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Dipeptydil peptidase-4 inhibitors in type 2 diabetes

Posted in Clinical & Translational, Curation, Diabetes Mellitus, Metabolism, Pharmaceutical Analytics, tagged Dipeptidyl Peptidase-4 inhibitors, meta-analysis, Type 2 diabetes mellitus on November 27, 2015| Leave a Comment »

Dipeptydil peptidase-4 inhibitors in type 2 diabetes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Dipeptydil peptidase-4 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials

M. Monami, I. Iacomelli, N. Marchionni, E. Mannucci

Unit of Geriatric Medicine, Department of Critical Care Medicine, University of Florence and Azienda Ospedaliera Careggi, Florence, Italy
Nutrition, Metabolism & Cardiovascular Diseases (NMCD) May 2010; 20(4):224–235  http://dx.doi.org/10.1016/j.numecd.2009.03.015

Background and Aim

The role of Dipeptidyl Peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information.

Methods and Results

All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with DPP-4 inhibitors, with a duration >12 weeks were meta-analyzed for HbA1c, BMI, hypoglycemia, and other adverse events. A total of 41 RCTs (9 of which are unpublished) was retrieved and included in the analysis. Gliptins determine a significant improvement of HbA1c in comparison with a placebo (−0.7 [−0.8:−0.6]), with a low risk of hypoglycemia. DPP-4 inhibitors show a similar efficacy in monotherapy and in combination with other agents. The risk of cardiovascular events and all-cause death with DPP-4 inhibitors is 0.76 [0.46–1.28] and 0.78 [0.40–1.51], respectively.

Conclusions

DPP-4 inhibitors reduce HbA1c, although to a lesser extent than sulphonylureas, with no weight gain and no hypoglycemic risk; further data are needed to assess their long-term safety.

 

 

Oral Dipeptidyl Peptidase-4 (DPP-4) inhibitors sitagliptin [1] and vildagliptin [2], which increase circulating levels of Glucagon-Like Peptide-1 (GLP-1), have recently been approved for use in type 2 diabetes; other molecules of the same class (such as saxagliptin and alogliptin) are under development.

The role of those new drugs in the treatment of type 2 diabetes is debated. The consensus algorithm of the American Diabetes Association and the European Association for the Study of Diabetes [[3], [4]], in its revised version [4], suggests limiting the use of GLP-1 receptor agonists and DPP-4 inhibitors only in some specific cases, without considering those agents in the mainstream (“Tier 1”) of the algorithm. Conversely, DPP-4 inhibitors are not even included as a second choice, although their use is contemplated in selected patients. The reasons for this exclusion are their perceived limited efficacy on HbA1c in comparison with other agents, their poorly defined safety profile, and their cost [[3], [4]].

Efficacy and safety need to be assessed through a comprehensive review of currently available clinical trials. Some detailed reviews of published studies have been recently published [[1], [2], [5]]; furthermore, some meta-analyses have been performed [[1], [6], [7], [8]]. However, currently available meta-analyses included only published studies, without any attempt at retrieving data from completed and publicly disclosed, although not formally published, clinical trials. Furthermore, several trials have been published in the last few months, increasing in a relevant manner the available data base for the assessment of the clinical profile of DPP-4 inhibitors.

The aim of the present study is to offer a comprehensive and updated synthesis of all available clinical data on the safety and efficacy of DPP-4 inhibitors.

The trial flow is summarized in Fig. 1, and the characteristics of the trials included in the meta-analysis are summarized in Table 1. Among the trials included, 32 were described in publications in peer-reviewed journals; results of 9 unpublished trials were disclosed on different websites. Furthermore, 10 unpublished trials, the results of which were undisclosed, could be identified (Table 2). Notably, results could be retrieved for the large majority of trials on currently available DPP-4 inhibitors (sitagliptin and vildagliptin), while only results of preliminary phase II studies were available for products currently under development (saxagliptin).

Figure 1

Trial flow diagram. RCT: randomized clinical trial.

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Table 1Characteristics of the studies included in the meta-analysis.

