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Viewing Gliptins – Cardiologist
Prospective
Dr. Neeraj Bhalla
Senior Consultant and Director
Deptt of Cardiology BLK Super Speciality Hospital
• Diabetes is a constellation of metabolic
abnormalities
• As there is no unifying causative mechanism ; there is no unique
treatment for it. Treatment includes managing its components
3
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
Global cardiometabolic risk (CMR)
4
5
Impact of Hypoglycemia & weight gain in T2DM
– Cardiovascular perspective
Hypoglycaemia
& Weight gain
HbA1c
The challenge of tight glucose control
6
Hypoglycemia as a cause for cardiovascular events -
Mechanisms
8
Desouza CV, et al.
Diabetes Care. 2010;
33:1389–394
Metabolic Syndrome facts…
• The relative risk of developing diabetes , hypertension
and CVD increases with an increase in body weight
1 kg weight gain
CVD risk by 3.1 %
Diabetes risk by 4.5-9 %
Ref : Curr. Med. Chem. – Imm., Endoc. & Metab. Agents, 2001, Vol. 1, No. 1 ; IDF Defination
• 78% of patients with metabolic syndrome have insulin resistance, & 48%
of people with insulin resistance have metabolic syndrome.
• People with metabolic syndrome are twice as likely to die from & thrice as
likely to have stroke or heart attack then people without it
9
10
The Unmet need with current therapy for T2DM
Most Insulin secretagogues , including glimepiride, associated with increased
mortality & cardiovascular risk compared with metformin
11
Monotherapy with the most used Insulin secretagogues (ISs), including glimepiride, glibenclamide,
glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk
compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk
than other ISs
N = 107 806 subjects
followed for up to 9 years
(median 3.3 years)
TK Schramm etal, European Heart Journal Advance Access published April 6, 2011
HazardRatio(%)
Hypoglycemia is Common with SUs
*Hypoglycemia: fingerstick blood glucose measurement 50 mg/dL (2.75 mmol/L)
1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 2. UKPDS Group. Lancet
1998; 352: 837–853. 3. Draeger KE, et al. Horm Metab Res. 1996; 28: 419–425. 4. McGavin JK, et al. Drugs 2002;
62; 1357–1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2002
Sulfonylureas
Glipizide5Gliclazide4Chlorpropamide2Glyburide1
0
5
10
15
20
25
IncidenceofHypoglycemia(%)
21.3%
15.3%
5%
2.9%*
14%
11%
Glibenclamide3 Glimepiride3
Weight Gain is a Common Side Effect of Diabetes Treatments
TZDs4–6
Metformin + TZD5,6,9
Metformin + SU1–3
Meglitinides4,7,8
SUs1–4
Metformin1–3
Weight Change (kg)OAD Agents
OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione.
1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004.
3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert].
Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ:
Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC:
GlaxoSmithKline, 2005.
−5 −4 −3 −2 −1 0 1 2 3 4 5
-3.8–0.5
-0.4–1.7
0.9–4.6
0.3–3.0
-0.3–1.9
0.8–2.1
Edema is Common with TZDs (Pioglitazone)
TZDs=thiazolidinediones.
1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004.
4.8
7.2
6.0
15.3
1.2
2.1 2.5
7.0
0
2
4
6
8
10
12
14
16
18
Monotherapy Combination
with SU
Combination
with
metformin
Combination
with insulin
ProportionofPatients(%)
Pioglitazone1
Placebo or combination
Use of TZDs is Associated with Increased Incidence of Congestive Heart Failure
NumberofCHFEvents
P=0.01
CHF=congestive heart failure; TZDs=thiazolidinediones.
Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105.
HF=heart failure
Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.
P <0.0001
14
2
0
5
10
15
20
11
8
0
5
10
15
Rosiglitazone
Placebo
PatientswithHF(%)
Placebo
Pioglitazone ≤45 mg daily
DREAM Study
PROactive Study
Risk of Myocardial Infarction and Death from Cardiovascular Causes with
Rosiglitazone
CI=confidence interval; CV=cardiovascular.
Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471.
