Novel combination treatment of type 2 diabetes
`DPP-4 inhibition + metformin
`
`R E V I E W
`
`Bo Ahrén
`Department of Clinical Sciences,
`Division of Medicine, Lund University,
`Lund, Sweden
`
`Correspondence: Bo Ahrén
`Department of Clinical Sciences, Division
`of Medicine, Lund University, B11 BMC,
`SE-221 84 LUND, Sweden
`Tel +46462220758
`Email bo.ahren@med.lu.se
`
`Abstract: Inhibition of dipeptidyl peptidase-4 (DPP-4) as a novel therapy for type 2 diabetes
`is based on prevention of the inactivation process of bioactive peptides, the most important in
`the context of treatment of diabetes of which is glucagon-like peptide-1 (GLP-1). Most clinical
`experience with DPP-4 inhibition is based on vildagliptin (GalvusR, Novartis) and sitagliptin
`(JanuviaR, Merck). These compounds improve glycemic control both in monotherapy and in
`combination with other oral hyperglycemic agents. Both have also been shown to effi ciently
`improve glycemic control when added to ongoing metformin therapy in patients with inadequate
`glycemic control. Under that condition, they reduce HbA1c levels by 0.65%–1.1% (baseline
`HbA1c 7.2–8.7%) in studies up to 52 weeks of duration in combination versus continuous therapy
`with metformin alone. Sitagliptin has also been examined in initial combination therapy with
`metformin have; HbA1c was reduced by this combination by 2.1% (baseline HbA1c 8.8%) after
`24 weeks of treatment. Both fasting and prandial glucose are reduced by DPP-4 inhibition in
`combination with metformin in association with improvement of insulin secretion and insulin
`resistance and increase in concentrations of active GLP-1. The combination of DPP-4 inhibi-
`tion and metformin has been shown to be highly tolerable with very low risk of hypoglycemia.
`Hence, DPP-4 inhibition in combination with metformin is an effi cient, safe and tolerable
`combination therapy for type 2 diabetes.
`Keywords: DPP-4 inhibition, sitagliptin, vildagliptin, metformin, type 2 diabetes
`
`Introduction
`It is known that both the level and the duration of hyperglycemia in type 2 diabetes are
`closely related to the risk of developing diabetic complications (Stratton et al 2000).
`Therefore, achieving glycemic control is a prerequisite for prevention of cardiovascular
`and microvascular complications in type 2 diabetes. Lifestyle interventions, including
`dietary adjustments and increased physical activity, are cornerstones of the therapy. For
`most patients, however, pharmacological intervention is required and present guide-
`lines suggest metformin to be a fi rst line treatment (Inzucchi 2000; Nathan et al 2006).
`Metformin is an inexpensive compound with documented glucose-lowering effect in
`both obese and non-obese subjects with type 2 diabetes (Inzucchi 2002; Hundal and
`Inzucchi 2003; Setter et al 2003; Consoli et al 2004; Donnelly et al 2006). Metformin
`reduces glycemic levels primarily by inhibiting hepatic glucose output (Bailey and
`Turner 1996; Leverve et al 2003; Stumvoll et al 1995). Metformin has also been shown
`to improve insu lin sensitivity in liver and muscle (Ginnarelli et al 2003). Additional
`suggested mechanistic effects of metformin are inhibition of glucose absorption in the
`gut (Ikeda et al 2000) and increase in plasma levels of GLP-1 (Mannucci et al 2001).
`As has been reviewed (Bailey and Turner 1996), metformin reduces HbA1c levels in
`the range of 1%–1.5%, depending on the baseline HbA1c levels and the compound is
`well tolerated, although gastrointestinal adverse events are quite common during the
`initiation of the therapy. Hypoglycemia is rarely seen during metformin therapy, and the
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`Ahrén
`
`potential fatal adverse event of lactic acidosis is uncommon;
`nevertheless cautious should always be exercised when treat-
`ing subjects with renal insuffi ciency with metformin.
`
`Add-on treatment to metformin
`often required
`In spite of the benefi cial effects of metformin in improving
`glycemic control, very often, however, metformin alone
`is insuffi cient for achievement of good metabolic control.
