Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors.

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Glimepiride 2 endocrinologydiseasesdrugs
Insulin 3 endocrinologydiseasesdrugs
glipizide 9 endocrinologydiseasesdrugs
metformin 11 endocrinologydiseasesdrugs
pioglitazone 75 endocrinologydiseasesdrugs
sitagliptin 5 endocrinologydiseasesdrugs
glyburide 1 endocrinologydiseasesdrugs
obesity 2 endocrinologydiseases
osteoporosis 1 endocrinologydiseases
rosiglitazone 4 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
Glimepiride 17046 and −0.51 glipizide5% sitagliptin vs 34% glipizideNon‐inferiorMatthews et al. 201043Vildagliptin Glimepiride 3118 randomized (vildagliptin, n = 1562; glimepiride, n = 1556) 7.3 (56) both groups−0.1 both
Glimepiride 17253 groups−0.1 both groupsVildagliptin 2.3% vs 18.2% glimepiride Non‐inferiorGallwitz et al. 201244Linagliptin Glimepiride 1519 PP (linagliptin, n = 764; glimepiride, n = 755) 7.7 (61) both groups−0.16 linagliptin
Insulin 11488 monotherapy provided only slight, not significant, improvement of beta‐cell function parameters.26 Insulin resistance is fully apparent in the pre‐diabetic state,27 and it is responsible for impaired glucose
Insulin 13264 expense of an increase in subcutaneous fat, a more benign fat tissue with milder metabolic implications. Insulin resistance also accounts for excessive hepatic glucose production in the post‐absorptive state and
Insulin 29365 stroke (HR, 0.53; 95% CI, 0.34‐0.85; P = .009)].62, 63 The latter finding set the basis for the Insulin Resistance Intervention after Stroke (IRIS) trial, exploring the effect of pioglitazone in insulin‐resistant,
glipizide 16883 HypoglycaemiaPrimary endpoint outcomeSeck et al. 201042SitagliptinGlipizide504 PP (sitagliptin, n = 248; glipizide , n = 256)7.3 (56) both groups−0.54 sitagliptin and −0.51 glipizide5% sitagliptin vs 34% glipizideNon‐inferiorMatthews
glipizide 16958 (sitagliptin, n = 248; glipizide, n = 256)7.3 (56) both groups−0.54 sitagliptin and −0.51 glipizide 5% sitagliptin vs 34% glipizideNon‐inferiorMatthews et al. 201043VildagliptinGlimepiride3118 randomized
glipizide 16989 glipizide, n = 256)7.3 (56) both groups−0.54 sitagliptin and −0.51 glipizide5% sitagliptin vs 34% glipizide Non‐inferiorMatthews et al. 201043VildagliptinGlimepiride3118 randomized (vildagliptin, n = 1562;
glipizide 17515 glimepirideNon‐inferiorGoke et al. 201345SaxagliptinGlipizide858 randomized (saxagliptin, n = 428; glipizide , n = 430) 7.65 (60) both groups−0.41 saxagliptin and −0.35 glipizideSaxagliptin 3.5% vs 38.4%
glipizide 17592 (saxagliptin, n = 428; glipizide, n = 430) 7.65 (60) both groups−0.41 saxagliptin and −0.35 glipizide Saxagliptin 3.5% vs 38.4% glipizideNon‐inferiorDel Prato et al. 201446AlogliptinGlipizide1089 PP (alogliptin
glipizide 17627 n = 430) 7.65 (60) both groups−0.41 saxagliptin and −0.35 glipizideSaxagliptin 3.5% vs 38.4% glipizide Non‐inferiorDel Prato et al. 201446AlogliptinGlipizide1089 PP (alogliptin 12.5 mg once daily, n = 371;
glipizide 17795 201446AlogliptinGlipizide1089 PP (alogliptin 12.5 mg once daily, n = 371; alogliptin 25 mg once daily, n = 382; and glipizide 5 mg once daily, n = 336)7.6 (60) both groups−0.68 alogliptin 12.5 mg, −0.72 alogliptin 25 mg,
glipizide 17924 n = 336)7.6 (60) both groups−0.68 alogliptin 12.5 mg, −0.72 alogliptin 25 mg, and −0.59 glipizide 2.5% and 1.4% alogliptin 12.5 and 25 mg, respectively vs 23.2% glipizideSuperior in alogliptin 25 mg
glipizide 17998 alogliptin 25 mg, and −0.59 glipizide2.5% and 1.4% alogliptin 12.5 and 25 mg, respectively vs 23.2% glipizide Superior in alogliptin 25 mg group Abbreviations: DPP4i, dipeptidyl peptidase‐4 inhibitor; PP, per
glyburide 15591 cumulative incidence of monotherapy failure was 15% with rosiglitazone, 21% with metformin and 34% with glyburide . The sustained efficacy of glitazones has been confirmed in many of the glitazone trials, as summarized
