CAMBRIDGESHIRE JOINT PRESCRIBING GROUP DECISION DOCUMENT Recommendation made by CJPG to Commissioners and Prescribers

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1 CAMBRIDGESHIRE JOINT PRESCRIBING GROUP DECISION DOCUMENT Recommendation made by CJPG to Commissioners and Prescribers Linagliptin (Trajenta, Boehringer Ingelheim Ltd) for the treatment of type 2 diabetes as mono or combination therapy. Date of last revision Document status Purpose of Document Recommendations A Dipeptidyl peptidase (DPP-4) inhibitor 19 July, version 1(1) Prepared by Debbie Morrison, Consultant Pharmacist, CJPG and HCD, Katie Smith, Director, East Anglia Medicines Information Service. For consideration by CJPG at the May 2012 meeting To inform clinicians about an impending new drug, review information currently available and give guidance on potential use and assign a R-A-G classification. It is recommended by Cambridgeshire JPG members, and through them to local NHS organisations, that the arrangements for use of linagliptin are as a Green drug and the drug is suitable for prescribing in both primary and secondary care but with restrictions on place in therapy. Rationale for Recommendation: Members noted the place in therapy defined by the NICE Clinical Guideline for the newer drugs in Type 2 diabetes (CG87) for the gliptins: second-line in combination with metformin or a sulfonylurea where metformin is not tolerated third-line in combination with both metformin and a sulfonylurea where blood glucose control remains or becomes inadequate. Members noted the different mechanism of excretion for the drug (i.e. not via the kidneys) and that other DPP-IV inhibitors are not recommended for people with moderate or severe renal impairment. Members noted that may be a potential for improved cardiovascular outcomes. CJPG agreed that Linagliptin should be designated a Green drug with restricted prescribing at the places in therapy defined by NICE CG87 for patients with moderate to severe renal impairment. Points Considered: Linagliptin is a xanthine analogue which acts as a selective and long-acting DPP-IV inhibitor (>80% DPP-4 inhibition at 24-h post-dose). It regulates blood glucose by prolonging the duration of incretin activity (glucagonlikepeptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)). Management strategies in type 2 diabetes aim to achieve and maintain glycaemic control to HbA1c levels of <6.5% or <7.0% to reduce the risk of complications or 7.5% for those at risk of severe hypoglycaemia. Despite treatment with lifestyle changes and effective oral hypoglycaemic monotherapy, progressive decline in glucose control persists, eventually

2 Numbers Needed to Treat (NNT) Numbers Needed to Harm (NNH) Other Submissions necessitating combination therapy for many patients. When added to metformin monotherapy, linagliptin provides similar HbA1C reductions to glimepiride but with less hypoglycaemia, relative weight loss, and significantly fewer adjudicated CV events. A long - term outcomes study (CAROLINA) is ongoing to confirm the promising CV safety data seen with linagliptin to date.(gallwitz, 2011). The treatment difference in the Taskinen study [1] was 0.64% (95% CI 0.78 to 0.50; p < ) however trial participants had their current additional anti-diabetic therapy stopped and one third of patients had not received prior metformin. Renal impairment (RI) is a common complication of type 2 diabetes mellitus (T2DM). Disease management in patients with RI is challenging and treatment options are limited. Linagliptin is not excreted via the kidneys, and as other DPP-IV inhibitors are not recommended for people with moderate or severe renal impairment, may offer an additional line of oral therapy for these patients. Clinical experience in patients > 75 years of age is limited. Safety and efficacy of linagliptin in children and adolescents has not yet been established. DPP-4 inhibitors have a low potential for drug-drug interactions with the exception of saxagliptin, which is metabolized by cytochrome P450 [CYP] 3A4/5. In one study, there was a dose-dependent relationship for the time to maximal inhibition, which occurred at 3 hours with the 2.5mg dose and was reduced to <0.7 hours with all doses 200mg. Plasma DPP-4 activity had not returned to baseline levels 96 hours post-dose. There have been concerns raised over the appropriateness of comparators in the trials. For an improvement in cardiovascular outcomes over glimepiride: NNT = 56 [2] NNH for hypoglycaemia for metformin treatment vs. metformin and linagliptin = 45, i.e. linagliptin is less likely to be associated with hypoglycaemia.[1] NICE NICE Clinical Guideline 87 (CG 87) places the DPP-4 inhibitors as alternative second-line therapies in combination with metformin or, where metformin is not tolerated, sulfonylureas or third line in combination with metformin and a sulfonylurea where blood glucose control remains or becomes inadequate. Scottish Medicines Consortium (SMC) The SMC has assessed linagliptin and has accepted it for use within NHS Scotland in combination with metformin when diet and exercise plus metformin alone does not provide adequate glycaemic control in patients for whom the addition of a sulphonylurea is inappropriate. The Committee was unable to recommend its use within the other licensed indications (as monotherapy or in combination with metformin and a sulphonylurea), as the company s submission related only to its use in combination with metformin. Treatment Oral anti-diabetes drugs (alone or in combination)