`Often, also, glycemic control deteriorates in metformin-
`treated patients. This necessitates combination therapy by
`adding a secondary compound to metformin. Most often,
`sulphonylureas are added (Inzucchi 2002; Nathan et al
`2006). The rationale for this combination is that sulphonyl-
`ureas stimulate insulin secretion, which is a complimentary
`mechanism to the improvement in insulin sensitivity by
`metformin. Other combinations with metformin include
`thiazolidinediones and insulin (Hundal and Inzucchi 2003;
`Setter et al 2003; Charbonnel et al 2005; Derosa et al 2006;
`Umpierrez et al 2006). However, the combinations with sul-
`phonylureas and thiazolidinediones have faced problems, in
`that sulphonylureas increase the risk of hypoglycemia (Del
`Prato and Pulizzi 2006; Green and Feinglos 2007) and thia-
`zolidinediones result in weight gain and potential problems of
`cardiovascular adverse events and increase in the risk of bone
`fractures in women (Kahn et al 2006; Levetran 2007; Nissen
`and Wolski 2007). Also the novel GLP-1 based therapy has
`been found to be successful in combination with metformin.
`This applies both to the strategy of activating the GLP-1
`receptors by exenatide (DeFronzo et al 2005) or liraglutide
`(Feinglos et al 2005), and by the strategy of preventing the
`inactivation of endogenous GLP-1 by inhibiting dipeptidyl
`peptidase-4 (DPP-4) (Ahrén et al 2004; Charbonnel et al
`2006; Bosi et al 2007; Brazg et al 2007; Goldstein et al
`2007). This review summarizes the experience of combining
`metformin and a DPP-4 inhibitor in the treatment.
`
`GLP-1 as a target for treatment
`of type 2 diabetes
`The rationale for the development of DPP-4 inhibition
`in the treatment of type 2 diabetes relies on augmentation
`of the incretin effect (Holst and Deacon 1998). The incre-
`tin effect is the exaggerated insulin secretion that follows
`oral glucose administration when compared to intravenous
`glucose administration and it is attributed to gut hormones
`augmenting glucose-stimulated insulin secretion (Drucker
`and Nauck 2006). The two most important incretin hormones
`are glucose-dependent insulinotropic polypeptide (GIP) and
`
`glucagon-like peptide-1 (GLP-1) (Drucker and Nauck 2006).
`GLP-1 is produced in L-cells, which are located mainly in
`the distal portion of the ileum. GLP-1 is released during
`meal ingestion and stimulates insulin secretion in a glucose-
`dependent manner (Drucker and Nauck 2006). GLP-1 also
`inhibits glucagon secretion (Dunning et al 2005), delays
`gastric emptying (Nauck et al 1997) and induces satiety
`(Gutzwiller et al 1999). In addition, animal studies have
`presented evidence that GLP-1 increases beta cell mass by
`stimulating proliferation and inhibiting apoptosis (Perfetti
`and Hui 2004), although it should be emphasized that such
`an effect has not been demonstrated in humans. Because all
`these effects would be important in the treatment of type
`2 diabetes, GLP-1 has been developed as a novel therapy
`(Ahrén and Schmitz 2004). The development of GLP-1 as a
`therapy has, however, been complicated by its rapid inacti-
`vation, which is due to removal of the N-terminal dipeptide
`end through DPP-4, which inactivates GLP-1 (Mentlein
`1999). To overcome this, two strategies have been used.
`One strategy is the development of GLP-1 receptor agonists
`(GLP-1 mimetics such as exenatide and liraglutide), which
`are resistant to DPP-4 (Ahrén and Schmitz 2004). The other
`strategy is the development of inhibitors of DPP-4, which
`prevent the inactivation of GLP-1 and thereby enhance and
`prolong the action of the endogenous incretin hormone
`(Ahrén and Schmitz 2004; Mari et al 2005; Ahrén 2007a,
`2007b). DPP-4 inhibition also prevents the inactivation of the
`other incretin hormone, GIP, and therefore the concentrations
`of the active form also of this hormone are increased dur-
`ing DPP-4 inhibition (Mari et al 2005). However, since the
`action of GIP to stimulate insulin secretion is almost entirely
`lost in type 2 diabetes (Vilsbøll et al 2002), this raise of GIP
`concentrations is of less importance.