metformin 5313 sensitizer, but pioglitazone exerts a stronger effect on insulin action in peripheral tissues.8 Although metformin CV protection was apparent in the United Kingdom Prospective Diabetes Study (UKPDS),9 more data lend
metformin 8753 of 48 to 58 mmol/mol (6.5%‐7.5%) were randomized to either early initiation of a vildagliptin– metformin combination or standard‐of‐care initiation of metformin monotherapy, followed by stepwise addition
metformin 8813 either early initiation of a vildagliptin–metformin combination or standard‐of‐care initiation of metformin monotherapy, followed by stepwise addition of vildagliptin. The aim of this study was to determine treatment
metformin 15347 (5) reducing gluconeogenesis.ACHIEVING LONG‐LASTING GLYCAEMIC CONTROL3The effect of rosiglitazone, metformin and glibenclamide as initial treatment was evaluated in 4360 T2DM patients in the ADOPT trial.38 After
metformin 15568 5 years of treatment the cumulative incidence of monotherapy failure was 15% with rosiglitazone, 21% with metformin and 34% with glyburide. The sustained efficacy of glitazones has been confirmed in many of the glitazone
metformin 15890 primary care observational study in 500 T2DM patients, showing that pioglitazone, as an add‐on to metformin , leads to significant benefits in long‐term glycaemic control compared with sulphonylureas.40 In Japanese
metformin 16324 clinical trials with DPP4i run up to 2 years and compare glucose‐lowering efficacy added‐on to metformin (Met) vs sulfonylureas. As shown in Table 1, 4 out of 5 trials showed non‐inferiority42, 43, 44, 45
metformin 16596 year.46Table 1Summary of the long‐term (2 year) efficacy and safety trials of DPP4i added‐on to metformin vs sulphonylureas in type 2 diabetesAuthor, year and referenceDPP4iComparatorNumber of patients (n)Baseline
metformin 19711 25 mg Alo once daily, or matching placebo. Groups were: (1) monotherapy (n = 185); (2) add‐on to metformin (n = 197); and (3) add‐on to Pio (with or without Met; n = 124) 16 weeksEntry criteria between
metformin 26562 combination; HbA1c, hemoglobin A1c; HDL, high‐density lipoprotein cholesterol; Lin, linagliptin; Met, metformin ; na, not applicable; PBO, placebo‐controlled; Pio, pioglitazone; q.d., once daily; Sax, saxagliptin;
metformin 26784 sulphonylurea; Ten, teneligliptin; TG, triglycerides; TZD, thiazolidinedione.Pioglitazone, when added to metformin in T2DM patients failing with this treatment, was associated with lower HbA1c reduction (−0.9% ± 0.05%)
pioglitazone 112 Diabetes, Obesity & MetabolismPractical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitorsAlternative Title: Del Prato and ChiltonStefano Del PratoRobert Chilton1Section of
pioglitazone 1578 summarized in this review, showing significant reduction of cardiovascular risk. Against this background, pioglitazone , in addition to exerting a sustained glucose‐lowering effect, also has ancillary metabolic actions
pioglitazone 2083 have a potential to preserve beta‐cell function, is available as a fixed‐dose combination with pioglitazone , and could, potentially, attenuate some of the side effects of pioglitazone, particularly if a lower
pioglitazone 2159 fixed‐dose combination with pioglitazone, and could, potentially, attenuate some of the side effects of pioglitazone , particularly if a lower dose of the thiazolidinedione is used. This review critically discusses the
pioglitazone 2308 thiazolidinedione is used. This review critically discusses the potential for early combination of pioglitazone and DPP4i.Del PratoS, ChiltonR. Practical strategies for improving outcomes in T2DM: The potential role
pioglitazone 2428 DPP4i.Del PratoS, ChiltonR. Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors. Diabetes Obes Metab. 2018;20:786–799. https://doi.org/10.1111/dom.1316929171700Stefano
