descriptive statistics. The respective International Federation of Clinical Chemistry Laboratory Medicine and International System of Units values for HbA1c and FPG were converted after statistical analyses had been conducted.
Results Participant disposition, demographics and clinical characteristics
Of the 1261 participants randomized in the parent study, 950 were on insulin and metformin background therapy (linagliptin, n = 475; placebo, n = 475). Of these, 815 participants completed the trial. In both arms, the main reasons for discontinuation were adverse events (n = 42) and refusal to continue trial medication (n = 36; Fig. 1). Baseline demographics and clinical characteristics were similar in the linagliptin and placebo groups (Table 1). The mean (SD) age of participants at baseline was 59.6 (9.8) years and the body mass index (BMI) was 31.0 (5.2) kg/m2. Overall, participants had a mean (SD) baseline HbA1c of 67 (9) mmol/mol [8.3 (0.8)%] and a mean FPG of 8.4 (2.5) mmol/l. More than half of participants had mild or moderate
Screened (n = 1221) Excluded (n = 270)* Adverse events (1) Did not meet inclusion criteria (195) Exclusion criteria met (32) Lost to follow-up (3) Consent withdrawn (24) Other (21) Randomized (n = 951) Not treated (n = 1) Treated set (n = 950)
Linagliptin (n = 475)
Placebo (n = 475)
Discontinued (n = 56) Adverse events (19) Lost to follow-up (6) Protocol violation (4) Lack of efficacy (2) Refused to continue medication (14) Other (11)
Discontinued (n = 79) Adverse events (23) Lost to follow-up (7) Protocol violation (3) Lack of efficacy (11) Refused to continue medication (22) Other (13) Completed (n = 419) FAS (n = 470)
Completed (n = 396) FAS (n = 464)
FIGURE 1 Participant disposition. *Participants may be counted in more than one category. FAS, full analysis set.
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Table 1 Baseline demographics and clinical characteristics Linagliptin Demographics Participants (treated set*), n 475 Men, n (%) 238 (50.1) Race, n (%) American Indian/Alaska 2 (0.4) Native Asian 69 (14.5) Black or African-American 21 (4.4) Hawaiian/Pacific Islander 2 (0.4) White 381 (80.2) Age, years, mean SD 59.3 9.9 Body weight, kg, mean SD 85.0 18.1 BMI, kg/m2, mean SD 30.9 5.4 Renal function (eGFR) according to MDRD, n Normal (≥90 ml/min/ 227 (47.8) 1.73 m2) 214 (45.1) Mild impairment (60 to <90 ml/min/1.73 m2) 34 (7.2) Moderate impairment (30 to <60 ml/min/1.73 m2) Clinical characteristics 470 Participants (full analysis set†), n HbA1c, mean SD mmol/mol 67 10 % 8.3 0.9 FPG‡, mmol/l, mean SD 8.3 2.5 Time since diagnosis of diabetes, n (%) ≤1 year 11 (2.3) >1 to ≤5 years 70 (14.9) >5 years 389 (82.8) Basal insulin dose, 40.2 30.2 U/day, mean SD Cardiovascular risk factors, n (%) Coronary artery disease 90 (18.9) Peripheral artery occlusive 23 (4.8) disease Cerebrovascular disease 28 (5.9) Hypertension 374 (78.7)
BMI, body mass index; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; MDRD, Modification of Diet in Renal Disease. *Treated set: all randomized participants who were treated with at least one dose of study medication. † Full analysis set: all randomized participants treated with at least one dose of study medication and who had a baseline and at least one on-treatment HbA1c measurement. ‡ Missing patients: linagliptin, n = 2; placebo, n = 3.