Study (Ref.)	Dose (mg/die)	Comparator	Add-on to	Description of randomization	Description of blinding	Reporting of drop-out	Intention-to-treat
Vildagliptin
Pan [33]	100	Acarbose	None	NA	NA	A	Yes
Schweizer [28]	100	Metformin	None	NA	NA	A	Yes
Rosenstock [34]	50–100	Rosiglitazone	None	NA	NA	A	Yes
2329 [14]	50–100	Pioglitazone	None	NR	NR	NR	Yes
Bolli [21]	100	Pioglitazone	Metformin	NA	NA	A	No
Rosenstock [35]	100	Pioglitazone	None	NA	A	A	Yes
	50–100	Placebo	Pioglitazone	NA	A	A	Yes
Dejager [36]	50–100	Placebo	None	NA	NA	A	Yes
Scherbaum [37]	50	Placebo	None	NA	NA	A	Yes
Mari [38]	50	Placebo	None	NA	NA	A	NR
Scherbaum [39]	50	Placebo	None	NA	NA	A	Yes
Pratley [27]	50	Placebo	None	NA	A	A	Yes
Pi-Sunyer [40]	50–100	Placebo	None	NA	NA	A	Yes
Ristic [41]	25–100	Placebo	None	NA	NA	NA	Yes
1202 [14]	20–100	Placebo	None	NR	NR	NR	Yes
Ahren [42]	50	Placebo	Metformin	NA	NA	A	NR
Bosi [22]	50–100	Placebo	Metformin	NA	NA	A	Yes
Garber [43]	50–100	Placebo	Pioglitazone	NA	NA	A	Yes
Garber [19]	50–100	Placebo	Glimepiride	A	NA	A	Yes
1302 [14]	100	Placebo	Glimepiride	NR	NR	NR	Yes
Fonseca [20]	100	Placebo	Insulin	NA	NA	A	Yes
1303 [14]	50–100	Placebo	NR	NR	NR	NR	Yes
D’Alessio [44]	100	Placebo	Metf./None	NA	NA	A	Yes
Sitagliptin
PN-036 [15]	50–100	Metformin	None	NA	A	A	Yes
Scott [45]	100	Rosiglitazone	Metformin	NA	NA	A	Yes
	100	Placebo	Metformin	NA	NA	A	Yes
PN-035 [15]	100	Pioglitazone	Glim±Met	NA	NA	A	Yes
Nauck [17]	100	Glipizide	Metformin	NA	NA	A	Yes
PN-028 [15]	25–50	Placebo/Glip.	OAD/Insulin	NR	NR	NR	Yes
Scott [18]	10–100	Glipizide	None	A	A	A	Yes
	10–100	Placebo	None	A	A	A	Yes
Nonaka [46]	100	Placebo	None	NA	NA	A	Yes
Hanefeld [16]	25–100	Placebo	None	NA	A	A	No
Raz [47]	100–200	Placebo	None	NA	NA	A	Yes
Goldstein [23]	50–100	Placebo	None	NA	A	A	Yes
Rosenstock [35]	100	Placebo	Pioglitazone	NA	NA	A	Yes
Hermansen [24]	100	Placebo	Glim±Metf	NA	NA	A	Yes
Goldstein [23]	50–100	Placebo	Metformin	NA	A	A	Yes
Charbonnel [48]	100	Placebo	Metformin	NA	NA	A	Yes
Aschner [49]	100–200	Placebo	None	NA	NA	A	Yes
Raz [50]	100	Placebo	Metformin	A	NA	A	Yes
PN-040 [15]	100	Placebo	OAD/None	NR	NR	NR	Yes
PN-044 [15]	25–200	Placebo	OAD/None	NR	NR	NR	Yes
Saxagliptin
Rosenstock [51]	2.5–40	Placebo	None	NA	NA	A	Yes

NA: not adequate or not adequately reported; A: adequate; NR: not reported; glip.: glipizide; glim±metf: glimepiride and/or metformin; metf.: metformin; OAD: oral antidiabetic drugs; and SU/metf: sulfonylureas or metformin.

Table 2Characteristics of the unpublished and undisclosed studies.

Study	# Patients planned	Comparator	Add-on to	Trial duration (weeks)	Design	Randomization	Study end datea
DPP-4 inhibitors
Vildagliptin
NCT00368134 [52]	370	Voglibose	None	12	PS	Double blind	June 2007
NCT00396227 [52]	2665	Glitazones	Metformin	12	PS	Open label	October 2007
Sitagliptin
NCT00411554 [52]	310	Voglibose	None	12	PS	Double blind	August 2007
Saxagliptin
NCT00327015 [52]	1396	Placebo	Metformin	52	PS	Double blind	November 2007
		Metformin	None	52	PS	Double blind
NCT00121641 [52]	460	Placebo	None	24	PS	Double blind	August 2007
NCT00374907 [52]	36	Placebo	None	12	PS	Double blind	October 2007
NCT00295633 [52]	555	Placebo	Glitazones	24	PS	Double blind	October 2007
NCT00121667 [52]	720	Placebo	Metformin	24	PS	Double blind	August 2006
NCT00313313 [52]	780	Placebo	Glyburide	24	PS	Double blind	September 2007
NCT00316082 [52]	365	Placebo	None	24	PS	Double blind	November 2007

PS: parallel series.

aFinal data collection date for primary outcome measure.

The Begg adjusted rank correlation test (Kendall tau: −74; p=0.13) and the Egger regression approach (intercept, −2.81 [CI, –6.91–1.27]) suggested no major publication bias.

…………….

Table 3Moderators and outcome variables in individual studies included in the meta-analysis.