pioglitazone 5224 considered.Metformin, the common front‐line therapy in T2DM treatment, is considered an insulin sensitizer, but pioglitazone exerts a stronger effect on insulin action in peripheral tissues.8 Although metformin CV protection
pioglitazone 5467 Kingdom Prospective Diabetes Study (UKPDS),9 more data lend support to the CV protection properties of pioglitazone .10, 11Among the agents used to improve beta‐cell function, incretins have a more physiologic mechanism
pioglitazone 5786 have a very good safety and tolerability profile and, as such, can be considered for combination with pioglitazone , even in the early stage of the disease.The purpose of this review article is to evaluate the potential
pioglitazone 5931 disease.The purpose of this review article is to evaluate the potential of combination therapy with pioglitazone and DPP4i with respect to: (1) addressing pathophysiologic mechanisms underlying T2DM; (2) maintenance
pioglitazone 7263 preserving beta‐cell function is important for ensuring durable glycaemic control.Both DPP4i and pioglitazone have the potential to exert such an effect. Several studies in animals16, 17 have shown that DPP4i can
pioglitazone 9857 slower decline of beta‐cell function.24 Against this background, it seems rational to propose that pioglitazone and DPP4i may work through complementary mechanisms, resulting in more efficient beta‐cell protection
pioglitazone 10056 beta‐cell protection and, therefore, more sustained glycaemic control.The effect of the combination of pioglitazone and DPP4i on beta‐cell function has been assessed in animal models as well as in human studies. In
pioglitazone 10378 insulin levels by 3.2‐fold and pancreatic insulin content by 2.2%.25 Yin et al.21 tested the ability of pioglitazone and alogliptin to enhance beta‐cell regeneration of endogenous and transplanted beta‐cells in transgenic
pioglitazone 10864 rapamycin and tacrolimus caused early loss of beta‐cell mass after islet transplantation, the use of pioglitazone and alogliptin partially promoted beta‐cell mass recovery.21 The effect of the combination of the
pioglitazone 12280 LDL.28While no significant effect on insulin sensitivity is exerted by DPP4i, it is widely recognized that pioglitazone is a potent insulin sensitizer. This effect is associated with a reduction in serum levels of triglycerides
pioglitazone 12706 modulation of lipid metabolism and the anti‐inflammatory property is the probable mechanism through which pioglitazone exerts powerful positive effects on nonalcoholic steatohepatitis (NASH).31 The latter effect is of importance
pioglitazone 14850 directly affect liver glucose metabolism37; therefore, even with respect to hepatic glucose production, pioglitazone and DPP4i can have a synergistic effect. In summary, the combination of pioglitazone and DPP4i addresses,
pioglitazone 14935 glucose production, pioglitazone and DPP4i can have a synergistic effect. In summary, the combination of pioglitazone and DPP4i addresses, in a synergistic manner, many of the pathogenic defects of T2DM by: (1) enhancing
pioglitazone 15858 been reported in an open‐label, primary care observational study in 500 T2DM patients, showing that pioglitazone , as an add‐on to metformin, leads to significant benefits in long‐term glycaemic control compared
pioglitazone 16032 in long‐term glycaemic control compared with sulphonylureas.40 In Japanese T2DM patients receiving pioglitazone , with or without other oral glucose‐lowering drugs, better glycaemic control was predicted to be maintained
pioglitazone 18197 inhibitor; PP, per protocol.Clinical trials have directly explored the clinical efficacy of the DPP4i and pioglitazone association as initial combination therapy in drug‐naive T2DM patients. Alogliptin (25 mg) and pioglitazone