renal impairment (51.7%) and most participants had been diagnosed with diabetes for > 5 years (84.8%). Efficacy: changes in HbA1c and fasting plasma glucose
At week 24, the adjusted mean (SE) changes from baseline in HbA1c were –7 (1) mmol/mol [–0.63 (0.06)%] with linagliptin and 0.4 (0.7) mmol/mol [0.04 (0.06)%] with placebo; this resulted in a placebo-corrected adjusted mean (SE) change of –7 (1) mmol/mol [–0.7 (0.1)%; 95% CI –0.8, –0.6; P < 0.0001 (Fig. 2)]. At week 52, the placebocorrected adjusted mean (SE) change from baseline in HbA1c with linagliptin was –6 (1) mmol/mol [–0.6 ª 2015 Diabetes UK
(0.1)%; 95% CI –0.7, –0.5; P < 0.0001]. Among participants with baseline HbA1c ≥53 mmol/mol (≥7.0%), more participants in the linagliptin group compared with the placebo group achieved a HbA1c target of <53 mmol/mol (<7.0%) after 52 weeks of treatment (16.4 vs 6.5%). Treatment with linagliptin was associated with a statistically significant placebo-corrected adjusted mean (SE) reduction in FPG of –0.8 (0.2) mmol/l (95% CI –1.1, –0.4; P < 0.0001) at week 24. During the remainder of the trial period when insulin titration was allowed, further decreases in FPG levels up to 52 weeks were observed with linagliptin and placebo (Fig. 3).
Efficacy: changes in background insulin dose and body weight
During the first 24 weeks, when the basal insulin dose was kept stable (within 10% of baseline), the mean (SD) change in insulin dose was 0.1 (4.7) U for participants treated with linagliptin and 0.5 (3.1) U for participants treated with placebo (full analysis set; last observation carried forward). From week 24, the mean basal insulin dose was increased to a lesser extent with linagliptin compared with placebo (Fig. 3). The adjusted mean (SE) changes from baseline in insulin dose at week 52 for linagliptin and placebo were 2.3 (0.5) U and 4.0 (0.4) U, respectively. There were no relevant changes in mean (SD) body weight from baseline to week 52 [linagliptin, –0.5 (3.2) kg; placebo, 0.0 (3.1) kg]. Overall safety and tolerability
The overall frequency of participants with at least one reported adverse event was similar in the two treatment groups (Table 2). The most frequently reported adverse events in both treatment groups were nasopharyngitis (linagliptin, 11.2%; placebo, 9.9%), hyperglycaemia (linagliptin, 14.1%; placebo, 18.3%), and hypoglycaemia (linagliptin, 29.9%; placebo, 29.9%). Drug-related adverse events occurred in 18.9% and 21.9% of participants in the linagliptin and placebo groups, respectively. Adverse events leading to discontinuation of trial medication were infrequent in both groups. The frequency of adverse events assessed by renal impairment status was similar between linagliptin and placebo (Table 3). Renal adverse events, evaluated according to a narrow standardized Medical Dictionary for Regulatory Activities (MedDRA)-based query, were reported for one participant (0.2%) with linagliptin and four participants (0.8%) with placebo. The renal adverse event in the linagliptin group was acute renal failure (participant had mild renal impairment at baseline); in the placebo group, three participants had acute renal failure (one participant in each of the three baseline renal function categories) and one participant had renal failure (mild renal impairment at baseline). There was no change in urine microalbumin/creatinine ratio from 929
Linagliptin as add-on to basal insulin and metformin in Type 2 diabetes S. Duran-Garcia et al.
Free insulin titration period 2
Placebo-corrected difference = –6 mmol/mol (–0.6%; 95% CI –0.7, –0.5; P < 0.0001)
Placebo-corrected difference = –7 mmol/mol (–0.7%; 95% CI –0.8, –0.6; P < 0.0001)
Adjusted* mean ±SE change in HbA 1c, %
Stable insulin dose 0.2
–6 –0.6 Linagliptin 5 mg once daily Placebo
FIGURE 2 Adjusted mean change in HbA1c from baseline over time up to 52 weeks (full analysis set; last observation carried forward). *ANCOVA model includes ‘treatment’ and ‘baseline renal function impairment category’ as fixed classification effects, and ‘baseline HbA1c’ as a covariate. The primary efficacy endpoint was assessed over 24 weeks (see grey boxed area).