Myocardial infarction
Small trials combined
DREAM
ADOPT
Overall
Death from CV causes
Small trials combined
DREAM
ADOPT
Overall
2.0 4.01.0
Log Odds Ratio (95% CI)
0.5
1.43 (1.03–1.98) P=0.03
1.45; P=0.15
1.65; P=0.22
1.33; P=0.27
2.40; P=0.02
1.20; P=0.67
0.80; P=0.78
1.64 (0.98–2.74) P=0.06
17
Cardiovascular effects of gliptins
Vildagliptin: less hypoglycaemia & Weight gain
than sulfonylurea
Hypoglycaemia
0
600
500
400
300
200
100
Ferrannini E, et al. Diabetes Obes Metab 2009; 11: 157–166
Body weight
88
91
90
Weight(kg)
89
-8 2 12 22 32 42 52
Weeks
39
554
No.hypoglycaemicevents
Safety population
Glimepiride + metformin (n=1383)
Vildagliptin + metformin (n=1389)
Beneficial effect on Blood pressure and Lipids
BL=baseline; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; BL=baseline; DBP=diastolic blood pressure; met=metformin;
PBO=placebo; SBP=systolic blood pressure met=metformin; PBO=placebo; TC=total cholesterol; TG=triglycerides; vilda=vildagliptin.
Primary intention-to-treat population; n refers to the patient number in the TG test. *P=0.014 vs PBO; all other values did not reach statistical significance. Bosi E, et al.
Diabetes Care. 2007; 30; 890–895.
Cardiovascular effects of gliptins
Potentially antiatherogenic and might reduce cardiovascular complications
André J. Scheen. Nat. Rev. Cardiol, January 2013
20
DPP4 inhibitors & Cardiac safety
An overall favorable effect of DPP4i on cardiac safety
23
Monami etal, Current Medical
Research & Opinion Volume 27,
Number S3 2011
Overall ODDS RATIO = 0.689
The FDA position on CV outcome studies
• Sponsors should compare the incidence of important cardiovascular events occurring with the investigational
agent to incidence of same types of events occurring with control group to show that upper bound of the 2-sided
95 percent confidence interval for estimated risk ratio is > 1.8.
• This can be accomplished in several ways.
• The integrated analysis (meta-analysis) of the phase 2 & phase 3 clinical trials can be used.
• If the data from all the studies that are part of meta-analysis will not by itself be able to show that the upper bound of
the two-sided 95 percent confidence interval for the estimated risk ratio is less than 1.8, then an additional single, large
safety trial should be conducted that alone, or added to other trials, would be able to satisfy this upper bound before
NDA/BLA submission.
24
(Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf)
If the premarketing application contains clinical
data that show that the upper bound of the two-
sided 95 percent confidence interval for the
estimated increased risk (i.e., risk ratio) is less than
1.3 and the overall risk-benefit analysis supports
approval, a postmarketing cardiovascular trial
generally may not be necessary
bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin.
*Vs all comparators=placebo, metformin, gliclazide, acarbose, rosiglitazone, pioglitazone and glimepiride. All-study safety population.
#Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, US Department
of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008.
Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494.
Vildagliptin Reference M-H RR
n / N (%) n / N (%) (95% CI)
Vilda 50 mg qd* 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11)
Vilda 50 mg bid* 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14)
Risk ratio
Incidences and odds ratios for adjudicated CV
events by treatment
Vildagliptin better Vildagliptin worse
0.1 1 10
#Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology set
by the US Food and Drug Administration [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)]
Pooled Meta-analysis of 25 Phase III studies of vildagliptin shows no increased
cardiovascular risk vs comparators
Cardiac Safety data of gliptins
1 = Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494. 2 = http://clinicaltrials.gov/ct2/show/NCT00894868?term=vildagliptin+%2B+heart+failure&rank=1 NCT00894868 Effect of
Vildagliptin on Left Ventricular Function in Patients With Type 2 Diabetes and Congestive Heart Failure – Recruiting patients 3 = VERIFY:A Study to Compare Combination Regimen With
Vildagliptin & Metformin Versus Metformin in Treatment-naïve Patients With Type 2 Diabetes Mellitus NCT01528254
4 = Scheen A, Expert Opin. Pharmacother. (2012) 13(1):81-99 * Based on routine search on www.clinicaltrial.gov
CONCLUSION
Gliptins are cardiac safe unlike other OHAs
-may be cardio protective
Thank You from Cardiology Team BLK

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Cv safety of gliptins

  • 1. 1 Viewing Gliptins – Cardiologist Prospective Dr. Neeraj Bhalla Senior Consultant and Director Deptt of Cardiology BLK Super Speciality Hospital
  • 2.