pioglitazone 18309 association as initial combination therapy in drug‐naive T2DM patients. Alogliptin (25 mg) and pioglitazone (30 mg) once daily for 26 weeks led to greater HbA1c reduction (−1.7% ± 0.1%) than that achieved
pioglitazone 18485 reduction (−1.7% ± 0.1%) than that achieved with alogliptin (−1.0% ± 0.1%; P < .001) or pioglitazone (−1.2% ± 0.1%; P < .001) monotherapy, without worsening the respective safety profile.47
pioglitazone 18809 extension trial, mean HbA1c reduction was −2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg vs −1.9% with pioglitazone monotherapy, and the mean reduction in fasting plasma glucose (FPG)
pioglitazone 18846 reduction was −2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg vs −1.9% with pioglitazone monotherapy, and the mean reduction in fasting plasma glucose (FPG) was −61.3 mg/dL vs −52.8 mg/dL,
pioglitazone 19185 published in the past few years, supporting the overall clinical efficacy of the treatment combination of pioglitazone and DPP4 inhibitors.Table 2Summary of recent clinical trials (last 5 years) evaluating the efficacy
pioglitazone 19317 inhibitors.Table 2Summary of recent clinical trials (last 5 years) evaluating the efficacy of the DPP4i and pioglitazone association in type 2 diabetesAuthor, year and referenceDPP4iDesignSubjects, nTreatment arm and doseDurationHbA1c
pioglitazone 26625 cholesterol; Lin, linagliptin; Met, metformin; na, not applicable; PBO, placebo‐controlled; Pio, pioglitazone ; q.d., once daily; Sax, saxagliptin; SU, sulphonylurea; Ten, teneligliptin; TG, triglycerides; TZD,
pioglitazone 26937 treatment, was associated with lower HbA1c reduction (−0.9% ± 0.05%) than that following addition of pioglitazone plus alogliptin (−1.4% ± 0.05%; P < .001) and with a better proinsulin:insulin ratio and
pioglitazone 27175 homeostasis model assessment of beta‐cell function.54 Moreover, 12‐week treatment with sitaglitpin and pioglitazone enhanced the index Φ, a measure of dynamic β‐cell responsiveness to glucose increments, to a greater
pioglitazone 27430 and vs either monotherapy alone.57Altogether, the results of these trials show how the combination of pioglitazone and DPP4i, 2 anti‐hyperglycaemic agents with different but complementary mechanisms of action, provide
pioglitazone 28476 1.42‐1.85) and 1.99 (95% CI, 1.70‐2.34) for CV risk, respectively.Along with sustained glycaemic control, pioglitazone conveys CV protection. In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive)
pioglitazone 28609 protection. In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial, adding pioglitazone to the existing therapy resulted in a non‐significant 10% relative risk (RR) reduction in the primary
pioglitazone 29448 the basis for the Insulin Resistance Intervention after Stroke (IRIS) trial, exploring the effect of pioglitazone in insulin‐resistant, non‐diabetic patients with a recent ischemic stroke or transient ischemic
pioglitazone 29788 CI, 0.62‐0.93).11 In a more recent meta‐analysis including 9 trials with 12 026 participants, pioglitazone was found to be associated with lower risk of a major adverse cardiovascular event (MACE) in patients
pioglitazone 30035 resistance (RR, 0.77; 95% CI, 0.64‐0.93) and diabetes (RR, 0.83; 95% CI, 0.72‐0.97). Treatment with pioglitazone , however, was also associated with increased risk of heart failure (RR, 1.32; 95% CI, 1.14‐1.54).64
pioglitazone 35741 achieved with DPP4i therapy, can also contribute to prevention of CIMT progression.83The effect of pioglitazone on atherosclerosis is more readily apparent. Two studies have demonstrated the beneficial impact of
pioglitazone 35854 on atherosclerosis is more readily apparent. Two studies have demonstrated the beneficial impact of pioglitazone on the attenuation of atherosclerosis progression in T2DM patients, as measured by carotid intima/medial