Stable insulin dose
Free insulin titration period 10
Linagliptin 5 mg once daily (insulin dose) Placebo (insulin dose)
–0.6 –0.8 –1.0 –1.2
–8 –10 Linagliptin 5 mg once daily (FPG)
Mean ±SE change in insulin dose, U
Mean ±SE change in FPG, mmol/l
Weeks Placebo, n 461 Linagliptin, n 468 Placebo, n 464 Linagliptin, n 470
416 448 454 464
FPG 380 410 Insulin 431 450
FIGURE 3 Mean change in fasting plasma glucose (FPG; full analysis set; observed cases) and mean change in insulin dose (full analysis set; original results) from baseline over time up to 52 weeks.
baseline to last value on treatment in either treatment group. The majority (88%) of participants in both groups had normal renal function or mild renal impairment at baseline and last value on treatment. The overall numbers of participants whose renal impairment stage worsened (~5% in each group) or improved (~2% in each group) from baseline to last value on treatment were low. Adjudicated cardiovascular events (participants who had at least one of the following events: cardiovascular 930
death, myocardial infarction, stroke and admission to hospital attributable to unstable angina) occurred in 13 participants (2.7%) in the linagliptin group and 10 (2.1%) in the placebo group. Six participants in each group (1.3%) were hospitalized because of unstable angina. Cardiovascular deaths occurred in three participants (0.6%) in the linagliptin group, none of which were drug-related as assessed by the investigators.
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Table 2 Overall summary of adverse events and investigator-reported hypoglycaemic events
Participants (treated set*), n Any adverse event, n (%) Severe adverse events, n (%) Drug-related adverse events, n (%) Adverse events leading to discontinuation of trial medication, n (%) Serious adverse events, n (%) Fatal Immediately life-threatening Disability/incapacitation Requiring hospitalization Prolonged hospitalization Other Pancreatitis†, n (%) Pancreatic cancer, n (%) Hypoglycaemic events, n (%) Investigator-reported hypoglycaemic adverse event at week 24 Investigator-reported hypoglycaemic adverse event at treatment end Severity of hypoglycaemia (treatment Any documented symptomatic hypoglycaemia‡ and measured plasma glucose ≤3.9 mmol/l Any documented symptomatic hypoglycaemia§ and measured plasma glucose <3.0 mmol/l Any severe hypoglycaemic episode¶
Hypoglycaemia was experienced by a similar percentage of participants in the linagliptin and placebo groups during the treatment period with stable insulin therapy as well as in the free insulin titration period. The frequency of participants who experienced investigator-reported hypoglycaemia at week 24 was 21.1% in the linagliptin group and 20.8% in the placebo group. At the end of the study, investigatorreported hypoglycaemic events were reported by 30.7% of participants in the linagliptin group and 31.6% of participants in the placebo group (Table 2). The percentage of participants with severe hypoglycaemia was low and similar between groups (linagliptin, 1.7%; placebo, 0.8%). In participants with mild renal impairment, no additional increase in the frequency of participants experiencing hypoglycaemia with linagliptin was observed (Table 3).
*Treated set: all randomized participants who were treated with at least one dose of study medication. † Analysis based on the narrow standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) ‘acute pancreatitis’ and MedDRA preferred term ‘chronic pancreatitis’. ‡ Accompanied by typical symptoms of hypoglycaemia. §Accompanied by typical symptoms of hypoglycaemia but no need for external assistance. ¶ Requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. MedDRA version 14.0 used for reporting.
