Improving Glycemic Control With Combination Therapy for Adult Patients With Type 2 Diabetes. Topic Highlights

Transcription

1 Improving Glycemic Control With Combination Therapy for Adult Patients With Type 2 Diabetes Featured Expert Topic Highlights CHARLES REASNER, MD Adjunct Professor of Medicine University of Texas Health Science Center San Antonio, Texas IMPORTANT SAFETY INFORMATION for Jentadueto (linagliptin and metformin hydrochloride) tablets WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately. Tradjenta (linagliptin) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. For adult patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy, American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) guidelines recommend add-on therapy with an agent that has a complementary mechanism of action (MOA). 1 Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as TRADJENTA, enhance active incretin levels, thus stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. 2 DPP-4 inhibitors predominantly lower postprandial glucose (PPG) levels. 1,3 The recommended dose of TRADJENTA is mg once daily (QD). 2 There is no dosage adjustment of TRADJENTA required regardless of declining renal function or in patients with hepatic impairment. 2 A pivotal clinical trial was conducted to evaluate the efficacy and safety of TRADJENTA as add-on therapy to metformin in patients with T2DM and inadequate glycemic control. 4 o Efficacy results showed that, in combination with metformin, TRADJENTA provided statistically significant improvements in glycated hemoglobin (A1C), PPG, and fasting plasma glucose (FPG) ( for all). 2,4 TRADJENTA has a primarily non-renal route of excretion, with 80% excreted via the bile and gut and % eliminated via the kidney within 4 days of dosing. 2 AACE/ACE guidelines recommend initial dual therapy for patients with baseline A1C levels between 7.6% and 9.0%. 1 Jentadueto (linagliptin and metformin hydrochloride) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis and has not been studied in combination with insulin. JENTADUETO has a boxed warning regarding the risk of lactic acidosis due to metformin accumulation. JENTADUETO is a combination tablet of linagliptin and metformin hydrochloride, two antihyperglycemic agents with complementary MOAs. JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO with coadministered linagliptin and metformin tablets was demonstrated in healthy subjects. The efficacy and safety of linagliptin as initial therapy with metformin were evaluated in a randomized, double-blind, placebo-controlled, parallel-group trial conducted in drug-naïve or previously treated patients with T2DM and insufficient glycemic control. o Efficacy results demonstrated that initial therapy with JENTADUETO provided significant improvements in A1C and FPG compared to placebo, to metformin alone, and to linagliptin alone (). Adverse reactions reported in % of patients treated with JENTADUETO and more commonly than in patients treated with placebo included nasopharyngitis (6.3% vs 1.4%, respectively) and diarrhea (6.3% vs 2.8%, respectively). TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity. JENTADUETO is contraindicated in patients with renal impairment (e.g., serum creatinine 1. mg/dl for men or 1.4 mg/dl for women, or abnormal creatinine clearance), patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis or in patients with a history of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. This promotional program was developed in conjunction with and funded by Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC, based on an interview with Charles Reasner, MD. Dr Reasner received fair market value compensation for participation in this program. Please see Important Safety Information for JENTADUETO on pages 6-7 and accompanying full Prescribing Information, including Boxed Warning regarding the risk of lactic acidosis, and Patient Information. Please see Important Safety Information for TRADJENTA on page 6 and accompanying full Prescribing Information, including Patient Information. ClinTopics