pioglitazone 36190 that included 462 patients with T2DM.85 This study demonstrated that CIMT progression was lower in the pioglitazone group compared to the glimepiride group (0.002 mm vs 0.026 mm, respectively; P = .008).85 The
pioglitazone 36450 to look at atherosclerotic progression in 543 T2DM patients with coronary artery disease.86 In the pioglitazone ‐treated group, plaque volume significantly decreased by 0.16%, whereas, in patients receiving glimepiride,
pioglitazone 36728 increments in serum triglyceride level are an independent risk factor for T2DM.87 In the PERISCOPE trial, pioglitazone significantly increased high‐density lipoprotein (HDL) cholesterol levels and lowered triglycerides.
pioglitazone 36924 lowered triglycerides. Interestingly, a study by Nicholls et al. showed that the favourable effects of pioglitazone on the triglyceride/HDL‐C ratio correlated with delayed atheroma progression in diabetic patients.88In
pioglitazone 37105 progression in diabetic patients.88In conclusion, several independent mechanisms may be activated by pioglitazone and DPP4i to support a complementary mechanism of action with the combination of the 2 medications in
pioglitazone 37311 medications in reducing the progression of atherosclerosis. There is evidence of such an effect as far as pioglitazone is concerned, whilst safety has been shown for DPP4i. Therefore, in light of the need for early intervention
pioglitazone 37656 rational, also with regard to CV protection. Nonetheless, because of the increased risk of HF with pioglitazone , and the concerns raised after the completion of the CV outcome trials with at least 2 out of the 4
pioglitazone 38163 caused by concomitant insulin‐delivery background therapy. In trials assessing the effect of DPP4i and pioglitazone , no significant increase in the rate of hypoglycaemia has been reported. Therefore, to the extent that
pioglitazone 38828 pancreatic neoplasia with the use of DPP4i.92 The initial concern about bladder cancer with use of pioglitazone has also been dismissed, in light of the results of a prospective study, mandated by the FDA,93 and
pioglitazone 39690 sulfonylurea‐treated patients.95 Nevertheless, careful assessment is required if a DPP4i combination with pioglitazone is considered, because of the common fluid retention associated with TZDs. In the PROactive trial, HF
pioglitazone 39869 with TZDs. In the PROactive trial, HF leading to hospital admission was more common in patients using pioglitazone compared with placebo (5.7% vs 4.1%). However, the HF‐related mortality rate was lower with pioglitazone
pioglitazone 39976 pioglitazone compared with placebo (5.7% vs 4.1%). However, the HF‐related mortality rate was lower with pioglitazone (26.8% vs 34.3%).10 It is worth considering that these studies have included patients with longstanding
pioglitazone 40504 a recent small clinical study using sophisticated measurement of heart function has suggested that pioglitazone can improve myocardial insulin sensitivity, LV diastolic function and systolic function in T2D.96 Improved
pioglitazone 41053 stores.97 DPP4i are usually neutral with respect to body weight and, when used in combination with pioglitazone , have resulted in either no change as compared to placebo98 or slightly more weight gain compared with
pioglitazone 41169 have resulted in either no change as compared to placebo98 or slightly more weight gain compared with pioglitazone monotherapy.99 Therefore, combination therapy with pioglitazone and DPP4i can be expected to result
pioglitazone 41233 slightly more weight gain compared with pioglitazone monotherapy.99 Therefore, combination therapy with pioglitazone and DPP4i can be expected to result in a mild, if any, increase in body weight in excess of the gain