3 Alternatives Metformin. Sulfonylureas: gliclazide, glibenclamide, glipizide, tolbutamide, glimepiride. Alpha-glucosidase inhibitors: acarbose. Thiazolidinediones (glitazones): rosiglitazone, pioglitazone. DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin. Place in current therapy Future Alternatives Injectable drugs Exenatide (twice daily SC, once weekly SC). Liraglutide (once daily SC). Insulin (human or analogue). Second or third line. Sodium-glucose co-transporter-2 inhibitors, e.g. dapagliflozin (which are furthest along in development); 11 beta-hydroxysteroid dehydrogenase (some of which are now in phase 2 trials); glycogen phosphorylase inhibitors; glucokinase activators; G protein coupled receptor 119 agonists; protein tyrosine phosphatase 1B inhibitors; and glucagon-receptor antagonists.[11] JPG Decision/Date May 2012 Review Date On provision of new information or on clinician request to consider new evidence. Indication(s) Linagliptin is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults: as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to intolerance, or contraindicated due to renal impairment. as combination therapy in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control. in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. Contraindications Cautions Hypersensitivity to the active substance or to any of the excipients. Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycaemia Linagliptin alone showed a comparable incidence of hypoglycaemia to placebo. In clinical trials of linagliptin as part of combination therapy with medicinal products not known to cause hypoglycaemia (metformin) rates of hypoglycaemia reported with linagliptin were similar to rates in patients taking placebo. When linagliptin was added to a sulphonylurea (on a background of metformin), the incidence of hypoglycaemia was increased over that of placebo. Sulphonylureas are known to cause hypoglycaemia. Therefore, caution is advised when linagliptin is used in combination with a sulphonylurea. A dose reduction of the sulphonylurea may be considered. Interactions:

4 Source of Review Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Interactions occur with ritonavir and rifampicin [1] Taskinen M-R, J. Rosenstock J 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, Obesity and Metabolism. 2011; 13: [2] Gallwitz B.,Uhlig-Laske B et al. Linagliptin has similar efficacy to glimepiride but improved cardiovascular safety over 2 years in patients with type 2 diabetes inadequately controlled on Metformin. Diabetes, 2011; 20: , [3] Owens DR, Swallow R et al. Efficacy and safety of linagliptin in persons with Type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabetic Medicine. 2011; 10: [4] Sloan L, Newman J et al. Safety and efficacy of linagliptin in type 2 diabetes patients with severe renal impairment. Diabetes. 2011; 60 /(A114), Monotherapy [5] Barnett AH; Harper R et al. Linagliptin Monotherapy Improves Glycaemic Control in Type 2 Diabetes Patients for Whom Metformin Therapy is Inappropriate. EASD poster Safety [6] Schernthaner G.,Von Eynatten M. et al. Safety and tolerability of linagliptin: A pooled analysis of data from 3572 patients with type 2 diabetes. Diabetes. 2011; 60, (July 2011) [7] Graefe-Mody U, Friedrich C et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes, Obesity and Metabolism. 2011; 13: [8] Groop P-H, von Eynatten M et al. Efficacy and Safety of Linagliptin in Type 2 Diabetes Patients at High Risk of Renal Complications: Results from a Large Phase 3 Program. American Diabetes Association Others [9] Scott LJ. Linagliptin; In Type 2 Diabetes Mellitus. Drugs 2011; 71: [10] Updated NICE Clinical Guideline in Type 2 diabetes - CG87;2009 [11] Nguyen QT, Thomas KT et al. Current Therapies and Emerging Drugs in the Pipeline for Type 2 Diabetes. American Health and Drug Benefits. 2011; 4: [12] INN-European Product Assessment Report. Trajenta (Linagliptin) _Public_assessment_report/human/002110/WC pdf Guidance on Use Clinical Efficacy The dose of linagliptin is 5 mg once daily. When linagliptin is added to metformin, the dose of metformin should be maintained, and linagliptin administered concomitantly. When linagliptin is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia. Linagliptin in Combination Therapy [1] The aim of this study was to evaluate the efficacy and safety of the selective dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control.