2 Clinical Question & Answer CHARLES REASNER, MD Adjunct Professor of Medicine University of Texas Health Science Center San Antonio, Texas Dr Charles Reasner is an adjunct professor of medicine at the University of Texas Health Science Center at San Antonio. His teaching and research interests focus on the treatment of the insulin resistance syndrome including T2DM, obesity, and diabetic dyslipidemia. In addition to his clinical duties, Dr Reasner is the editor of the journal Practical Diabetology. Most adult patients with T2DM do not achieve lasting control of their A1C levels with monotherapy. What is the effect of FPG and PPG on A1C levels? The AACE guidelines recommend an A1C of 6.% for adult patients with T2DM. For patients with history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or other extensive comorbid conditions, AACE recommends consideration of less stringent A1C goal of 7% to 8%. 6 To help achieve A1C target goals, AACE/ACE recommends metformin as the initial choice for monotherapy. 1 If the AACE A1C treatment goal of 6.% is not met within 2 to 3 months of monotherapy, the AACE/ACE guidelines recommend intensifying treatment by adding an agent from a different class and with a complementary mechanism of action. Agents recommended by the AACE/ACE as add-on to metformin monotherapy include DPP-4 inhibitors, thiazolidinediones, glucagon-like peptide-1 agonists and alpha-glucosidase inhibitors. 1 A1C provides an average measure of glycemic control over several months and remains the gold standard for monitoring glycemic control. 7 FPG and PPG levels are important indicators of glycemic variability throughout the day. 8 Interestingly, the level of contribution of FPG and PPG levels to hyperglycemia depends on a patient s baseline A1C levels. Monnier et al conducted a study to assess the relative impact of FPG and PPG on A1C levels in patients with T2DM (n=290). Results from this study indicated that in patients with baseline A1C levels <8.%, PPG levels had a greater effect on the A1C level. Conversely, in patients with higher baseline A1C levels (eg, A1C levels 8.%), FPG levels made the largest contribution. In the quintile of patients who had the highest levels of A1C, PPG accounted for approximately one-fourth of the total hyperglycemia. 9 Lastly, results from a prospective intervention trial (n=164, A1C=8.7%) further showed that while both FPG and PPG contribute to the management of A1C, 94% of patients who achieved a target PPG of 140 mg/dl achieved an A1C goal of 7%, whereas 64% of patients who achieved a target FPG of 100 mg/dl achieved an A1C goal of 7%. The relative contribution of PPG decreased progressively as A1C levels increased. PPG accounted for approximately 90% of A1C values below 6.2% but accounted for only about 40% when A1C was above 9%. 10 For patients not achieving glycemic control with metformin monotherapy, what are some considerations when selecting a DPP-4 inhibitor as add-on therapy? Patients with T2DM typically have three pathophysiological defects: insulin resistance, decreased insulin secretion, and increased hepatic glucose production. 3,6 Many patients with T2DM are unable to achieve adequate glycemic control with oral agent monotherapy, so it is appropriate to consider combining antihyperglycemic agents. 6 Metformin, the preferred agent for first-line monotherapy, is an insulin sensitizer that has its major impact to lower hepatic glucose production in the fasting state and, thus, primarily lowers FPG. 1,11 When considering add-on therapy to metformin, it is advisable to choose an agent with an MOA that is complementary and addresses different physiological defects of T2DM. 1,6,12 Incretin hormones are released from the intestine when an individual eats, and they serve to signal the pancreas to increase insulin secretion and decrease glucagon secretion. Both of these actions lower PPG. 3, DPP-4 inhibitors, such as linagliptin, work by blocking DPP-4, an enzyme that degrades incretin hormones involved in glucose homeostasis, thereby enhancing active incretin levels. This, in turn, results in stimulating the release of insulin in a glucosedependent manner and decreasing the levels of glucagon in the circulation. 2 DPP-4 inhibitors have a predominant effect on PPG levels. 1,3 When metformin and DPP-4 inhibitors are used in combination, all three pathophysiological defects of T2DM are addressed. The metformin component addresses insulin resistance and lowers hepatic glucose production, thus primarily lowering FPG. 1 The DPP-4 inhibitor increases insulin secretion in a glucosedependent manner and reduces glucagon secretion from pancreatic alpha cells, primarily lowering PPG. 1, Renal function is among many of the considerations when treating patients with T2DM. 13 There is no dosage adjustment of Tradjenta (linagliptin) tablets required regardless of declining renal function or in patients with hepatic impairment. TRADJENTA offers a single -mg dose QD for adult patients with T2DM, including those with declining renal function or hepatic impairment. 2 2 IMPORTANT SAFETY INFORMATION for Tradjenta (linagliptin) tablets WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug. Please see Important Safety Information for TRADJENTA on page 6 and JENTADUETO on pages 6-7 and accompanying full Prescribing Information, including including Boxed Warning regarding the risk of lactic acidosis, and Patient Information for JENTADUETO.