Three cases of pancreatitis were observed in the linagliptin group, two of which were considered chronic. None of the cases were fatal, necrotizing or haemorrhagic. All three participants had hepatobiliary disorders recorded as concomitant diagnoses at baseline (either chronic hepatitis, hepatitis steatosis or liver disorder). One participant also had chronic pancreatitis recorded as a concomitant diagnosis. No cases of pancreatitis were reported in the placebo group. Pancreatic cancer was not observed in either treatment group. The mean (SD) change from baseline in amylase was 4.8 (20.4) U/l in the linagliptin group and –0.1 (21.0) U/l in the placebo group. The relative change from baseline in amylase was 10.7 (32.2)% for linagliptin and 2.3 (29.3)% for placebo. ª 2015 Diabetes UK
Adding basal insulin to metformin is a well-established standard regimen for the treatment of Type 2 diabetes, given that metformin has the potential to reduce the need for high doses of insulin and thereby minimize the risk of hypoglycaemia and body weight gain . Combining incretin-based therapies with insulin is an emerging approach in the management of Type 2 diabetes, because this drug class generally has a low risk of hypoglycaemia and is weightneutral. The addition of linagliptin to the combination of insulin and metformin may be a valuable treatment option in patients with Type 2 diabetes who have inadequate glycaemic control, as linagliptin has a complementary mechanism of action to both insulin and metformin, and can reduce glucose levels with a low additional risk of hypoglycaemia. The results of the present subanalysis of a global phase III study showed that linagliptin, when added to background basal insulin and metformin, significantly improved glycaemic control compared with placebo, with a low additional risk of hypoglycaemia or body weight gain. As in the parent study , treatment with linagliptin resulted in a clinically meaningful improvement in glycaemic control and showed a similar placebo-corrected adjusted mean change in HbA1c (approximately –7 mmol/mol in both studies) and in FPG (–0.8 mmol/l in this study and –0.6 mmol/l in the parent study) at week 24. The overall frequency of participants with at least one reported adverse event and the frequency of participants with investigator-reported hypoglycaemia were also similar to the frequencies reported in the parent study. Thus, the results from this analysis support the use of this combination as an effective treatment option when basal insulin and metformin combination therapy fails to maintain glycaemic control. These findings may be particularly relevant to patients with long-standing Type 2 diabetes as such patients are more likely to use insulin in combination with background therapy. A pooled analysis of 931
Linagliptin as add-on to basal insulin and metformin in Type 2 diabetes S. Duran-Garcia et al.
Table 3 Overall summary of adverse events by renal impairment status
Participants (treated set*), n Any adverse event, n (%) Adverse events leading to discontinuation of trial medication, n (%) Serious adverse events, n (%) Drug-related adverse events, n (%) Hypoglycaemia, n (%)
Normal renal function ≥90 ml/min/1.73 m2
Mild renal impairment 60 to <90 ml/min/1.73 m2
Moderate renal impairment 30 to <60 ml/min/ 1.73 m2
227 176 (77.5) 9 (4.0)
232 182 (78.4) 12 (5.2)
214 176 (82.2) 7 (3.3)
207 173 (83.6) 8 (3.9)
34 27 (79.4) 1 (2.9)
36 31 (86.1) 1 (2.8)
27 (11.9) 40 (17.6) 25 (11.0)
22 (9.5) 38 (16.4) 23 (9.9)
34 (15.9) 45 (21.0) 33 (15.4)
32 (15.5) 57 (27.5) 41 (19.8)
7 (20.6) 5 (14.7) 4 (11.8)
6 (16.7) 9 (25.0) 5 (13.9)
*Treated set: all randomized participants who were treated with at least one dose of study medication. Medical Dictionary for Regulatory Activities (MedDRA) version 14.0 used for reporting.
clinical trial data from participants with a Type 2 diabetes duration of >10 years showed that linagliptin was well tolerated and significantly improved hyperglycaemia . The extent of glucose-lowering was similar to that observed in linagliptin trials that largely included participants in the earlier stages of Type 2 diabetes. In this study, despite a clinically significant reduction in HbA1c, linagliptin treatment had a low additional risk of hypoglycaemia, even after uptitration of basal insulin; however, insulin titrations were not systematically enforced and it is conceivable that if further insulin adjustments had been consistently made, the rate of hypoglycaemia could have been slightly higher but HbA1c levels would have been much lower. Hypoglycaemia is a major limiting factor in the management of Type 2 diabetes because it can preclude the attainment and maintenance of near-normoglycaemia during the course of the disease. The lack of increase in the risk of hypoglycaemia with linagliptin vs placebo seen in the present study may have been attributable to the glucose-dependent mechanism of action of linagliptin; however, there was also no increased risk of hypoglycaemia in the subgroup of participants with renal impairment, a population that is particularly susceptible to iatrogenic hypoglycaemia . The reason for this is unclear but may be related to enhancement of the glucagon counter-regulatory response by DPP-4 inhibition [16–18]. In advanced Type 2 diabetes, both physiological and behavioural glucose counter-regulation are markedly defective, resulting in greater susceptibility to hypoglycaemia. In addition, comorbid renal impairment in Type 2 diabetes can further aggravate hypoglycaemia, not only via reduced clearance of insulin (endogenous and exogenous) but via impaired renal glucose production [19,20]. There is evidence that DPP-4 inhibition enhances a-cell sensing, leading to an increase in glucagon secretion [16–18]; therefore, normalization of the glucagon counterregulatory response by DPP-4 inhibition may be an important mediator in counteracting any increased risk of hypoglycaemia when patients have multiple defects in glucose counter-regulation. 932