Study (Ref.)	# Patients (ID/C)	Comparator	Trial duration (weeks)	>Agea(years)	Duration of DMa(years)	HbA1c baselinea(%)	HbA1c endpoint (%, ID/C)	BMI baselinea(Kg/m2)	BMI endpoint (Kg/m2)
DPP-4 inhibitors
Vildagliptin
Pan [33]	440/220	Acarbose	24	52	1.2	8.6	7.2/7.3	26.1	26.3/25.2
Schweizer [28]	526/254	Metformin	52	53	1.0	8.7	7.7/7.3	32.4	32.5/31.8
Rosenstock [34]	459/238	Rosiglitazone	24	54	2.5	8.7	7.6/7.4	32.5	32.1/33.5
2329 [14]	218/55	Pioglitazone	12	52	2.0	10.0	NR	NR	NR
Bolli [21]	295/280	Pioglitazone	24	56	6.4	8.4	7.5/7.5	32.1	32.1/32.8
Rosenstock [35]	154/161	Pioglitazone	24	51	2.0	8.7	7.0/7.3	29.4	29.9/29.4
	292/161	Placebo	24	52	2.0	8.7	7.5/7.3	29.3	29.5/29.4
Dejager [36]	472/160	Placebo	24	54	2.1	8.4	7.6/8.1	32.9	NR
Scherbaum [37]	67/61	Placebo	52	64	3.3	6.6	6.6/7.1	30.2	NR
Mari [38]	156/150	Placebo	52	63	2.6	6.7	6.5/6.9	30.2	NR
Scherbaum [39]	156/150	Placebo	52	63	2.5	6.7	6.5/6.9	30.2	30.2/29.9
Pratley [27]	70/28	Placebo	12	55	4.0	8.0	7.4/8.1	29.9	NR
Pi-Sunyer [40]	262/92	Placebo	24	51	2.1	8.4	7.7/8.4	32.2	31.9/32.2
Ristic [41]	221/58	Placebo	12	56	3.0	7.7	7.2/7.7	31.1	31.0/31.4
1202 [14]	219/72	Placebo	12	59	NR	7.4	6.7/7.	24.0	NR
Ahren [42]	56/51	Placebo	12	57	5.5	7.8	7.1/7.8	29.7	NR
Bosi [22]	349/171	Placebo	24	54	6.2	8.4	7.5/8.4	32.7	32.5/31.7
Garber [43]	260/138	Placebo	24	54	4.7	8.7	7.6/8.1	32.4	NR
Garber [19]	264/144	Placebo	16	58	7.1	8.5	7.9/8.6	31.4	31.8/31.2
1302	102/100	Placebo	12	60	9.0	7.9	6.8/7.9	NR	NR
Fonseca [20]	144/152	Placebo	24	59	14.7	8.4	7.9/8.2	33.1	33.8/33.1
1303 [14]	178/61	Placebo	12	60	6.5	7.4	6.5/7.7	NR	NR
D’Alessio [44]	20/19	Placebo	12	55	3.5	6.7	6.3/6.3	32.3	NR
Sitagliptin
PN-036 [15]	179/176	Metformin	30	53	4.5	8.9	8.1/7.6	31.9	NR
Scott [45]	94/87	Rosiglitazone	18	55	5.0	7.7	7.0/6.9	30.2	30.1/30.9
	94/92	Placebo	18	55	5.0	7.7	7.0/7.5	30.1	30.1/29.8
PN-035 [15]	91/68	Pioglitazone	30	56	8.7	8.2	7.6/8.0	31.2	NR
Nauck [17]	576/559	Glipizide	52	57	6.3	7.7	7.2/7.0	31.2	30.7/31.7
PN-028 [15]	65/26	Placebo/Glip	54	68	13.5	7.7	7.0/7.6	NR	NR
Scott [18]	595/123	Glipizide	12	55	5.0	7.9	7.5/7.1	30.8	NR
	595/125	Placebo	12	55	5.0	7.9	7.5/8.1	31.0	NR
Nonaka [46]	75/76	Placebo	12	55	4.0	7.6	6.9/8.1	25.2	NR
Hanefeld [16]	444/111	Placebo	12	56	3.7	7.7	7.4/7.8	31.7	NR
Raz [47]	411/110	Placebo	18	55	4.6	8.0	7.7/8.2	32.1	31.8/32.3
Goldstein [23]	179/176	Placebo	24	53	4.5	8.7	8.2/8.9	31.9	NR
Rosenstock [35]	175/178	Placebo	24	56	6.1	8.1	7.2/7.8	31.5	32.6/31.5
Hermansen [24]	222/219	Placebo	24	56	8.7	8.3	7.8/8.6	31.0	31.5/31.2
Goldstein [23]	372/364	Placebo	54	53	4.4	8.8	7.1/7.8	32.2	NR
Charbonnel [48]	429/206	Placebo	24	54	6.3	8.0	7.3/7.9	31.3	NR
Aschner [49]	488/253	Placebo	24	54	4.4	8.0	7.3/8.2	30.5	30.3/30.5
Raz [50]	96/94	Placebo	30	55	8.0	9.2	8.3/9.1	30.2	NR
PN-040 [15]	352/178	Placebo	18	NR	NR	8.7	NR	NR	NR
PN-044 [15]	290/73	Placebo	12	NR	NR	7.6	NR	NR	NR
Saxagliptin
Rosenstock [51]	271/67	Placebo	12	53	1.0	7.9	7.1/7.7	31.0	30.7/30.7

ID/C: investigational drug/comparator; DM: diabetes mellitus; and glip.: glipizide.

aMean values.

Figure 2

Standardized differences (with 95% CI) of mean HbA1c at endpoint.

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………………………….