5 This 24-week, randomized, placebo-controlled, double-blind, parallel-group study was carried out in 82 centres in 10 countries. A total of 1,268 patients were enrolled and 701 randomised to treatment (524 to linagliptin, 177 to placebo). Patients with HbA1c levels of % on metformin and a maximum of one additional anti-diabetes medication, which was discontinued at screening, continued on metformin 1500 mg/day for 6 weeks, including a placebo run-in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add-on. Approximately two thirds of patients had previously been treated with metformin monotherapy. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c ( 0.49% vs. 0.15%), FPG ( 0.59 vs mmol/l) and 2h post-prandial glucose ( 2.7 vs. 1.0 mmol/l); all p < Among patients with a baseline HbA1c of 7.0%, 26% of individuals treated with linagliptin vs. 9% of those in the placebo group achieved the HbA1c target of <7.0% at 24 weeks. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups ( 0.5 kg placebo, 0.4 kg linagliptin). [2] This 2-year double-blind trial investigated the long-term efficacy and safety of adding linagliptin or glimepiride to ongoing metformin to treat T2DM. T2DM patients on stable metformin (>=1500mg/day) for >= 10 weeks were randomised to linagliptin 5mg/day (N=764) or glimepiride 1-4mg/day (N=755) over 2 years. Efficacy analyses were based on HbA1c change from baseline in the full analysis set (FAS) and per-protocol (PP) population. Safety evaluations included prespecified, prospective, and adjudicated capture of cardiovascular (CV) events (CV death, non-fatal myocardial infarction or stroke, unstable angina with hospitalisation). Baseline characteristics were well-balanced in the 2 groups (HbA1c: 7.7% for both). In the PP population, adjusted mean (+/- SE) HbA1c changes from baseline were -0.4 %(+/- 0.04%) for linagliptin 5mg/day versus -0.5 % (+/-0.04%) for glimepiride (mean dose 3mg/day). Mean between-group difference was 0.17% (95% confidence interval [CI], 0.07-

6 0.28%; P= for non-inferiority). Similar results were observed in the FAS population. Fewer patients experienced investigator-defined, drug-related hypoglycaemia with linagliptin than glimepiride (7.5 % vs. 36.1%; P <0.0001). Body weight was decreased with linagliptin and increased with glimepiride (-1.4 kg vs kg; adjusted mean difference, -2.7 kg; P < ). CV events occurred in 12 (1.6%) linagliptin patients versus 26 (3.4%) glimepiride patients revealing a significant 54 % reduction in relative risk for the combined CV endpoint (relative risk, 0.46; 95% CI ; P=0.02). [3] This study aimed to examine the efficacy and safety of the dipeptidyl peptidase- 4 inhibitor linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA1c mmol/ mol ( %)] by metformin and sulphonylurea combination treatment. This was a multi-centre, 24-week, randomized, double-blind, parallel-group study in 1,058 patients comparing linagliptin (5 mg once daily) and placebo when added to metformin plus sulphonylurea. The primary endpoint was the change in HbA1c after 24 weeks. At week 24, the linagliptin placebo-corrected HbA1c adjusted mean change from baseline was 7 mmol/ mol (-0.62%) [95% CI -8 to -6 mmol/mol (-0.73 to -0.50%); P < ]. More participants with baseline HbA1c 53 mmol mol ( 7.0%) achieved an HbA1c < 53 mmol/mol (< 7.0%) with linagliptin compared with placebo (29.2% vs. 8.1%, P < ). Fasting plasma glucose was reduced with linagliptin relative to placebo (-0.7 mmol /l, 95% CI -1.0 to -0.4; P < ). Improvements in homeostasis model assessment of β-cell function were seen with linagliptin (P < 0.001). The proportion of patients who reported a severe adverse event was low in both groups (linagliptin 2.4%; placebo 1.5%). Symptomatic hypoglycaemia occurred in 16.7% and 10.3% of the linagliptin and placebo groups, respectively. Hypoglycaemia was generally mild or moderate; severe hypoglycaemia was reported in 2.7 and 4.8% of the participants experiencing hypoglycaemic episodes in the linagliptin and placebo groups, respectively. No significant weight changes were noted. [4] This randomized, double-blind, placebo (PBO)-controlled Phase 3 trial evaluated the efficacy and safety of the novel dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM (HbA1c %) and severe RI (glomerular filtration rate [GFR] <30 ml/ min/1.73 m 2 ).