3 Tradjenta (linagliptin) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with T2DM. What was the impact on glycemic parameters seen in the clinical trial that evaluated TRADJENTA as add-on therapy to metformin? The efficacy of TRADJENTA as an add-on therapy to metformin was evaluated in a randomized, double-blind, 24-week, placebocontrolled, parallel-group clinical trial of adult patients with T2DM and insufficient glycemic control despite metformin therapy (N=701). Patients were randomized to receive TRADJENTA mg QD added to metformin 100 mg/day (n=24) or placebo added to metformin (n=177). The primary efficacy endpoint was the change from baseline in A1C at 24 weeks. Secondary endpoints included the change from baseline in FPG and 2-hour PPG. 4 Efficacy results showed that TRADJENTA added to metformin provided statistically significant improvements in A1C, PPG, and FPG vs placebo added to metformin ( for all). TRADJENTA added to metformin reduced the mean A1C level by 0.% from baseline (8.1%), compared to placebo added to metformin, where the mean A1C level increased by 0.1% from baseline (8.0%), resulting in a treatment difference of -0.6% () (Figure 1). 2,4 Figure 1: Significant Placebo-Adjusted A1C Reductions With TRADJENTA mg Add-On to Metformin 2,4a-c 0 TRADJENTA added to metformin, compared with an increase of 18 mg/dl in the placebo added to metformin group. This equated to a treatment difference of -67 mg/dl favoring TRADJENTA () (Figure 2). 2,4 Lastly, there was no difference in incidence of hypoglycemia between the two arms. 4 The reductions in A1C and PPG seen with TRADJENTA added to metformin are clinically significant. Figure 2: Glycemic Efficacy in Patients Treated With TRADJENTA mg Add-On to Metformin Versus Placebo Add-On to Metformin FPG and 2-Hour PPG 2,4 Placebo-Adjusted Mean Change in FPG From Baseline at Week 24 (mg/dl) TRADJENTA add-on to metformin (n=49) -21 mg/dl Placebo-Adjusted Mean Change in A1C at 24 Weeks (%) TRADJENTA add-on to metformin (n=13) -0.6% a Prespecified primary analysis of primary endpoint. Full analysis set (FAS) (defined as all randomized, treated with at least one dose of study drug, with a baseline A1C value and at least one on-treatment A1C value). FAS is basis for the intent-to-treat analysis. 4 b Analysis of covariance model included treatment and number of prior oral antihyperglycemic drugs as class effects, as well as baseline A1C, FPG, and 2-hour PPG as continuous covariates. 2 c 0.1% adjusted mean increase from baseline A1C 8.0% with placebo add-on to metformin (n=17). 2 Placebo-Adjusted Mean Change in 2-Hour PPG From Baseline at Week 24 (mg/dl) TRADJENTA add-on to metformin (n=78) mg/dl TRADJENTA added to metformin also led to a significant reduction vs placebo added to metformin in adjusted mean FPG levels (-11 mg/dl vs +11 mg/dl, respectively), representing a treatment difference of -21 mg/dl () (Figure 2). 2,4 Similarly, TRADJENTA added to metformin showed a significant impact in controlling PPG levels (). 4 From baseline to Week 24, the adjusted mean 2-hour PPG level decreased by 49 mg/dl with What studies have been conducted with TRADJENTA as add-on therapy to metformin compared to the sulfonylurea (SU) glimepiride as add-on to metformin? The efficacy of TRADJENTA as add-on therapy to metformin compared to an SU as add-on therapy to metformin was evaluated in a double-blind, 104-week, glimepiride-controlled, noninferiority trial in patients with T2DM who had not achieved glycemic IMPORTANT SAFETY INFORMATION for Tradjenta (linagliptin) tablets WARNINGS AND PRECAUTIONS (cont d) ADVERSE REACTIONS Adverse reactions reported in % of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When TRADJENTA was administered in combination with metformin and a sulfonylurea,181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 1.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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. 3