Safety: hypoglycemia

Information on hypoglycemia could be retrieved for 15 out of 18 trials with sitagliptin, and 19 out of 21 with vildagliptin. In some trials (1302 [14], 1303 [14], PN-035 [15], PN-036 [15], and PN-044 [15]), the overall number of hypoglycemic episodes was not reported. Of the remaining 34 studies, 5 (2 with sitagliptin and 3 with vildagliptin) reported that no hypoglycemic event had occurred during the trial. In the remaining studies, hypoglycemia was observed in 184 of 9944 patients treated with DPP-4 inhibitors (103 of 4573, 81 of 5100, and 0 of 271 with sitagliptin, vildagliptin and saxagliptin, respectively) and 293 of 5698 in comparator groups. The incidence of hypoglycemia with DPP-4 inhibitors (both sitagliptin and vildagliptin) was not significantly different from that observed with a placebo, even when those agents were used in combination with sulphonylureas or insulin (Fig. 3). In direct comparison, DPP-4 inhibitors were associated with a significantly lower hypoglycemic risk than sulphonylureas, whereas no significant differences were detected with respect to thiazolidinediones (Fig. 3). The number needed to harm (NNH) for sulphonylureas in comparison with DPP-4 inhibitors, with respect to hypoglycemia, on an yearly basis, was 128.

Figure 3

Mantel–Haenszel odds ratio (with 95% CI) for any hypoglycemia (logarithmic scale).

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All trials with DPP-4 inhibitors reported information on severe hypoglycemia, except 10 (6 with sitagliptin, 4 with vildagliptin). In three distinct trials [[16], [17], [18]], severe hypoglycemia was reported by 5 patients treated with sitagliptin, in monotherapy (N=4) or in combination with metformin (N=1), versus 9 cases in comparator groups (all treated with sulphonylureas). No case of severe hypoglycemia was reported in patients treated with vildagliptin, versus 5 with comparator (placebo in all cases); the severe hypoglycemic episodes detected in vildagliptin trials occurred in combination studies with sulphonylureas [19] or insulin [20].

……………………….

DPP-4 inhibitors have been proposed as an alternative to currently available therapies (sulphonylureas, thiazolidinediones or insulin), mainly as an add-on treatment in patients failing with metformin monotherapy. However, even the most recent version of the ADA–EASD consensus algorithm does not consider these drugs a viable option, except for selected cases [4]. The reasons for exclusion from the main treatment algorithm are scarce efficacy, limited amount of available evidence and high cost. With respect to available evidence, it should be recognized that several trials, which had not been included in previous meta-analyses [6], have been recently published [[19], [21], [22], [23], [24], [25]]. Furthermore, there are a relevant number of unpublished trials, the results of which have been disclosed on different websites, and are therefore available. The decision to publish a trial is, in most instances, performed by the sponsor which has a specific interest in pursuing the greater safety and tolerability of the new drug. This bias is unfortunate and limits the reliability of this and other meta-analysis, often based only on data provided from manufacturers; however, the retrieval of all available information should always be attempted, although the possibility of including some information of poorer methodological quality should be taken into account. The overall amount of evidence from randomized clinical trials which can be retrieved using this comprehensive approach is relevant, and probably sufficient for a reliable assessment of the clinical profile of this new class.

The overall efficacy on HbA1c of DPP-4 inhibitors in placebo-controlled trials is similar to that reported in previous meta-analyses [[1], [6], [7], [8]]. However, the greater number of available studies allowed separate analyses of trials in which DPP-4 inhibitors were used either as monotherapy or as an add-on to other agents. In fact, most currently available hypoglycemic treatments show a smaller additional effect on HbA1c when used as an add-on to metformin, in comparison with monotherapy trials [26]. Conversely, DPP-4 inhibitors produce a similar placebo-subtracted reduction of HbA1c either in monotherapy or as an add-on to other agents. This pattern resembles that of other drugs specifically active on post-prandial glucose, such as acarbose or glinides [26]. In fact, DPP-4 inhibitors, as well as GLP-1 receptor agonists, show a relevant effect on post-prandial hyperglycemia. Although data on post-prandial glucose measured through self-monitoring were not available, the results obtained in many trials with meal tests [[7], [27]] support the hypothesis of a specific action of DPP-4 inhibitors on post-prandial hyperglycemia.

Based on the considerations reported above, DPP-4 inhibitors, when used in combination with other drugs, should not be expected to be less effective on HbA1c than other agents (such as sulphonylureas, thiazolidinediones or insulin). Unfortunately, only a small number of head-to-head comparisons with other drugs are currently available. The efficacy of DPP-4 inhibitors on HbA1c, either in monotherapy or in combination with metformin, appears to be somewhat smaller than that of sulphonylureas, and similar to thiazolidinediones; the only two available comparisons with metformin, both in monotherapy, one with vildagliptin [28] and one with sitagliptin (PN-036 on www.merck.com/mrl/clinical_trials/results.html) suggest a smaller effect on HbA1c. It should be considered that most trials are of a relatively short duration and it is possible that sulphonylureas, which are known to produce a less durable effect on glucose than other available agents, [29] could provide less favorable results in the long-term.

Taken together, the present results on efficacy do not support the use of DPP-4 inhibitors in monotherapy as an alternative to metformin. On the other hand, these drugs appear to be effective as add-on treatments in patients failing with metformin monotherapy, with a specific effect on post-prandial glucose, although the short-term efficacy of sulphonylureas on HbA1c could be greater than that of DPP-4 inhibitors.