7 Patients were treated with either linagliptin 5 mg qd (n=68) or PBO (n=65); antidiabetic background therapy remained unchanged. The primary endpoint was HbA1c change from baseline at week 12. Mean (+/-SD) baseline age, HbA1c, and GFR were 64.4+/-10.3 years, 8.2+/-1.0%, and 23.5+/-6.7 ml/min/1.73 m 2, respectively. Diabetes duration was >5 years in 96% of patients. The HbA1c change from baseline in the full analysis set and in the subgroup of poorly controlled patients (baseline HbA1c9%) are shown in the figure. Adverse event (AE) and serious AE rates were 86.8% and 23.5% for linagliptin and 81.5% and 26.2% for PBO, respectively. Hypoglycemia occurred in 51.5% of linagliptin and 27.7% of PBO-treated patients. Notably, 61/66 patients receiving linagliptin were on insulin and/or sulfonylurea background; their unchanged doses may account for the hypoglycemic event rate in this arm. Renal function remained stable throughout the study in both treatment arms and cardiovascular deaths in this high-risk population were low: 1 (1.5%) on linagliptin and 3 (4.6%) on PBO. This is the first trial evaluating the safety and efficacy of a DPP-4 inhibitor exclusively in patients with severe RI. Results confirm that linagliptin is likely to be a valuable treatment option for T2DM patients with insufficiently controlled hyperglycemia in whom renal function is severely impaired Monotherapy [5] Dose-related adverse events, such as diarrhoea, nausea and abdominal bloating, and a potential risk for lactic acidosis in subjects with renal impairment, may limit metformin use in patients with type 2 diabetes mellitus (T2DM). This multi-centre, 18-week, randomised, double-blind, placebo-controlled, parallel group study (followed by an on-going 34-week double-blind extension period in which placebo patients were switched to glimepiride) assessed the efficacy, safety and tolerability of the oral DPP-4 inhibitor linagliptin (5 mg qd) in patients with inadequately controlled T2DM for whom metformin therapy is inappropriate due to intolerability or contraindication. Materials and methods: Hyperglycaemic T2DM patients who were treatment-naïve (HbA1c 7.0 to 10.0%, or HbA1c 7.0 to 9.0% in Canada) or pre-treated with 1 oral anti-diabetes drug (OAD) (HbA1c 6.5 to 9.0% after a 6-week washout period) were randomised to linagliptin (n=151) or placebo (n=76) following a 2-week placebo run-in (previously treated patients went without medication for 4 weeks prior to this). The primary endpoint for the trial was the change in HbA1c from baseline after 18 weeks of treatment evaluated with an analysis of covariance (ANCOVA) adjusted for prior OAD(s), baseline HbA1c and reason for metformin ineligibility. This interim analysis was conducted after all patients had completed 18 weeks of treatment. There were no differences between the linagliptin and placebo groups for mean baseline characteristics (overall HbA1c 8.09% [SD, 0.93]; fasting plasma glucose (FPG), 10.1 [2.5] mmol/l; age, 56.5 [10.3] yrs; BMI, 29.5 [5.4] kg/m2). Most of the patients (61.2%) were female. The majority of patients had either normal renal function (55.9%) or mild renal impairment (34.4%). Metformin was inappropriate due to intolerance from gastrointestinal adverse events in 93% of the randomised

8 patients, with the remainder of cases due to raised creatinine. After 18 weeks of treatment, the adjusted mean difference between linagliptin and placebo was -0.57% with 95% confidence interval (CI; -0.86, -0.29) (P<0.0001) in favour of linagliptin for change in HbA1c (%). Statistically significant differences between linagliptin and placebo for HbA1c were seen by Week 6 and were sustained through Week 18. Among patients with baseline HbA1c 7.0%, 11.8% of patients in the placebo group and 23.5% of the patients in the linagliptin group achieved HbA1c <7.0% at Week 18. At Week 18, linagliptin was superior to placebo in reducing the mean FPG from baseline (adjusted mean difference -1.1 mmol/l with 95% CI (-1.7, -0.6); P=0.0002). The percentage of patients requiring rescue therapy was higher in the placebo group (17.8%) compared with the linagliptin group (11.6%). The proportion of patients experiencing 1 adverse event classed as drug-related within the linagliptin and placebo groups was 6.6% and 1.3%, respectively. Hypoglycaemia was rare, occurring in 2 patients (1.3%) in the linagliptin group and none in the placebo group and there were no severe cases in either group. No difference in weight was seen between groups. Safety [6] The most commonly observed adverse events (AEs) listed in labels of currently available DPP-4 inhibitors include infections, headache, and hypersensitivity; other AEs of interest include renal or hepatic dysfunction and hypoglycemia. To extend current knowledge of the safety and tolerability profile of linagliptin, a new DPP-4 inhibitor currently in late-stage development, a large pooled-analysis of 3572 patients with T2DM was conducted. Data from 8 randomized, placebocontrolled, Phase 3 clinical trials were analyzed and 1049 patients received linagliptin 5 mg qd or placebo, respectively. The overall incidence rate of AEs or serious AEs with linagliptin was similar to placebo (AEs 55.0% vs 55.8%; serious AEs 2.8% vs 2.7%). Overall aggregated infection rates were 19.5% for linagliptin and 21.4% for placebo. Fewer or similar rates of AEs vs placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs 4.9%), headache (2.9% vs 3.1%), urinary tract infection (2.2% vs 2.7%), blood and lymphatic disorders (1.0% vs 1.2%), hypersensitivity (0.1% vs 0.1%), hepatic enzyme increase (0.1% and 0.1%), and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs 5.1%) and cough (1.7% vs 1.0%) with linagliptin. In general, hypoglycemia rates were similar with linagliptin (8.2%) and placebo (5.1%). Incidence of hypoglycemia was increased in patients with background sulfonylurea (SU) therapy (linagliptin 20.7%), which is in agreement with other reports where DPP-4 inhibitors were added to SUs. Overall, the hypoglycemic