4 control despite treatment with metformin (N=127). Patients were randomized to receive Tradjenta (linagliptin) tablets mg added to metformin (n=766) or glimepiride added to metformin (n=761). The average dose of glimepiride in the study was 3 mg QD. After 2 and 104 weeks, TRADJENTA added to metformin and glimepiride added to metformin both showed reductions from a mean baseline A1C of 7.7% (-0.2% vs -0.4% at 104 weeks, respectively). The mean difference between groups in A1C change from baseline was 0.2% for the intent-to-treat population, which met the pre-specified margin of 0.3%, thus demonstrating non-inferiority of linagliptin to glimepiride. 14 Similarly, reductions in FPG were seen with both TRADJENTA added to metformin and glimepiride added to metformin at both 2 weeks and 104 weeks (-2 mg/dl vs -9 mg/dl at 104 weeks, respectively). 2 Importantly, after 2 and 104 weeks of treatment, TRADJENTA added to metformin was associated with a significantly lower incidence of hypoglycemia and a weight difference. After 104 weeks, the incidence of hypoglycemia in patients receiving TRADJENTA added to metformin was 7.% vs 36.1% in the group receiving glimepiride added to metformin (). In addition, after 104 weeks, patients receiving TRADJENTA added to metformin had a mean decrease in body weight of 1.4 kg while those receiving glimepiride added to metformin had a mean increase of 1.3 kg. The difference between the 2 groups of -2.7 kg (.9 lbs) was statistically significant (). 2 When is combination therapy recommended as initial therapy for the treatment of T2DM? What are important clinical considerations in the selection of combination oral antihyperglycemic agents? The AACE/ACE Diabetes Algorithm stratifies the therapeutic approach according to a patient s baseline A1C level. For patients with baseline A1C levels between 7.6% and 9.0%, AACE/ACE recommends initial dual therapy. 1 When selecting initial combination therapy, important clinical considerations include efficacy, as glycemic control is a key treatment goal in the management of adult patients with diabetes, and the risk of hypoglycemia. 1,7 When combination therapy is prescribed, AACE/ACE guidelines recommend selecting agents that have complementary MOAs. 1 Other considerations include an agent s side effect profile, particularly gastrointestinal side effects, the potential to cause weight gain, and the potential for drug-drug interactions. 1,6 Similar to when considering add-on therapy to metformin, when selecting the individual components for initial dual therapy, the AACE/ACE guidelines recommend combinations of agents with complementary MOAs. As noted in the AACE/ACE guidelines, possible agents for initial dual therapy in combination with metformin are DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones, SUs, and glinides. 1 What improvements in glycemic control have been observed in clinical trials involving the combination of linagliptin and metformin, now available as Jentadueto (linagliptin and metformin hydrochloride) tablets, as initial dual therapy? JENTADUETO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both linagliptin and metformin is appropriate. JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis and has not been studied in combination with insulin. JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO with coadministered linagliptin and metformin tablets was demonstrated in healthy subjects. The efficacy of JENTADUETO was evaluated in a randomized, doubleblind, placebo-controlled, parallel-group trial with drug-naïve or previously treated patients with T2DM and insufficient glycemic control (N=791). Enrolled patients underwent 4 weeks washout Placebo-Adjusted Mean Change in A1C at 24 Weeks (%) Figure 3: JENTADUETO Significant Placebo-Adjusted A1C Reductions at 24 Weeks a-d Linagliptin mg Once Daily Baseline A1C: 8.7% (n=13) -0.6% Metformin 00 mg Twice Daily Baseline A1C: 8.7% (n=141) -0.8% Linagliptin 2. mg Metformin 00 mg Twice Daily d Baseline A1C: 8.7% (n=137) a Full analysis population using last observation on study. b Superiority of both free combination therapies, consisting of BID administration of linagliptin 2. mg and metformin (00 mg or 1000 mg), was shown over the individual metformin components (00 mg and 1000 mg, both BID) and over linagliptin mg QD for change in A1C from baseline at Week Linagliptin 2. mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID; linagliptin 2. mg BID + metformin 1000 mg BID was superior to linagliptin mg QD; linagliptin 2. mg BID + metformin 00 mg BID was superior to metformin 00 mg BID; linagliptin 2. mg BID + metformin 00 mg BID was superior to linagliptin mg QD ( for all). 