Although slightly more cardiovascular events were reported in the linagliptin group than in the placebo group, the frequency of events was very low and the individual events were not considered to be drug-related. A pooled analysis of cardiovascular events in 22 phase I–III studies indicated that linagliptin does not increase the risk of cardiovascular adverse events compared with placebo . The CAROLINA (NCT01243424) and CARMELINA (NCT01897532) outcome trials have been specifically designed to investigate the efficacy and safety of linagliptin 5 mg once daily on cardiovascular and renal microvascular outcomes in participants with Type 2 diabetes who are at risk of cardiovascular events. Participants enrolled in the CARMELINA trial included those receiving background insulin therapies and the results will therefore provide further information about the long-term effects of treatment with linagliptin combined with insulin on cardiovascular safety. The results of these trials are expected in 2018. The results of the present subanalysis are limited by the post hoc nature of the study. Additionally, as this study population was primarily of white race, further studies may be required to confirm the efficacy and tolerability of linagliptin as add-on therapy to basal insulin and metformin in other racial or ethnic populations. In conclusion, the results of this subgroup analysis show that the addition of linagliptin to basal insulin and metformin significantly improved glycaemic control, with a low additional increased risk of hypoglycaemia or body weight gain. These results suggest that linagliptin may be an effective treatment option for patients with Type 2 diabetes who have failed to reach glycaemic targets with insulin and metformin. In addition, these findings provide further evidence of the efficacy and tolerability profile of linagliptin in a broad range of patients.
This study was supported by Boehringer Ingelheim, and Eli Lilly and Company.
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S. D.-G. has received consulting fees from Boehringer Ingelheim. H. Y.-J. has received research support from Lilly-Amylin and Boehringer Ingelheim. She has also received honoraria for consultancy for Sanofi, Novartis, AstraZeneca, MSD, Bristol-Myers Squibb, and for lectures at meetings sponsored by Sanofi and MSD. J. R. has served on scientific advisory boards and received honoraria or consulting fees from Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmith Kline, Takeda, Merck, Daiichi Sankyo, Janssen, Novartis, Boehringer Ingelheim, MannKind, Intarcia and Lexicon. In addition, he has received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Janssen, Daiichi Sankyo, MannKind, Boehringer Ingelheim, Intarcia and Lexicon. J. L., U. H., S. T. and H.-J. W. are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. S. P. was an employee of Boehringer Ingelheim Ltd. at the time of the study, and is now an employee of Daiichi Sankyo Development Ltd.
Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Claire Stevens and Paul MacCallum, of Envision Scientific Solutions during the preparation of this article. This article contains data previously presented at the 49th Annual Meeting of the European Association for the Study of Diabetes; 23–27 September 2013, Barcelona, Spain; Lee J., et al. Diabetologia 2013; 56(Suppl. 1): S355.
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For patients with type 2 diabetes mellitus, management of hyperglycemia is typically complex, and few patients successfully achieve and maintain recommended targets for glycated hemoglobin (HbA1c). Increasingly, combination therapy is recommended ear
The objective of this study was to evaluate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase-4 inhibitor, as an add-on to metformin in Japanese patients with type 2 diabetes mellitus (T2DM).
To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents.
There is no consensus on the selection of specific drug therapies when metformin fails in Type 2 diabetes (T2D). This meta-analysis was performed to determine the efficacy and safety of Dipeptidyl peptidase-4 inhibitors (DPP4-I) compared to sulfonylu
Type 2 diabetes mellitus (T2DM) is a progressive condition requiring long-term treatment. Most patients with T2DM are unable to maintain normoglycemia using metformin alone; thus, combination therapy is a pivotal part of disease management. Addition
Despite the increasing prevalence of type 2 diabetes mellitus (T2DM) in Asia, clinical trials for glucose-lowering therapies are often dominated by Caucasian and/or Western populations. The present Phase III randomized placebo-controlled double-blind