With respect to body mass index, this meta-analysis confirms the neutrality of DPP-4 inhibitors [[1], [6], [7], [8]]. In direct comparison, DPP-4 inhibitors appear to have an advantage in this respect over thiazolidinediones.

GLP-1 stimulates insulin secretion and inhibits glucagon production in a glucose-dependent manner, i.e. its effects are blunted when blood glucose reaches the lower limits of the normal range [30]. Therefore, DPP-4 inhibitors are expected to reduce glycemia with a low hypoglycemic risk. In fact, DPP-4 inhibitors do not induce any additional risk, in comparison with a placebo, either in monotherapy or in combination with sulphonylureas or insulin. This confirms the results of a recent meta-analysis performed on patient-level data from randomized clinical trials with sitagliptin [31]. Interestingly, in the only trial performed in insulin-treated patients, vildagliptin reduced the incidence of hypoglycemia in comparison with a placebo [20]. The mechanisms underlying this phenomenon need to be further elucidated. As expected, DPP-4 inhibitors do not increase the incidence of hypoglycemic episodes when compared with insulin-sensitizing drugs; on the other hand, they show a markedly reduced risk of hypoglycemia in head-to-head comparisons with sulphonylureas. This difference, which could be partly determined by a marginally greater efficacy of sulphonylureas on HbA1c, is consistent with the different mechanisms of action of the classes of drugs.

No patient experienced severe hypoglycemia during vildagliptin therapy. Unexpectedly, episodes of severe hypoglycemia occurred in five patients treated with sitagliptin, either in monotherapy or in combination with metformin, in three different trials [[16], [17], [18]]. Notably, two of those trials [[16], [18]], although published, did not report those events but since those trials were included in the registration data for drug approval in the US, the information on severe hypoglycemia can be retrieved from the FDA website. Furthermore, episodes of severe hypoglycemia were not considered in a recent meta-analysis of trials with sitagliptin, although a greater number of such events had occurred in comparator groups, which included sulphonylureas [31]. It should also be considered that some of the trials did not report any information on severe hypoglycemia, raising the possibility of a selective reporting bias. The occurrence of cases of severe hypoglycemia with DPP-4 inhibitor monotherapy is difficult to explain on the basis of the current knowledge of the mechanism of action of those drugs, and deserved further investigation.

Among other expected adverse events, the previously reported increased incidence of some infections during DPP-4 inhibitor therapy [[6], [8]] is confirmed, with sitagliptin, but not vildagliptin, associated with nasopharyngitis, and with a nonsignificant trend toward an increased risk of urinary tract infections. These results are consistent with those of a recent meta-analysis on patient-level data from trials with sitagliptin, which included only a fraction of the studies summarized in the present meta-analysis, and which showed a similar trend toward the increase of risk of nasopharyngitis with the DPP-4 inhibitor, although it failed to reach statistical significance [31]. It should be considered that DPP-4 is involved in the interaction between immune cells and that it could therefore modulate immune responses [32]; however, there is no evidence from mechanistic studies that inhibition of DPP-4 with currently available agents has an immunodepressant effect. Consistently, treatment with DPP-4 inhibitors does not appear to increase the risk of infections other than nasopharyngitis and urinary tract infections.

The introduction of a new class of drugs which are designed for long-term use always raises some concerns about safety during prolonged treatment. The possibility of rare, unexpected serious adverse events, which could not be detected in registration trials, should be considered. The number of reported deaths in available trials is still very small; however, there is no evidence suggesting an increase in mortality during treatment with DPP-4 inhibitors. The number of cardiovascular events registered in clinical trials is remarkably greater, although still inadequate to detect minor differences between groups. The two drugs which have been more thoroughly studied (sitagliptin and vildagliptin) do not seem to be associated with increased cardiovascular risk; in fact, the actual risk is lower than with comparators, although differences do not reach statistical significance. In fact, available data do not rule out the possibility of an increase of cardiovascular risk up to 28%, or of a reduction up to 54%. It should be considered that the duration of the available trials (up to one year) is insufficient to detect any effect of treatment (either detrimental or beneficial) on atherogenesis.

The addition of unpublished trials does not substantially modify the estimates of efficacy of DPP-4 inhibitors. However, the retrieval of unpublished, but publicly disclosed, information allowed the identification of some potentially interesting phenomena, such as cases of severe hypoglycemia with DPP-4 inhibitor monotherapy, which could not be detected in published papers.

The limitations of the present meta-analysis should be recognized and considered when interpreting the results. The analysis was performed on summary data, therefore lacking the accuracy of assessment which can be obtained when using patient-level data. For the very same reason, a time-to-event analysis for categorial outcomes (including cardiovascular events) could not be performed; the proportion of patients experiencing at least one event during the trial, which was used for meta-analysis, approximates the actual incidence of events only if this incidence is assumed to be constant throughout the duration of the trial. Furthermore, the number of subject studies and the duration of trials performed is insufficient to draw any definitive conclusion on the long-term cardiovascular safety of DPP-4 inhibitors.