`
`DPP-4 inhibition as a target
`for treatment of type 2 diabetes
`The rational of DPP-4 inhibition for the treatment of type
`2 diabetes was outlined already in 1998 (Holst and Deacon
`1998). The fi rst proof-of-concept study of DPP-4 inhibition
`showed improved meta bolic control with reduced fasting and
`prandial glucose levels and reduction of HbA1c after 4 weeks
`of treatment of the DPP-4 inhibitor, NVP-DPP728 (Ahrén
`et al 2002). Improved glycemic control by DPP-4 inhibition
`has been confi rmed in many studies with other compounds
`and today several DPP-4 inhibitors are in the progress of
`development (Ahrén 2007a, 2007b). Most experience exists
`for vil dagliptin (LAF237, GalvusR, Novartis) and sitagliptin
`(MK-0431, JanuviaR, Merck), which are orally active
`
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`compounds, which effi ciently inhibit DPP-4 activity (Ahrén
`2006; Kim et al 2005). Both compounds inhibit plasma
`DPP-4 activity for more than 16 hours after a single admin-
`istration and are therefore both possible to administer once
`daily. Furthermore, they have both been shown to improve
`glycemic control when used in monotherapy as well as in
`combination therapy with metformin and thiazodilidinedione
`(Ahrén 2006; Deacon 2007; Gallwitz 2007). Sitagliptin has
`been approved for treatment of type 2 diabetes in the US and
`in Europe in combination with metformin and vildagliptin has
`been approved for treatment of type 2 diabetes in Europe. Of
`particular importance is that DPP-4 inhibitors are safe and
`tolerable and that this in combination with their effi ciency
`allow them to be used in early stages of the disease. One
`such early indication would be to use DPP-4 inhibitors in
`combination with metformin.
`
`Rationale for combining metformin
`with DPP-4 inhibition
`Type 2 diabetes develops when insulin secretion is insuf-
`fi ciently raised to match insulin resistance (Kahn 2001;
`DeFronzo 2004). In addition, glucagon levels are inap-
`propriately elevated, which enhances hepatic glucose
`output and increases fasting glucose (Dunning et al 2005).
`Therefore, diabetes is a disease with at least three main
`defects, which need to be corrected: impaired insulin secre-
`tion, insulin resistance and hypersecretion of glucagon. The
`rationale for combining metformin with DPP-4 inhibitors is
`the complimentary mechanism of action of the two strate-
`gies. Thus, metformin acts primarily by reducing hepatic
`glucose output and improving insulin sensitivity in liver
`and muscle (Stumvoll et al 1995; Bailey and Turner 1996;
`Hundal and Inzucchi 2003; Leverve et al 2003; Setter 2003)
`whereas DPP-4 inhibitors act by increasing GLP-1 levels
`and thereby stimulating insulin secretion and inhibiting
`glucagon secretion (Ahrén 2007a; Ahrén 2007b). The two
`strategies therefore have the potential to improve different
`mechanisms, which are defective in type 2 diabetes and
`therefore an additive or synergistic action when used in
`combination is anticipated. In addition, metformin has been
`shown to increase GLP-1 levels (Mannucci et al 2001), which
`would be a potential for an additional synergistic ac tion with
`DPP-4 inhibitors. The mechanism underlying the increase in
`GLP-1 levels by metformin remains to be fi nally established;
`it has been suggested to be caused by inhibition of DPP-4
`(Lindsay et al 2005; Mannucci et al 2001), although there are
`also fi ndings that metformin does not affect DPP-4 activity
`(Hinke et al 2002). Instead, more recent fi ndings suggest
`
`DPP-4 inhibition plus metformin in the treatment of type 2 diabetes
`
`that metformin stimulates the secretion of GLP-1 from the
`gut (Migoya et al 2007). Hence, from a mechanistic point
`of view, there is a clear rationale for combining metformin
`with DPP-4 inhibitors. Another important information is that
`the pharmacokinetics of metformin and a DPP-4 inhibitor do
`not change by combining the two, as shown for sitagliptin,
`which further indicates the feasibility of the combination
`(Herman et al 2006).