pioglitazone 41357 can be expected to result in a mild, if any, increase in body weight in excess of the gain caused by pioglitazone itself.Bone fractures are another potential side effect of pioglitazone treatment. These are mainly
pioglitazone 41429 excess of the gain caused by pioglitazone itself.Bone fractures are another potential side effect of pioglitazone treatment. These are mainly low energy fractures (ie, associated with a fall) of distal long bones of
pioglitazone 41782 reported with the use of DPP4i; thus, no additional risk is expected when used in combination with pioglitazone . Actually, preclinical studies have suggested a protective effect of DPP4i on bone metabolism in animals
pioglitazone 41913 preclinical studies have suggested a protective effect of DPP4i on bone metabolism in animals treated with pioglitazone . The administration of vildagliptin to T2DM diabetic rats restored bone mass density, trabecular bone
pioglitazone 42094 bone mass density, trabecular bone volume and trabecular bone thickness, all parameters decreased by pioglitazone .101 Also, the risk of fracture can be mitigated by fall prevention and by screening and treatment of
pioglitazone 42398 treatment, this could outweigh the risk of fractures.Most of the side effects associated with the use of pioglitazone , including the risk of bone fractures, appear to be dose dependent. Therefore, use of low doses of pioglitazone
pioglitazone 42510 pioglitazone, including the risk of bone fractures, appear to be dose dependent. Therefore, use of low doses of pioglitazone in combination with DPP4i may further reduce the risk of these side effects. In this regard, the effect
pioglitazone 42630 combination with DPP4i may further reduce the risk of these side effects. In this regard, the effect of pioglitazone 7.5 mg/day as an add‐on therapy in T2DM patients was compared to the 15 and 30 mg doses,102 and
pioglitazone 42848 showed that a significant increase in body weight and body fat was achieved with the 2 higher doses of pioglitazone , but not with the lowest dose. Moreover, a significant reduction in triglyceride and an increase in
pioglitazone 43040 triglyceride and an increase in HDL cholesterol levels occurred in all 3 groups.In summary, the combination of pioglitazone and DPP4i, as far as we can determine from the available data, is unlikely to exacerbate any of the
pioglitazone 43190 from the available data, is unlikely to exacerbate any of the known side effects mainly related to pioglitazone . Actually, the concomitant use of DPP4i may attenuate some of these effects, particularly if a lower
pioglitazone 43312 Actually, the concomitant use of DPP4i may attenuate some of these effects, particularly if a lower dose of pioglitazone is used.CONCLUSIONS6In recent years, more emphasis has been placed on earlier use of combination therapies
pioglitazone 44402 (Figure 1), the pre‐specified secondary endpoint and subsequent post‐hoc analyses support a role for pioglitazone in reducing CV risk. The main secondary endpoint (ie, cardiovascular death, non‐fatal MI and stroke)
pioglitazone 44949 and with a prior stroke.11 In addition, a newly published secondary analysis from IRIS reported that pioglitazone reduced the risk of acute coronary syndrome (HR, 0.71; 95% Cl, 0.54‐0.94; P = .02).105 Moreover,
pioglitazone 45412 component of the primary endpoint. It is of interest to note that all show less patient events with pioglitazone treatment, with the exception of leg revascularization. Adapted from 10Figure 2Secondary analysis from
pioglitazone 45640 trial finding important and significant reductions in acute coronary syndrome (ACS) patients receiving pioglitazone . The reduction in ACS, ST‐Elevation Myocardial Infarction (STEMI) and risk of larger myocardial infarctions