  • 3. • Diabetes is a constellation of metabolic abnormalities • As there is no unifying causative mechanism ; there is no unique treatment for it. Treatment includes managing its components 3
  • 4. Gelfand EV et al, 2006; Vasudevan AR et al, 2005 Global cardiometabolic risk (CMR) 4
  • 5. 5 Impact of Hypoglycemia & weight gain in T2DM – Cardiovascular perspective
  • 6. Hypoglycaemia & Weight gain HbA1c The challenge of tight glucose control 6
  • 7. Hypoglycemia as a cause for cardiovascular events - Mechanisms 8 Desouza CV, et al. Diabetes Care. 2010; 33:1389–394
  • 8. Metabolic Syndrome facts… • The relative risk of developing diabetes , hypertension and CVD increases with an increase in body weight 1 kg weight gain CVD risk by 3.1 % Diabetes risk by 4.5-9 % Ref : Curr. Med. Chem. – Imm., Endoc. & Metab. Agents, 2001, Vol. 1, No. 1 ; IDF Defination • 78% of patients with metabolic syndrome have insulin resistance, & 48% of people with insulin resistance have metabolic syndrome. • People with metabolic syndrome are twice as likely to die from & thrice as likely to have stroke or heart attack then people without it 9
  • 9. 10 The Unmet need with current therapy for T2DM
  • 10. Most Insulin secretagogues , including glimepiride, associated with increased mortality & cardiovascular risk compared with metformin 11 Monotherapy with the most used Insulin secretagogues (ISs), including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs N = 107 806 subjects followed for up to 9 years (median 3.3 years) TK Schramm etal, European Heart Journal Advance Access published April 6, 2011 HazardRatio(%)
  • 11. Hypoglycemia is Common with SUs *Hypoglycemia: fingerstick blood glucose measurement 50 mg/dL (2.75 mmol/L) 1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 2. UKPDS Group. Lancet 1998; 352: 837–853. 3. Draeger KE, et al. Horm Metab Res. 1996; 28: 419–425. 4. McGavin JK, et al. Drugs 2002; 62; 1357–1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2002 Sulfonylureas Glipizide5Gliclazide4Chlorpropamide2Glyburide1 0 5 10 15 20 25 IncidenceofHypoglycemia(%) 21.3% 15.3% 5% 2.9%* 14% 11% Glibenclamide3 Glimepiride3
  • 12. Weight Gain is a Common Side Effect of Diabetes Treatments TZDs4–6 Metformin + TZD5,6,9 Metformin + SU1–3 Meglitinides4,7,8 SUs1–4 Metformin1–3 Weight Change (kg)OAD Agents OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione. 1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. −5 −4 −3 −2 −1 0 1 2 3 4 5 -3.8–0.5 -0.4–1.7 0.9–4.6 0.3–3.0 -0.3–1.9 0.8–2.1
  • 13. Edema is Common with TZDs (Pioglitazone) TZDs=thiazolidinediones. 1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004. 4.8 7.2 6.0 15.3 1.2 2.1 2.5 7.0 0 2 4 6 8 10 12 14 16 18 Monotherapy Combination with SU Combination with metformin Combination with insulin ProportionofPatients(%) Pioglitazone1 Placebo or combination
  • 14. Use of TZDs is Associated with Increased Incidence of Congestive Heart Failure NumberofCHFEvents P=0.01 CHF=congestive heart failure; TZDs=thiazolidinediones. Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105. HF=heart failure Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289. P <0.0001 14 2 0 5 10 15 20 11 8 0 5 10 15 Rosiglitazone Placebo PatientswithHF(%) Placebo Pioglitazone ≤45 mg daily DREAM Study PROactive Study
  • 15. Risk of Myocardial Infarction and Death from Cardiovascular Causes with Rosiglitazone CI=confidence interval; CV=cardiovascular. Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471. Myocardial infarction Small trials combined DREAM ADOPT Overall Death from CV causes Small trials combined DREAM ADOPT Overall 2.0 4.01.0 Log Odds Ratio (95% CI) 0.5 1.43 (1.03–1.98) P=0.03 1.45; P=0.15 1.65; P=0.22 1.33; P=0.27 2.40; P=0.02 1.20; P=0.67 0.80; P=0.78 1.64 (0.98–2.74) P=0.06
  • 17. Vildagliptin: less hypoglycaemia & Weight gain than sulfonylurea Hypoglycaemia 0 600 500 400 300 200 100 Ferrannini E, et al. Diabetes Obes Metab 2009; 11: 157–166 Body weight 88 91 90 Weight(kg) 89 -8 2 12 22 32 42 52 Weeks 39 554 No.hypoglycaemicevents Safety population Glimepiride + metformin (n=1383) Vildagliptin + metformin (n=1389)
  • 18. Beneficial effect on Blood pressure and Lipids BL=baseline; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; BL=baseline; DBP=diastolic blood pressure; met=metformin; PBO=placebo; SBP=systolic blood pressure met=metformin; PBO=placebo; TC=total cholesterol; TG=triglycerides; vilda=vildagliptin. Primary intention-to-treat population; n refers to the patient number in the TG test. *P=0.014 vs PBO; all other values did not reach statistical significance. Bosi E, et al. Diabetes Care. 2007; 30; 890–895.