`
`Vildagliptin and sitagliptin
`as monotherapy
`Both vildagliptin and sitagliptin reduce fasting and prandial
`glucose as well as HbA1c when used in monotherapy for the
`treatment of type 2 diabetes; HbA1c has been shown to be
`reduced by these compounds by 0.65%–1.1% after study
`periods of 3–12 months from baseline levels of 7.2%–8.7%
`(Ahrén et al 2004b; Ristic et al 2005; Aschner et al 2006;
`Pratley et al 2006; Raz et al 2006; Rosenstock et al 2007;
`Schweizer et al 2007; Scott et al 2007). Furthermore, these
`studies have shown that both vildagliptin and sitagliptin are
`safe and tolerable with incidences of adverse events not dif-
`ferent from what is seen after placebo treatment and that there
`is a very low rate of hypoglycemia during the treatment with
`the DPP-4 inhibitors. Recent reviews have summarized these
`monotherapy studies in more detail (Ahrén 2007a, 2007b).
`
`DPP-4 inhibition as add-on therapy
`to metformin
`Several studies have reported the experience of treatment with
`a DPP-4 inhibitor in combina tion with metformin. The fi rst
`combination study was a 52 week trial, in which vildagliptin
`at 50 mg daily or placebo was added to ongoing treatment with
`metformin (1.5–3 g daily) in patients with a mean baseline
`HbA1c of 7.8% (Ahrén et al 2004a). The patients had a mean
`diabetes duration of 5.5 years and they had been on metformin
`treatment for 29 months as a mean. The results are illustrated
`in Figure 1 and show that following the ini tial 12 week
`study period, HbA1c was reduced by 0.7% by vildagliptin in
`combination with metformin compared to metformin alone.
`After the fi rst 12 weeks of study, patients were followed
`for another 40 weeks. During this period, HbA1c increased
`by 0.066%/month in patients given metformin alone versus
`only by 0.013%/month after vildagliptin plus metformin.
`The between-group difference in change of HbA1c after 52
`week of treatment was 1.1%, showing a clinically important
`improvement of the glycemic control by adding vildagliptin
`to metformin. Furthermore, fasting glucose was also reduced
`by vildagliptin in combination with metformin compared to
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`Figure 1 Time course of HbA1c in a 12 week core study and a 40 week extension study when vildagliptin (LAF; 50 mg once daily) was given as add-on to metformin (MET).
`PBO = placebo. Reproduced from Ahrén et al 2004a after permission from the American Diabetes Association.
`
`metformin alone. Thus, from a mean baseline fasting glucose
`of 9.8 mmol/l across all patients, the between-group difference
`in fasting glucose after 52 weeks of treatment was 1.1 mmol/l.
`The study therefore suggests that addition of vildagliptin to
`metformin prevents the deterioration of glycemic control seen
`in these patients when given metformin alone. The study also
`shows that the combination of vildagliptin and metformin is
`safe and highly tolerable with an overall incidence of any
`adverse event being similar in the two groups.
`A second study in 416 patients added vildagliptin at 50
`mg once or twice daily to on-going treatment with metformin
`for a study period of 24 weeks (Bosi et al 2007). The patients
`in this study had a mean diabetes duration of 6 years and
`had been treated with met formin for a mean of 16 months,
`their mean daily metformin dose was 2.1 g (inclusion criteria
`⬎1.5 g daily). They had a mean baseline HbA1c was 8.4%.
`Figure 2 shows the HbA1c levels in this study. It is seen that
`HbA1c was reduced by 0.5% in patients given vildagliptin at
`50 mg daily and 0.9% in patients given vildagliptin at 100 mg
`daily, both in combination with metformin, versus an increase
`by 0.2% in patients given placebo with on-going metformin.