In conclusion, DPP-4 inhibitors are effective in reducing HbA1c and post-prandial glucose; when used as an add-on to metformin, they show a medium-term efficacy on HbA1c similar to thiazolidinediones and marginally inferior to sulphonylureas, with a reassuring short- and medium-term safety profile. In fact, the hypoglycemic risk is low, and there is no evidence of detrimental effects on cardiovascular disease. In comparison with sulphonylureas or insulin, which have been proposed as first-choice agents in patients failing with metformin [4], DPP-4 inhibitors exhibit, at least in the short- and medium-term, a lower hypoglycemic risk and a more favorable action on body weight, at the price of a somewhat smaller efficacy and higher cost. The choice of the drugs to be used as add-ons to metformin in monotherapy failure largely depends on the relative weight attributed to each of these three components (safety, efficacy on HbA1c and cost).

 

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Glucokinase target for type 2 diabetes

Posted in Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Diabetes Mellitus, FDA Regulatory Affairs, Gastroenterology, Lasers and photonics, Liver & Digestive Diseases Research, Metabolism, Patents, Pharmaceutical Drug Discovery, Pharmaceutical R&D Investment, tagged glucokinase activator, type 2 diabetes on November 27, 2015| Leave a Comment »

Glucokinase target for type 2 diabetes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Pfizer’s PF 04991532 a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus
DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER
http://newdrugapprovals.org/2015/11/27/pfizers-pf-04991532-a-hepatoselective-glucokinase-activator-clinical-candidate-for-treating-type-2-diabetes-mellitus/

 

PF 04991532

GKA PF-04991532

(S)-6-{3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamido}nicotinic acid

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid

(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid

MW 396.36, MF C₁₈ H₁₉ F₃ N₄ O₃

CAS 1215197-37-7

3-​Pyridinecarboxylic acid, 6-​[[(2S)​-​3-​cyclopentyl-​1-​oxo-​2-​[4-​(trifluoromethyl)​-​1H-​imidazol-​1-​yl]​propyl]​amino]​-

http://www.biochemj.org/content/441/3/881

 

Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic affecting over 300 million people worldwide. This disease is characterized by elevated fasting plasma glucose (FPG), insulin resistance, abnormally elevated hepatic glucose production (HGP), and reduced glucose-stimulated insulin secretion (GSIS). Moreover, long-term lack of glycemic control increases risk of complications from neuropathic, microvascular, and macrovascular diseases.

The standard of care for T2DM is metformin followed by sulfonylureas, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and thiazolidinediones (TZD) as second line oral therapies. As disease progression continues, patients typically require injectable agents such as glucagon-like peptide-1 (GLP-1) analogues and, ultimately, insulin to help maintain glycemic control. Despite these current therapies, many patients still remain unable to safely achieve and maintain tight glycemic control, placing them at risk of diabetic complications and highlighting the need for novel therapeutic options.

 

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia.

While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index.

 

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM.

As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type II diabetes and the metabolic syndrome” Nature414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.

Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication Nos. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

 

 

 

PATENT

US 20100063063

http://www.google.com/patents/US20100063063

SYNTHESIS CONSTRUCTION

6-aminonicotinic acid

 

BENZYL BROMIDE

 

FIRST KEY INTERMEDIATE

 

SECOND SERIES FOR NEXT INTERMEDIATE

CONDENSED WITH

4-Trifluoromethyl-1H-imidazole

TO  GIVE PRODUCT SHOWN BELOW

 

(S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

 

CONVERTED TO ACID CHLORIDE, (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)

AND CONDENSED WITH

WILL GIVE BENZYL DERIVATIVE

THEN DEBENZYLATION TO FINAL PRODUCT

 

 

 

¹H NMR (400 MHz, DMSO-d₆) δ 13.10-13.25 (1H), 11.44 (1H), 8.83 (1H), 8.23-8.26 (1H), 8.09-8.12 (1H), 7.94-7.95 (2H), 5.22-5.26 (1H), 2.06-2.17 (2H), 1.29-1.64 (8H), 1.04-1.07 (1H); m/z 397.3 (M+H)⁺.

 

Organic Process Research & Development (2012), 16(10), 1635-1645

http://pubs.acs.org/doi/abs/10.1021/op300194c

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (1)

 

Journal of Medicinal Chemistry (2012), 55(3), 1318-1333

http://pubs.acs.org/doi/abs/10.1021/jm2014887

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure–activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Bioorganic & Medicinal Chemistry Letters (2013), 23(24), 6588-6592

http://www.sciencedirect.com/science/article/pii/S0960894X13012638

 

Figure 1.

Structure of Hepatoselective GKA PF-04991532 (1).

 

Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes
DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER
http://newdrugapprovals.org/2015/11/27/pfizers-pf-04937319-glucokinase-activators-for-the-treatment-of-type-2-diabetes/

PF 04937319

N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide

MW 432.43

MF C₂₂ H₂₀ N₆ O₄

CAS 1245603-92-2

2-​Pyrimidinecarboxamid​e, N,​N-​dimethyl-​5-​[[2-​methyl-​6-​[[(5-​methyl-​2-​pyrazinyl)​amino]​carbonyl]​-​4-​benzofuranyl]​oxy]​-

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide

Pfizer Inc. clinical candidate currently in Phase 2 development.

