Side effects and safety

Side Effects

Linagliptin/Metformin

The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1,800 mg) has been evaluated in 2,816 patients with type 2 diabetes mellitus treated for more than 12 weeks in clinical trials.

Table 1. Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study.

	Placebo n=72	Linagliptin monotherapy n=142	Metformin monotherapy n=291	Combination of linagliptin with metformin n=286
	n (%)	n (%)	n (%)	n (%)
Nasopharyngitis	1 (1.4)	8 (5.6)	8 (2.7)	18 (6.3)
Diarrhea	2 (2.8)	5 (3.5)	11 (3.8)	18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.

Hypoglycemia
In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. The incidence of hypoglycemia with plasma glucose <54 mg/dL was 8.1% in the linagliptin group (N=792) compared to 5.3% in the placebo.

Linagliptin

Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).

Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin therapy.

Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia
The incidence of severe hypoglycemia (requiring assistance) was 1.7% in the linagliptin group (N=631) compared to 1.1% in the placebo group (N=630) when administered in combination with basal insulin in a 52 week study.

Metformin

The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

Safety

Linagliptin cardiovascular safety trials

CARMELINA

The cardiovascular risk of linagliptin was evaluated in CARMELINA, a multi-national, multi-center, placebo-controlled, double-blind, parallel group trial comparing linagliptin (N=3,494) to placebo (N=3,485) in adult patients with type 2 diabetes mellitus and a history of established macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and placebo when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.

The results of CARMELINA, including the contribution of each component to the primary composite endpoint, are shown in Table 2. The estimated hazard ratio for MACE associated with linagliptin relative to placebo was 1.02 with a 95% confidence interval of (0.89, 1.17). The upper bound of this confidence interval, 1.17, excluded the risk margin of 1.3. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 1.

Table 2. Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CARMELINA Trial

	Number of Subjects (%)	Incidence Rate per 1,000 patient years	Number of Subjects (%)	Incidence Rate per 1,000 patient years	(95% CI)
	Linagliptin 5 mg n=3,494		Placebo n=3,485		Hazard Ratio
Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE)	434 (12.4)	57.7	420 (12.1)	56.3	1.02 (0.89, 1.17)
CV death^*	255 (7.3)	32.6	264 (7.6)	34.0	0.96 (0.81, 1.14)
Non-fatal MI^*	156 (4.5)	20.6	135 (3.9)	18.0	1.15 (0.91, 1.45)
Non-fatal stroke^*	65 (1.9)	8.5	73 (2.1)	9.6	0.88 (0.63, 1.23)

Figure 1. Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial.

CAROLINA

The cardiovascular risk of linagliptin was evaluated in CAROLINA, a multi-center, multi-national, randomized, double-blind, parallel group trial comparing linagliptin (N=3,023) to glimepiride (N=3,010) in adult patients with type 2 diabetes mellitus and a history of established cardiovascular disease and/or multiple cardiovascular risk factors. The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and glimepiride when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 6.23 years and vital status was obtained for 99.3% of patients.

The results of CAROLINA, including the contribution of each component to the primary composite endpoint, are shown in Table 3. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 2.

Table 3. Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CAROLINA Trial

	Number of Subjects (%)	Incidence Rate per 1,000 patient years	Number of Subjects (%)	Incidence Rate per 1,000 patient years	(95% CI)
	Linagliptin 5 mg n=3,023		Glimepiride (1 mg to 4 mg) n=3,010		Hazard Ratio
Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE)	356 (11.8)	20.7	362 (12.0)	21.2	0.98 (0.84, 1.14)
CV death^*	169 (5.6)	9.2	168 (5.6)	9.2	1.00 (0.81, 1.24)
Non-fatal MI^*	145 (4.8)	8.3	142 (4.7)	8.2	1.01 (0.80, 1.28)
Non-fatal stroke^*	91 (3.0)	5.2	104 (3.5)	6.0	0.87 (0.66, 1.15)

Figure 2. Time to First Occurrence of 3P-MACE in CAROLINA.

Footnotes:

*
*A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome.
CV, cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction.

Reference:

TRAJENTA DUO® approved package insert. Updated in December 2020 and approved in February 2021.

TRAJENTA DUO®