`The placebo-adjusted mean reduction in HbA1c was therefore
`0.7% by vildagliptin at 50 mg and 1.1% by vildagliptin at
`100 mg daily. The data were also analysed with respect to
`how many patients who experienced improved glycemic con-
`trol or had a deterioration of glycemic control. The analysis
`revealed that in the group given metformin alone, 35% of
`patients had a deterioration of glycemic control and 31%
`
`had no meaningful change in glycemic control. In contrast,
`of the patients given vildagliptin at 50 mg in combination
`with metformin, 38% showed a meaningful improve ment
`in glycemic control and 29% had a marked improvement in
`glycemic control (defi ned as reduction in HbA1c by more than
`1%). Also fasting plasma glucose was reduced by vildagliptin
`in combination with metformin. Baseline fasting glucose was
`9.7 mmol/l across all groups. In the group given metformin
`alone, fasting glucose increased by 0.7 mmol/l and the pla-
`cebo-adjusted reduction in fasting glucose was 0.8 mmol/l
`in subjects given vildagliptin at 50 mg daily and 1.7 mmol/l
`in subjects given vildagliptin at 100 mg in combina tion with
`metformin. Except for fasting triglycerides, lipid values were
`not signifi cantly altered in any of the groups. However, fast-
`ing triglycerides increased from a mean value of 2.3 mmol/l
`by 19% in subjects given metformin alone but only by 1%
`in subjects given vildagliptin at 50 mg in combination with
` metformin and by 5% in the group given vildagliptin at
`100 mg in combination with metformin. Mean body weight
`was 94 kg as a mean across all study groups and did not change
` signifi cantly in the subjects given vildagliptin at either 50 or
`100 mg daily in combination with metformin, whereas body
`weight was reduced by 1.0 kg in subjects given metformin
`alone. Finally, total number of adverse events was not signifi -
`cantly different between the groups; the only difference was
`a reduction in gastrointestinal ad verse events in the subjects
`given vildagliptin at 50 mg in combination with metformin
`(9.6%) versus in those given metformin alone (18.2%). In
`
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`DPP-4 inhibition plus metformin in the treatment of type 2 diabetes
`
`Figure 2 Time course of mean HbA1c levels during 24 week treatment with vildagliptin at 50 mg daily (∆) or 100 mg daily ((cid:83)) or placebo ((cid:129)) in patients with type 2 diabe-
`tes continuing stable metformin treatment (ⱖ1.5 g daily). Reproduced from Bosi et al 2007 after permission from the American Diabetes Association.
`
`conclusion, this large study showed that vildagliptin is well
`tolerated when given as add-on to metformin for a study
`period of 24 weeks and that vildagliptin shows a clinically
`meaningful improvement in glycemic control as verifi ed by
`dose-related reductions in HbA1c and fasting glucose.
`The fi rst study on the effect of sitagliptin as add-on
`therapy to patients with inadequate glycaemic control on
`metformin monotherapy was a four week study in 28 patients
`(Brazg et al 2007). The patients had a mean duration of dia-
`betes of 6.6 years, the mean baseline HbA1c was 7.7% and
`the mean fasting plasma glucose was 8.4 mmol/l. The study
`showed that fasting glucose was reduced by 1.3 mmo/l by
`sitagliptin in combination with metformin versus only by
`0.4 mmol/l by metformin alone. The study also included a
`24 hr measurement of glucose after the four week treatment
` period, and this showed a reduction of glucose by approxi-
`mately 1–1.5 mmol/l throughout the entire 24 h period. Both
`fasting and prandial glycemia were reduced by this degree.
`Furthermore, the number of adverse events was not different
`when sitagliptin was given in combination with metformin
`versus when metformin was given alone. Hence, this short-
`term study verifi ed the effi cient improvement in glycemic
`control by the addition of DPP-4 inhibition to on-going
`metformin therapy in asso ciation with safety and tolerability
`of the combination therapy.