CLINICAL TRIALS

A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)

Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)

Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)

 

SYNTHESIS

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification ofN,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

 

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

 

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

Jeffrey A. Pfefferkorn,*^a   et al

*Corresponding authors

^aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421

Med. Chem. Commun., 2011,2, 828-839

DOI: 10.1039/C1MD00116G

http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract

http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification ofN,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28).

 

PAPER

 

http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract

 

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578

http://www.sciencedirect.com/science/article/pii/S0960894X13007452

Figure 1.

Glucokinase activators 1 and 2.

 

PATENT

Pfizer Inc.

WO 2010103437

https://www.google.co.in/patents/WO2010103437A1?cl=en

Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).

Preparations of Starting Materials and Key Intermediates

 

 

Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P

 

Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751

 

Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)

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Artificial Pancreas

Posted in Clinical & Translational, Curation, Diabetes Mellitus, Nephrology, Nephrology & Regenerative medicine, tagged artificial kidney, Diabetes on November 21, 2015| Leave a Comment »

Artificial Pancreas

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Artificial Pancreas Therapy Performs Well in Pilot Study

Fri, 11/20/2015 – by Wiley

http://www.mdtmag.com/news/2015/11/artificial-pancreas-therapy-performs-well-pilot-study

 

Researchers are reporting a breakthrough toward developing an artificial pancreas as a treatment for diabetes and other conditions by combining mechanical artificial pancreas technology with transplantation of islet cells, which produce insulin.

In a study of 14 patients with pancreatitis who underwent standard surgery and auto-islet transplantation treatments, a closed-loop insulin pump, which relies on a continuous cycle of feedback information related to blood measurements, was better than multiple daily insulin injections for maintaining normal blood glucose levels.

“Use of the mechanical artificial pancreas in patients after islet transplantation may help the transplanted cells to survive longer and produce more insulin for longer,” said Dr. Gregory Forlenza, lead author of the American Journal of Transplantation study. “It is our hope that combining these technologies will aid a wide spectrum of patients, including patients with diabetes, in the future.”

 

Artificial Pancreas Works for Length of Entire School Term

Fri, 09/18/2015 – by University of Cambridge

Daniel Walls, a 12-year-old with type 1 diabetes who has taken part in the trial.

An artificial pancreas given to children and adults with type 1 diabetes going about their daily lives has been proven to work for 12 weeks – meaning the technology, developed at the University of Cambridge, can now offer a whole school term of extra freedom for children with the condition.

Artificial pancreas trials for people at home, work and school have previously been limited to short periods of time. But a study, published today in the New England Journal of Medicine, saw the technology safely provide three whole months of use, bringing us closer to the day when the wearable, smartphone-like device can be made available to patients.

The lives of the 400,000 UK people with type 1 diabetes currently involves a relentless balancing act of controlling their blood glucose levels by finger-prick blood tests and taking insulin via injections or a pump. But the artificial pancreas sees tight blood glucose control achieved automatically.

This latest Cambridge study showed the artificial pancreas significantly improved control of blood glucose levels among participants – lessening their risk of hypoglycemia. Known as ‘having a hypo,’ hypoglycemia is a drop in blood glucose levels that can be highly dangerous and is what people with type 1 diabetes hate most.

Susan Walls is mother to Daniel Walls, a 12-year-old with type 1 diabetes who has taken part in the trial. She said: “Daniel goes back to school this month after the summer holidays – so it’s a perfect time to hear this wonderful news that the artificial pancreas is proving reliable, offering a whole school term of support.

“The artificial pancreas could change my son’s life, and the lives of so many others. Daniel has absolutely no hypoglycaemia awareness at night. His blood glucose levels could be very low and he wouldn’t wake up. The artificial pancreas could give me the peace of mind that I’ve been missing.”

“The data clearly demonstrate the benefits of the artificial pancreas when used over several months,” said Dr. Roman Hovorka, Director of Research at the University’s Metabolic Research Laboratories, who developed the artificial pancreas. “We have seen improved glucose control and reduced risk of unwanted low glucose levels.”

The Cambridge study is being funded by JDRF, the type 1 diabetes charity. Karen Addington, Chief Executive of JDRF, said: “JDRF launched its goal of perfecting the artificial pancreas in 2006. These results today show that we are thrillingly close to what will be a breakthrough in medical science.”

 

Highly Sensitive Biosensor Measures Glucose in Saliva

Tue, 11/03/2015 – by The Hong Kong Polytechnic University

The glucose biosensor fabricated with flexible substrates can perform in a variety of curved and moving surfaces, including human skin, smart textile and medical bandage.

Diabetic patients have to monitor blood glucose regularly and frequently, but conventional method of taking blood sample for measuring glucose level is painful. It is therefore important to develop high performance biological sensors for monitoring the glucose level at a reasonable cost.

The challenge to develop biosensor to test glucose in saliva is that the amount of glucose in saliva is too small for detection, and it requires a super sensitive biosensor to perform the job. The biosensor developed by PolyU researchers is fabricated with a glucose oxidase enzyme (GOx) layer, which is sensitive to glucose alone and nothing else. By detecting the electrical current, the glucose level can be known. However, there can be interference with current from other possible biological elements in saliva, such as dopamine, uric acid and ascorbic acid. To block such interference, researchers have coated Polyaniline (PANI) / Nafion-graphene bilayer films between the top enzyme layer and gate electrode. The strong adhesion of this top layer to the GOx layer enables the latter to stabilize and perform well in glucose detection.