pioglitazone 48409 agents may also have potential in preserving beta‐cell function, making a rational combination with pioglitazone while potentially attenuating some of the side effects of the latter, particularly if lower doses of
pioglitazone 48523 while potentially attenuating some of the side effects of the latter, particularly if lower doses of pioglitazone are used.In summary, the rationale for combining DPP4i and pioglitazone, particularly in the early stage
pioglitazone 48595 particularly if lower doses of pioglitazone are used.In summary, the rationale for combining DPP4i and pioglitazone , particularly in the early stage of T2DM, is sound with respect to the pathophysiologic background of
pioglitazone 49010 may also facilitate early introduction of this combination. Moreover, the combination of DPP4i and pioglitazone provides a useful example of what the diabetologist must do in the future, that is, carefully weigh
rosiglitazone 9467 (PPAR‐γ) mRNA and impaired glucose‐induced insulin secretion, a phenomenon practically reversed by rosiglitazone .23 As discussed below, glitazones exert quite a durable effect, with more patients sustaining good glycaemic
rosiglitazone 9647 with more patients sustaining good glycaemic control over time. In the ADOPT trial, the durability of rosiglitazone was associated not only with a significant improvement in insulin sensitivity, but also with a slower
rosiglitazone 15332 lipolysis; and (5) reducing gluconeogenesis.ACHIEVING LONG‐LASTING GLYCAEMIC CONTROL3The effect of rosiglitazone , metformin and glibenclamide as initial treatment was evaluated in 4360 T2DM patients in the ADOPT trial.38
rosiglitazone 15544 trial.38 After 5 years of treatment the cumulative incidence of monotherapy failure was 15% with rosiglitazone , 21% with metformin and 34% with glyburide. The sustained efficacy of glitazones has been confirmed
sitagliptin 16857 to 104 weeks% HypoglycaemiaPrimary endpoint outcomeSeck et al. 201042SitagliptinGlipizide504 PP ( sitagliptin , n = 248; glipizide, n = 256)7.3 (56) both groups−0.54 sitagliptin and −0.51 glipizide5%
sitagliptin 16934 201042SitagliptinGlipizide504 PP (sitagliptin, n = 248; glipizide, n = 256)7.3 (56) both groups−0.54 sitagliptin and −0.51 glipizide5% sitagliptin vs 34% glipizideNon‐inferiorMatthews et al. 201043VildagliptinGlimepiride3118
sitagliptin 16970 n = 248; glipizide, n = 256)7.3 (56) both groups−0.54 sitagliptin and −0.51 glipizide5% sitagliptin vs 34% glipizideNon‐inferiorMatthews et al. 201043VildagliptinGlimepiride3118 randomized (vildagliptin,
sitagliptin 18784 54‐week randomized, controlled extension trial, mean HbA1c reduction was −2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg vs −1.9% with pioglitazone monotherapy, and the mean reduction in
sitagliptin 35315 anti‐atherogenic effects of DPP4 inhibitors. Attenuation of CIMT progression has been observed with sitagliptin as an add‐on to insulin treatment in T2DM patients free of apparent cardiovascular disease,81 as well
Select Disease Character Offset Disease Term Instance
obesity 3419 disease.2T2DM, although heralded by hyperglycaemia, is commonly associated with factors (eg, central obesity , dyslipidaemia, hypertension and inflammation, among others) that increase the risk of cardiovascular
obesity 11749 skeletal muscle, adipose tissue and liver). Impaired insulin action can be exacerbated by concomitant obesity , as the result of the excess of circulating free fatty acids (FFA), adipose‐tissue mediated inflammatory
osteoporosis 42208 pioglitazone.101 Also, the risk of fracture can be mitigated by fall prevention and by screening and treatment of osteoporosis . Moreover, if CV risk were to be favourably affected by the combination treatment, this could outweigh

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