`In a long-term study on the effect of sitagliptin as add-on to
`metformin in subjects with inadequate glycemic control, sita-
`gliptin (100 mg once daily) was added to metformin (⬎1.5 g
`daily) for 24 weeks (Charbonnel et al 2006). The study
`
`comprised a total of 701 patients who had a mean diabetes
`duration of 6.2 years, a mean baseline HbA1c of 8.0% and
`a mean baseline fasting glucose of 9.5 mmol/l. Figure 3
`shows the HbA1c in this study. It is seen that addition of
`sitagliptin signifi cantly reduced the HbA1c levels after the
`24 week treatment period. The placebo-subtracted reduction
`in HbA1c by sitagliptin was 0.65%. A total of 47% of the
`patients treated with sitagliptin in combination with metfor-
`min reached the target of ⬍7% in HbA1c while the target
`was reached by only 18% of the subjects given metformin
`alone. Also fasting glucose was reduced by sitagliptin in
`combination with metformin versus metformin alone; the
`placebo-subtracted reduction by sitagliptin was 1.4 mmol/l.
`The study also showed that sitagliptin in combination with
`metformin slightly, although signifi cantly, reduced total
`cholesterol and triglycerides, whereas HDL-cholesterol
`was slightly increased. Body weight was slightly reduced
`in both groups, with no difference between the groups, and,
`similarly, the degree of adverse events did not differ between
`the groups. Hence, this 24 week trial in a large number of
`patients showed that sitagliptin when added to on-going
`therapy with metformin effi ciently reduces HbA1c and fasting
`glucose in combination of being a safe and highly tolerable
`combination therapy. Following the end of the 24 week
`trial, patients who did not receive glycemic rescue medica-
`tion continued to an extension study. During this exten sion,
`387 patients continued with the combination of sitagliptin
`with metformin throughout a 54 week study period. It was
`found that the mean HbA1c remained stable at 7.1% during
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`Ahrén
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`Figure 3 Time course of mean HbA1c levels during 24 week treatment with sitagliptin (100 mg once daily; (cid:32)) or placebo ((cid:123)) in patients with type 2 diabetes with on-going
`treatment with metformin (ⱖ1.5 g daily). Reproduced from Charbonnel et al 2006 after permission from the American Diabetes Association.
`
`this entire period and, furthermore, the combination was
`well tolerated during the period (Karasik et al 2007). Hence,
`combination of sitagliptin and metformin produced a durable
`reduction in HbA1c.
`Another study with sitagliptin the addition of the
`compound (100 mg once daily) with that of glipizide (dose-
`titration to a maximal doe of 20 mg daily) to the on-going
`treatment with metformin (⬎1.5 g daily) in a 52 week study
`comprising a total of 1,172 patients (Nauck et al 2007). The
`mean baseline HbA1c levels was 7.5% and this was reduced
`by 0.67% both by sitagliptin and by glipizide. The occurrence
`of hypoglycemia was higher in the group given glipizide
`(32% of patients exhibited one episode of hypoglycemia)
`than in the group receiving sitagliptin (5%). Furthermore,
`the mean body weight in creased by 1.1 kg in the group given
`glimepiride versus a reduction by 1.5 kg in the group given
`sitagliptin. Hence, also this study showed a good improve-
`ment in glycemic control by the combina tion of a DPP-4
`inhibitor with metformin.
`Recently, it was also reported that the DPP-4 inhibitor,
`saxagliptin (Bristol-Myers-Squibb), improved glycemic
`control when added to metformin (DeFronzo et al 2007).
`The study comprised a total of 743 patients with a mean
`HbA1c of 8.0% and a mean fast ing glucose of 9.8 mmol/l
`when treated with metformin alone. Saxagliptin was added
`at 2.5, 5 or 10 mg daily and the study also included a placebo
`arm; all patients continued with metformin. It was found
`that after 24 weeks of treatment, saxagliptin had reduced
`HbA1c by 0.7 or 0.8% when adjusted for placebo in the
`three arms. Fasting glucose was reduced by 0.9–1.1 mmol/l.
`
`As for the other DPP-4 inhibitors, also saxagliptin was
`safe and tolerable and body weight neutral when added to
`metformin.