  • 19. Cardiovascular effects of gliptins Potentially antiatherogenic and might reduce cardiovascular complications André J. Scheen. Nat. Rev. Cardiol, January 2013 20
  • 20.
  • 21.
  • 22. DPP4 inhibitors & Cardiac safety An overall favorable effect of DPP4i on cardiac safety 23 Monami etal, Current Medical Research & Opinion Volume 27, Number S3 2011 Overall ODDS RATIO = 0.689
  • 23. The FDA position on CV outcome studies • Sponsors should compare the incidence of important cardiovascular events occurring with the investigational agent to incidence of same types of events occurring with control group to show that upper bound of the 2-sided 95 percent confidence interval for estimated risk ratio is > 1.8. • This can be accomplished in several ways. • The integrated analysis (meta-analysis) of the phase 2 & phase 3 clinical trials can be used. • If the data from all the studies that are part of meta-analysis will not by itself be able to show that the upper bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less than 1.8, then an additional single, large safety trial should be conducted that alone, or added to other trials, would be able to satisfy this upper bound before NDA/BLA submission. 24 (Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf) If the premarketing application contains clinical data that show that the upper bound of the two- sided 95 percent confidence interval for the estimated increased risk (i.e., risk ratio) is less than 1.3 and the overall risk-benefit analysis supports approval, a postmarketing cardiovascular trial generally may not be necessary
  • 24. bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin. *Vs all comparators=placebo, metformin, gliclazide, acarbose, rosiglitazone, pioglitazone and glimepiride. All-study safety population. #Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008. Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494. Vildagliptin Reference M-H RR n / N (%) n / N (%) (95% CI) Vilda 50 mg qd* 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11) Vilda 50 mg bid* 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14) Risk ratio Incidences and odds ratios for adjudicated CV events by treatment Vildagliptin better Vildagliptin worse 0.1 1 10 #Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology set by the US Food and Drug Administration [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)] Pooled Meta-analysis of 25 Phase III studies of vildagliptin shows no increased cardiovascular risk vs comparators
  • 25. Cardiac Safety data of gliptins 1 = Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494. 2 = http://clinicaltrials.gov/ct2/show/NCT00894868?term=vildagliptin+%2B+heart+failure&rank=1 NCT00894868 Effect of Vildagliptin on Left Ventricular Function in Patients With Type 2 Diabetes and Congestive Heart Failure – Recruiting patients 3 = VERIFY:A Study to Compare Combination Regimen With Vildagliptin & Metformin Versus Metformin in Treatment-naïve Patients With Type 2 Diabetes Mellitus NCT01528254 4 = Scheen A, Expert Opin. Pharmacother. (2012) 13(1):81-99 * Based on routine search on www.clinicaltrial.gov
  • 26. CONCLUSION Gliptins are cardiac safe unlike other OHAs -may be cardio protective
  • 27. Thank You from Cardiology Team BLK

Editor's Notes

  1. Hypoglycaemia and weight gain may adversely impact HbA1c control
  2. Agents capable of triggering hypoglycemic episodes can also promote weight gain, especially as part of an intensified regimen aimed at achieving normal or near-normal glycemic levels. The weight gain may be related in part to an increase in “defensive eating” to prevent a decline from normoglycemia to hypoglycemia.Foley J, et al. Weight neutrality with the DPP-4 inhibitor, vildagliptin: Mechanistic basis and clinical experience. Vascular Health and Risk Management. 2010;6:541–548.