9 event rate with linagliptin was very low (<1.0%) when used without SUs. This large pooled analysis provides further evidence that linagliptin is well tolerated. Continued assessment of AEs reported from the ongoing clinical trial program is desirable to establish its long-term safety. [7] This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM). Linagliptin pharmacokinetics were studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM). Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration time profiles. These showed a similar decline and almost identical plasma concentrations 24 h post-dosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20 60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C max values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from h in subjects with normal renal function. [8] Type 2 diabetes mellitus (T2DM) is frequently associated with kidney damage and progressive renal impairment (RI). Renal risk factors include arterial hypertension, uncontrolled hyperglycemia, albuminuria, and existing RI. The novel dipeptidyl peptidase (DPP)-4 inhibitor linagliptin is excreted by a primarily non-renal route and is likely to be suitable for patients at risk of renal complications. This pooled analysis of 3 randomized, placebo-controlled, Phase 3 clinical trials was conducted to determine the efficacy and safety of linagliptin in T2DM subjects at high risk of renal complications. Data were available for 2045 subjects, with 1731 having 1 renal risk factor. Prevalence of renal risk factors was: 34% hypertension ( 140/90 mmhg) and 71% use of antihypertensive medication; 20% poor glycemic control (baseline HbA1c >9%); 27% urine albumin/creatinine ratio >30 mg/gcrea; and 49% RI (glomerular filtration rate <90 ml/min/1.73 m 2 ). Outcomes were analyzed according to the number of risk factors present and results are shown in the figure below.[figure1] The mean adjusted changes from baseline in HbA1c with linagliptin for patients with 1 to 5 renal risk factors were 0.6%, 0.7%, 0.7%, 0.9%, and 1.5% (all p<0.005 vs. placebo), respectively. Linagliptin was well tolerated and the overall incidence of adverse events for linagliptin was similar to placebo (60.2% vs. 58.5%).

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11 Impact for Cambridgeshire and Peterborough PCTs From the NICE costing template for the clinical guideline for newer agents in Type 2 diabetes (CG87) the estimated prevalence of Type II diabetes is 2.89%, based on prevalence figures taken from a sample of primary care data provided by the Information Centre. This equates to 23,120 (based on population statistics from the year 2006) patients with Type 2 diabetes for the NHS Cambridgeshire and Peterborough population of 800,000. The number of patients who are likely to be prescribed a DPP-4 inhibitor, from the costing template, is likely to be: For the NHS Cambridgeshire and Peterborough population: Drug Combination Prevalent Population Patient numbers (n= 21,552) Metformin + DPP-4 Inhibitor 2% 462 Sulfonlyurea + DPP-4 Inhibitor 3% 694 Triple therapy; Metformin + 1% 231 Sulfonlyurea + DPP-4 Inhibitor Total 6% 1,387 Costs The cost of a 28 day supply of linagliptin is excluding VAT. The cost of treating one NHS Cambridgeshire and Peterborough patient with linagliptin for one year is therefore Drug Dose Annual cost Sitagliptin (Januvia; MSD) 100mg once daily Vildagliptin (Galvus; 50mg once daily/twice daily Novartis) Saxagliptin 5mg once daily Pioglitazone 30mg once daily Clinician Comments Comments to: Therefore the cost of using linagliptin as add on therapy to metformin for 1,387 NHS C&P patients will be: 1,387 x = 601,362, i.e. the same as the currently most commonly prescribed gliptin. Debbie Morrison, Consultant Pharmacist, PHN and HCD, Civic Suite, Pathfinder House, Huntingdon, Cambs, PE29 3TN debbie.morrison@cambsphn.nhs.uk