`The studies thus presented sofar with DPP-4 inhibitors
`as add-on therapy to metformin show clinically important
`improvement in glycemic control. Mean HbA1c levels are
`reduced by approximately 0.65%–1% from a baseline of
`7.8%–8.4%. Furthermore, the combination is tolerable and
`safe with similar adverse events profi le as placebo-treated
`patients given metformin alone.
`
`DPP-4 inhibition and metformin
`as initial combination therapy
`During recent years there has been a discussion of introducing
`initial combination therapy when pharmacological treatment
`is required for type 2 diabetes, in order to reach therapeu tic
`goal at an earlier stage and to avoid or delay subsequent
`changes in therapy for the maintenance of therapeutic goal.
`One study has examined the possibility of combining DPP-4
`inhibition with metformin as initial combination (Goldstein
`et al 2007). The study was a 24-week randomized trial com-
`prising 1,092 patients with type 2 diabetes having a mean
`baseline HbA1c value of 8.7% and a mean baseline fasting
`glucose of 11 mmol/l. The pa tients were assigned to one of
`six treatment arms with sitagliptin 50 mg + metformin
`500 mg twice daily, sitagliptin 50 mg + metformin 1000 mg
`twice daily, metformin alone at 500 or 1000 twice daily,
`sitagliptin alone at 100 mg once daily or placebo. The results
`showed that in all treatment groups, except the placebo group,
`
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`a signifi cant reduction in HbA1c after the 24 week trial period
`occurred. The placebo-controlled reduc tion of HbA1c was in
`the range of 0.8%–2.1% in the different groups (Figure 4),
`and when compar ing monother apy versus the initial combina-
`tion therapy, it was found that combina tion ther apy produced
`additive effects of improved glycemic control. Hence, the
`larg est reduction in HbA1c (2.1%) was seen in the group
`given sitagliptin 50 mg + met formin 1000 mg twice daily.
`Similarly, fasting glucose was additively reduced by the
`combi nation therapy, and the placebo-adjusted reduction in
`fasting glucose in the group given sitagliptin 50 mg + met-
`formin 1000 mg twice daily was 3.8 mmol/l. The percent age
`of subjects in each group who reached the treatment target
`of HbA1c ⬍7.0% was 66% in the group given sitagliptin
`
`DPP-4 inhibition plus metformin in the treatment of type 2 diabetes
`
`50 mg + metformin 1000 mg twice daily versus only 38% in
`the group given metformin at 1000 mg twice daily alone or
`20% in the group given sitagliptin at 100 mg daily alone and
`only 9% in the placebo group. Hence, the initial combi nation
`of sitagliptin and metformin effi ciently improved glycemic
`control over a 24 week study pe riod. The number of adverse
`events was low and the incidences of gastrointesti nal ad verse
`events were similar when sitagliptin was added to metfor-
`min as when metformin was given alone. Furthermore, the
`incidence of hypoglycemia was low (0.5%–2.2% in the dif-
`ferent actively treated groups) and not signifi cantly different
`from the placebo group (0.6%). Finally, in regard to body
`weight, there was a signifi cant reduction in body weight
`after 24 weeks of treatment in all actively treated groups
`
`Figure 4 Changes in HbA1c, fasting and 2 h prandial glucose and insulin secretion (as determined by 2 hr AUCinsulin divided by AUCglucose after a meal tolerance test) after
`24 weeks treatment of sitagliptin and/or metformin, as indicated in bottom. Results reported are adjusted for changes after treatment with placebo. Fig. is drawn after results
`reported in Goldstein et al 2007.
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`Ahrén
`
`(0.6–1.3 kg) except in the group given sitagliptin alone as
`monotherapy.