1 c JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to mg. d Results are adjusted for a 0.1% mean A1C increase for placebo (n=6). -1.3% Metformin 1000 mg Twice Daily Baseline A1C: 8.% (n=138) -1.2% (n=140) Linagliptin 2. mg Metformin 1000 mg Twice Daily d Baseline A1C: 8.7% (n=140) -1.7% 4 IMPORTANT SAFETY INFORMATION for Tradjenta (linagliptin) tablets WARNINGS AND PRECAUTIONS (cont d) DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended. Please see Important Safety Information for TRADJENTA on page 6 and JENTADUETO on pages 6-7 and accompanying full Prescribing Information, including including Boxed Warning regarding the risk of lactic acidosis, and Patient Information for JENTADUETO.

5 Table 1: Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin and Metformin, Alone and in Combination, in Randomized Patients With T2DM Inadequately Controlled on Diet and Exercise a Placebo Linagliptin Metformin mg QD b 00 mg BID Jentadueto (linagliptin and metformin hydrochloride) tablets Linagliptin 2. mg BID b + Metformin 00 mg BID Metformin 1000 mg BID JENTADUETO Linagliptin 2. mg BID b + Metformin 1000 mg BID A1C (%) Number of patients n=6 n=13 n=141 n=137 n=138 n=140 Patients achieving A1C <7% [n (%)] 7 (10.8) 14 (10.4) 27 (19.1) 42 (30.7) 43 (31.2) 76 (4.3) FPG (mg/dl) Number of patients n=61 n=134 n=136 n=13 n=132 n=136 Baseline (mean) Change from baseline (adjusted mean) Difference from placebo (adjusted mean) (9% CI) Patients requiring rescue therapy (%) -19 (-31, -6) CI=confidence interval. a Full analysis population using last observation on study. b Total daily dose of linagliptin is equal to mg. -26 (-38, -14) -43 (-6, -31) -42 (-, -30) -60 (-72, -47) and 2 weeks placebo run-in and were then randomized to 1 of 6 treatment arms: placebo, linagliptin mg QD, linagliptin 2. mg plus metformin 00 mg twice daily (BID), linagliptin 2. mg plus metformin 1000 mg BID, metformin 00 mg BID, or metformin 1000 mg BID. The primary efficacy endpoint was the mean change in A1C from baseline to Week Secondary endpoints included the percentage of patients achieving target A1C, and the mean change in FPG from baseline. 14,1 Primary efficacy results showed that, at 24 weeks, JENTADUETO 2. mg/1000 mg BID delivered improved glycemic control, with a 1.7% placebo-adjusted reduction in A1C from a baseline of 8.7% () (Figure 3). Likewise, at Week 24, 4.3% of patients treated with linagliptin 2. mg BID + metformin 1000 mg BID achieved an A1C <7% (Table 1). Efficacy results further showed that initial therapy with the combination of linagliptin and metformin provided significant improvements in FPG compared to placebo, to metformin alone, and to linagliptin alone (Table 1). Lastly, the percent of patients requiring rescue therapy at Week 24 for inadequate glycemic control was lower in the linagliptin plus metformin combination therapy groups than with either linagliptin or metformin monotherapy, or placebo (Table 1). 1 What is the adverse reaction and safety profile reported in clinical trials for JENTADUETO? The safety of concomitantly administered linagliptin and metformin has been evaluated in 2816 patients with T2DM treated for 12 weeks in clinical trials. Adverse reactions reported in % of patients treated with JENTADUETO and more commonly than in patients Table 2: Adverse Reactions Reported in % 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 (.6) 8 (2.7) 18 (6.3) Diarrhea 2 (2.8) (3.) 11 (3.8) 18 (6.3) treated with placebo included nasopharyngitis and diarrhea, as shown in Table 2. The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Additionally, in a 24-week factorial-design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin and metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin plus an SU, 181 (22.9%) of 792 patients reported hypoglycemia vs 39 (14.8%) of 263 patients administered placebo in combination with metformin plus an SU. IMPORTANT SAFETY INFORMATION for Jentadueto (linagliptin and metformin hydrochloride) tablets CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine 1. mg/dl for men or 1.4 mg/dl for women, or abnormal creatinine clearance). Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. WARNINGS AND PRECAUTIONS Lactic Acidosis Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 0% of cases.