  3. Hypoglycemic events may trigger inflammation by inducing the release of C-reactive protein (CRP), IL-6, and vascular endothelial growth factor (VEGF). Hypoglycemia also induces increased platelet and neutrophil activation. The sympathoadrenal response during hypoglycemia increases adrenaline secretion and may induce arrhythmias and increase cardiac workload. Underlying endothelial dysfunction leading to decreased vasodilation may also contribute to cardiovascular risk.Desouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care. 2010; 33: 1389-1394.
  4. Methods - All Danish residents &gt;20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI.Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24–1.40), glibenclamide: 1.19 (1.11–1.28), glipizide: 1.27 (1.17–1.38), and tolbutamide: 1.28 (1.17–1.39) were associated with increased all cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11–1.44), glibenclamide: 1.47 (1.22–1.76), glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47 (1.17–1.84). Results for gliclazide [1.05 (0.94–1.16) and 0.90 (0.68–1.20)] and repaglinide and [0.97 (0.81–1.15) and 1.29 (0.86–1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint Conclusions - Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
  5. Vildagliptin Add-on to Metformin: Effect on Blood Pressure in HypertensivePatients (SBP ≥140 mmHg and DBP ≥90 mmHg)This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1,2As hypertension is an important cardiovascular risk factor in diabetic patients, the effect of vildagliptin 50 mg twice daily on blood pressure was evaluated in a subset of patients with hypertension (systolic blood pressure [SBP] ≥140 mmHg and diastolic blood pressure [DBP] ≥90 mmHg).2Compared with placebo, vildagliptin 50 mg twice daily resulted in larger decreases in DBP (−4.0 vs −0.9) and SBP (−9.8 vs −6.3).1,2The effect seen on blood pressure needs further investigation but these reductions suggest a favorable effect of vildagliptin on blood pressure in hypertensive patients with T2DM.ReferencesBosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30: 890-895.Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL, 2165-PO.Vildagliptin Add-on to Metformin: Neutral Effect on Fasting LipidsThis 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1Change in lipid levels at 24 weeks was a secondary end point. Total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels did not change significantly over the 24-week treatment period in all treatment groups.1,2In patients receiving placebo while maintaining metforminmonotherapy, fasting triglyceride (TG) increased by 19% whereas in patients receiving vildagliptin50 mg once daily, fasting TG increased by 1% (P=0.014 vs placebo). In patients receiving vildagliptin 50 mg twice daily, fasting TG increased by 5% (P=0.052 vs placebo).Thus, vildagliptin has a neutral effect on the fasting lipid profile when added to metforminmonotherapy in patients with T2DM.ReferencesBosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30; 890-895.
  6. The biggest point to consider here is that Prospective data “will evaluate efficacy/safety”  however retrospective data with vildagliptin “has already proved efficacy/safety”Schweizer etal Diabetes Obes Metab. 2010 is a metaanalysis on &gt;7500 ptsVilda pooled data is an ongoing process.. Pharmocovigilance is onging processLina, Sita &amp; Saxa are doing prospective studies as a part of USFDA commitment.. Also worth commenting is that the study is just a non-inferiority study vs comparators and not a planned superiority study .Also USFDA states that any compound with OR &lt; 1.3 does not need a outcome study.... We all know our OR is 0.84 which is less than 1.3. We do not need a prospective study as we already have a pooled analysis confirming an OR of 0.84Relative risk is the ratio of the chance of a disease developing among members of a population exposed to a factor compared with a similar population not exposed to the factor
  7. No increase in cardiovascular risk—consistently adjudicated* CV events showing no increased risk relative to comparators† in more than 7500 patients‡2 [Schweitzer et al. 2010/pg 487/Col 1/Para 3/B; Fig. 1/A]No risk of weight gain—GALVUS is weight-neutral3 and weight gain itself is an independent risk factor for cardiovascular events4 [Bolli_Diabetes_Obes Metab. 2008/p86/col 1/para3] [Anderson 2001/pg 329S/col 2/para 2/A]