`
`Mechanisms of improved
`antidiabetic action by combining
`DPP-4 inhibitors with metformin
`DPP-4 inhibitors have been shown to increase GLP-1 levels
`both under fasting conditions and following meal ingestion
`(Ahrén et al 2004b; Mari et al 2005). Furthermore, DPP-4
`inhibition improves islet func tion by stimulating insulin
`secretion, by improving the glu cose sensitivity of the beta
`cells, and by inhibiting glucagon secretion from the alpha
`cells (Balas et al 2007; Dunning et al 2005). This reduces
`both fasting and prandial glucose which reduces HbA1c
`levels. In contrast to GLP-1, DPP-4 inhibi tion does not
`seem to inhibit gastric emptying (Vella et al 2007) and it
`does not reduce body weight (Ahrén et al 2004b; Aschner
`et al 2006; Pratley et al 2006; Raz et al 2006; Ristic et al
`2005; Rosenstock et al 2007; Schweizer et al 2007; Scott
`et al 2007). Metformin, on the other hand, reduces hepatic
`glucose production and improves insulin sensitivity in
`muscle and liver cells, which improve overall insulin action
`and reduce mainly fasting glucose (Bailey and Turner
`1996; Consoli et al 2994; Donnelly et al 2006; Hundal and
`Inzucchi 2003; Leverve et al 2003; Stumvoll et al 1995).
`The effi cient improved glycemic control by combing DPP-4
`inhibitors with metformin would rely on the complementary
`mechanism of the two treatments. It has therefore been of
`interest to mechanistically examine the combination of
`DPP-4 inhibition and metformin.
`
`GLP-1 levels
`One study has examined the effect of the combination of sita-
`gliptin and metformin on concentrations of active and inactive
`GLP-1 after meal ingestion following 24 weeks of treatment
`(Migoya et al 2007). It was found that both sitagliptin and
`metformin alone increased the postmeal concentration of
`active GLP-1. Furthermore, when given in combination, the
`increase in active GLP-1 was more than additive, suggesting
`a synergistic action of the two compounds.
`
`Islet effects when DPP-4 inhibition
`is added to metformin
`In the initial study on the add-on of vildagliptin to
`metformin treatment, in which vildagliptin and metformin
`in combina tion was compared with metformin alone for 52
`weeks (Ahrén et al 2004a), a standardized break fast meal
`
`comprising of 465 kcal was served at baseline and after 12,
`24 and 52 weeks of treatment. The study evaluated insulin
`secretion by calculating the suprabasal 30 min area under the
`C-peptide curve divided by the 30 min increase in glucose
`after meal ingestion (Ahrén et al 2005). It was found that
`glucose tolerance was improved by the combination therapy
`versus metformin alone. Thus, the mean between-group
`difference in AUCglu cose was 256 mmol/240 min compared
`to a baseline of 545 mmol/240 min. Further more, insulin
`secretion increased gradually during the fi rst 24 weeks by
`the combina tion therapy and thereafter remained stable
`for the remaining period of the study (Figure 5). This
`shows that the combination of vildagliptin with metformin
`improves beta cell function. The same study also evaluated
`insulin sensitivity after meal inges tion by calculating the
`OGIS index (oral glucose insulin sensitivity index). This
`is a vali dated index which is based on a model of glucose
`clearance in relation to meal-derived insulin data (Mari et al
`2001). It was found that OGIS gradually increased by the
`combination therapy (Figure 5). The combined estimation
`of insulin secretion and insulin sensitivity allowed the
`estimation of the adaptation index (the product of insulin
`secretion and sensitivity); the adaptation index gives a fi gure
`of the ability of the beta-cell to adapt insu lin secretion to
`the ambient insulin sensitivity (Ahrén and Pacini 1997).
`It was found (see also Figure 5) that the adaptation
`index increased by the combination of vildagliptin and
`metformin versus metformin alone. This change in
`adaptation index across the entire study group showed a
`negative correlation with the change in HbA1c (r = −0.39,
`p = 0.004) (see Figure 5). Hence, this analysis of potential
`mechanisms of action underlying the im proved glycemic
`control by the combination of vildagliptin and metformin
`versus metformin alone showed a marked improvement
`in beta cell function and a slight improvement in insulin
`sensitivity which together results in improved beta cell
`adaptation ability to insulin resistance, a measure that
`correlated to the reduction in HbA1c. Furthermore, from
`this study, also baseline and prandial proinsulin levels
`have been carefully analyzed, and the results have shown a
`reduction in proinsulin