6 6 INDICATION AND IMPORTANT LIMITATIONS OF USE for Tradjenta (linagliptin) tablets TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity. WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug. ADVERSE REACTIONS Adverse reactions reported in % of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 1.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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. DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended. USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI Sept Please see accompanying full Prescribing Information, including Patient Information. INDICATION AND IMPORTANT LIMITATIONS OF USE for Jentadueto (linagliptin and metformin hydrochloride) tablets JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin. IMPORTANT SAFETY INFORMATION WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately. CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine 1. mg/dl for men or 1.4 mg/dl for women, or abnormal creatinine clearance). Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. WARNINGS AND PRECAUTIONS Lactic Acidosis Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 0% of cases. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.01 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.

7 IMPORTANT SAFETY INFORMATION for Jentadueto (linagliptin and metformin hydrochloride) tablets (cont d) Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Monitoring of Renal Function Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. Impaired Hepatic Function Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Hypoglycemia Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Vitamin B 12 Levels Vitamin B 12 deficiency: Metformin may lower Vitamin B 12 levels. Monitor hematologic parameters annually. Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. Hypoxic States Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug. ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in % of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea. 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. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placeboand metformin with SU (14.8%). Pancreatitis was reported more often in patients randomized to linagliptin (1 per 38 person-years versus 0 in 433 person-years for comparator). DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended. The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase. USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established. JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function. JD PROF ISI MAR12012 Please see accompanying full Prescribing Information, including Patient Information. 7

8 Additional Resources Tradjenta (linagliptin) tablets Web site: Jentadueto (linagliptin and metformin hydrochloride) tablets Web site: References 1. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;1(6):40-9. Erratum in: Endocr Pract. 2009;1(7): TRADJENTA Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; Freeman JS. Managing hyperglycemia in patients with type 2 diabetes mellitus: rationale for the use of dipeptidyl peptidase-4 inhibitors in combination with other oral antidiabetic drugs. J Am Osteopath Assoc. 2010;110(9): Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13(1): JENTADUETO Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; Handelsman Y, Mechanick JI, Blonde L, et al; for the AACE Task Force for Developing a Diabetes Comprehensive Care Plan. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2): American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2012;3(suppl 1):S11-S Heine RJ, Balkau B, Ceriello A, Del Prato S, Horton ES, Taskinen M-R. What does postprandial hyperglycaemia mean? Diabet Med. 2004;21(3): Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26(3): Woerle HJ, Neumann C, Zschau S, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes: importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract. 2007;77(2): Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes mellitus: 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(1): Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;8(4): Plantinga LC, Crews DC, Coresh J, et al; for the CDC CKD Surveillance Team. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;(4): Data on File. Boehringer Ingelheim. 1. Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2012;14(6):6-74. This promotional program was developed in conjunction with and funded by Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC, based on an interview with Charles Reasner, MD. Dr Reasner received fair market value compensation for participation in this program. ClinTopics is a registered trademark of BioPharm Communications, LLC. TRADJENTA and JENTADUETO are registered trademarks of Boehringer Ingelheim International GmbH. Copyright 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (11/12) TJ4261PROF 8