Our novel biosensor is selectively sensitive to glucose, accurate, flexible and low in cost. The highly sensitive biosensor shows a detection lower limit of 10-5 mmol/L, which is nearly 1000 times sensitive than the conventional device for measuring blood glucose. This means with this biosensor, as little as 5 gram of glucose in a standard swimming pool of 50 m x 25 m x 2 m can be detected. Between the wide range of glucose level from 10-5 mmol/L up to 10 mmol/L (equivalent to 5 g – 5000 Kg of glucose in a standard swimming pool), the biosensor demonstrates linear response, which is good enough for measuring the possible range of glucose in the human body. Accuracy of the biosensor has been ascertained through laboratory experiments with repeatable results using glucose solutions of known glucose levels.

The glucose biosensor fabricated with flexible substrates can perform in a variety of curved and moving surfaces, including human skin, smart textile and medical bandage. Thus, it has great potential for development into wearable electronic applications, such as wearable biosensor for analysis of glucose level in sweat during exercise. It can also be mass produced at a low cost of HK$ 3 to 5 per test chip, which is comparable or even cheaper than the currently available commercialized products. In addition, this newly invented transistor-based biosensor platform is highly versatile. By changing to suitable enzymes, the platform can be used to measure the level of uric acid and other materials in saliva. For instance, if the biosensor is fabricated with enzyme uricase (UOx) and Polyaniline (PANI) / Nafion-graphene bilayer films, the platform can specifically be sensitive to uric acid only and other interference signals can be blocked.

 

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Mirogabalin for diabetic neuropathy

Posted in Ca2+ triggered activation, Calcium Signaling, Diabetes Mellitus, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Signaling & Cell Circuits, tagged calcium channel inhibitor, fibromyalgia pain, neuropathy, type 2 DM on November 19, 2015| Leave a Comment »

Mirogabalin for diabetic neuropathy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Mirogabalin by DR ANTHONY MELVIN CRASTO Ph.D

 

Mirogabalin, A-2000700, DS-5565

1138245-13-2, C12H19NO2, 209.28

[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid

2-[(1R,5S,6S)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid

UNII-S7LK2KDM5U

Originator	Daiichi Sankyo
Therapeutic Claim	Treatment of fibromyalgia

Phase III clinical trials at Daiichi Sankyo for the treatment of pain associated with fibromyalgia

 

Class	Analgesic drugs (small molecules)
Mechanism of action	CACNA2D1 protein modulators

 

Mirogabalin (DS-5565) is a drug developed by Daiichi Sankyo and related to drugs such as gabapentin and pregabalin. Similarly to these drugs, mirogabalin binds to the α₂δ calcium channels (1 and 2), but with significantly higher potency than pregabalin. It has shown promising results in Phase II clinical trials for the treatment of diabeticperipheral neuropathic pain,^[1][2] and is currently in Phase III trials.

Mirogabalin, a voltage-dependent calcium channel subunit alpha-2/delta-1 ligand, is in phase III clinical trials at Daiichi Sankyo for the treatment of pain associated with fibromyalgia. The company is also conducting phase III clinical studies for the treatment of chronic pain and pain associated with diabetic peripheral neuropathy.

PATENTS

WO 2009041453

https://www.google.co.in/patents/EP2192109A1

JP 2010241796

WO 2012169475

WO 2012169474

WO2015005298

https://patentscope.wipo.int/search/en/detail.jsf

 

In the present invention, compounds having formula (IX) prepared via the process F from Step A (and / or its enantiomer) may be very produced as pure compounds. Compounds of formula (IX) which can be obtained by the present invention typically have a quality below.

The content of the diastereomer represented by the formula (X): 0.1% less than the content of the enantiomers represented by the formula (XI): 1.0% less than the formula (XII) and the double bond represented by the formula (XIII) The total content of regioisomers: less than 0.5% (Note that each content is calculated from the area percentage of the free form of formula (IX) (VII) in the by test High Performance Liquid Chromatography) [formula 23] [of 24]

 

　Next, the present invention is described by examples in detail, the present invention is, which however shall not be construed as limited thereto.
The internal standard substance in a magnetic resonance spectra (NMR), and using tetramethylsilane and abbreviations indicate the multiplicity, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and brs = It shows a broad singlet.
In the name of the compound, “R” and “S” indicate the absolute configuration at the asymmetric carbon. Furthermore, “RS” and “SR” indicates that the asymmetric carbon atom is racemic. In addition, “(1RS, and 5SR) -” if such a can shows the relative arrangement of the 1-position and the 5-position, as well shows only one of the diastereomers, its diastereomers are racemic We show that.
In the name of the compound, “E” and “Z” indicates the arrangement of positional isomers in the structure of the compound having a position isomerism.

“EZ” and “ZE” indicates that it is a mixture of regioisomers. Way more notation, is in accordance with the conventions in this area of the normal.

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