Update on Diabetes Drugs and CVD Risk Silvio E. Inzucchi, MD Sunday, February 19, 2017 11:30 a.m. – 12:15 p.m. The most common cause of death in patients with type 2 diabetes (T2DM) is cardiovascular disease (CVD.) However, to date, intensive control of the most obvious metabolic abnormality in this disease, namely hyperglycemia, has had little effect on reducing CV complications. Moreover, until recently, no individual diabetes medication has been convincingly proven to reduce overall macrovascular events in high-risk T2DM patients. This is despite the fact that several of these have been proposed to have beneficial effects on CV risk factors or markers of CV disease. In 2008, the FDA presented a Guidance to Industry, mandating the demonstration of CV safety in any new glucose lowering therapy. This has led to a series of large CV outcome trials initially set up to rule out any undue CV risk from these medications. This guidance was initially roundly criticized as futile and resulting in an inefficient use of financial resources. However, over the past 2 years, several of these outcome trials have demonstrated not only safety but actual effectiveness in reducing CV complications in these high-risk patients. The results of these trials will be reviewed and placed in historical context. Specific attention will be paid to EMPA-REG OUTCOME, IRIS, LEADER and SUSTAIN-6. Based on their results, the approach to glucose lowering in patients with T2DM and established CVD is apt to change dramatically over the next few years. References: 1. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient- centered approach. Update to a position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 38(1):140-149, 2015; Diabetologia 58(3):429-42, 2015. 2. Inzucchi SE, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 12(2):90-100, 2015 3. Fox CS, et al. Update on prevention of cardiovascular disease in people with Type 2 diabetes in light of recent evidence. A scientific statement from the American Heart Association and the American Diabetes Association. Circulation 132:691-718, 2015; Diabetes Care 38:1777–1803, 2015. 4. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117-28, 2015. 5. Lathief S, Inzucchi SE. Approach to diabetes management in patients with CVD. Trends Cardiovasc Med 26(2):165-79, 2016. 6. Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374:1321-31. 7. Inzucchi SE, et al. Pioglitazone prevents diabetes in insulin-resistant patients with cerebrovascular disease. Diabetes Care 39(10):1684-92, 2016 8. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322 9. Stamatouli AM, Inzucchi SE Implications of the EMPA-REG OUTCOME Trial for Clinical Care and Research. Curr Diabetes Rep 2016 16:131. doi:10.1007/s11892-016-0822-7 10. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375:1834-1844
Transcript
Update on Diabetes Drugs and CVD Risk Silvio E. Inzucchi, MD
Sunday, February 19, 2017 11:30 a.m. – 12:15 p.m.
The most common cause of death in patients with type 2 diabetes (T2DM) is cardiovascular disease (CVD.) However, to date, intensive control of the most obvious metabolic abnormality in this disease, namely hyperglycemia, has had little effect on reducing CV complications. Moreover, until recently, no individual diabetes medication has been convincingly proven to reduce overall macrovascular events in high-risk T2DM patients. This is despite the fact that several of these have been proposed to have beneficial effects on CV risk factors or markers of CV disease. In 2008, the FDA presented a Guidance to Industry, mandating the demonstration of CV safety in any new glucose lowering therapy. This has led to a series of large CV outcome trials initially set up to rule out any undue CV risk from these medications. This guidance was initially roundly criticized as futile and resulting in an inefficient use of financial resources. However, over the past 2 years, several of these outcome trials have demonstrated not only safety but actual effectiveness in reducing CV complications in these high-risk patients. The results of these trials will be reviewed and placed in historical context. Specific attention will be paid to EMPA-REG OUTCOME, IRIS, LEADER and SUSTAIN-6. Based on their results, the approach to glucose lowering in patients with T2DM and established CVD is apt to change dramatically over the next few years. References: 1. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-
centered approach. Update to a position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 38(1):140-149, 2015; Diabetologia 58(3):429-42, 2015.
2. Inzucchi SE, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 12(2):90-100, 2015
3. Fox CS, et al. Update on prevention of cardiovascular disease in people with Type 2 diabetes in light of recent evidence. A scientific statement from the American Heart Association and the American Diabetes Association. Circulation 132:691-718, 2015; Diabetes Care 38:1777–1803, 2015.
4. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117-28, 2015.
5. Lathief S, Inzucchi SE. Approach to diabetes management in patients with CVD. Trends Cardiovasc Med 26(2):165-79, 2016.
6. Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374:1321-31.
7. Inzucchi SE, et al. Pioglitazone prevents diabetes in insulin-resistant patients with cerebrovascular disease. Diabetes Care 39(10):1684-92, 2016
8. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322
9. Stamatouli AM, Inzucchi SE Implications of the EMPA-REG OUTCOME Trial for Clinical Care and Research. Curr Diabetes Rep 2016 16:131. doi:10.1007/s11892-016-0822-7
10. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375:1834-1844
Silvio E. Inzucchi MDYale School of MedicineNews Haven, Connecticut
American Diabetes Association64th Advanced Postgraduate Course
Washington, DCFebruary 19, 2017 1. More intensive glycemic control (HbA1c 7%, perhaps
lower) reduces microvascular complications in both T1DM and T2DM (RRR 25‐60%.)2. Impact of intensive glycemic control itself on macro‐vascular complications in T2DM is small (15% RRR), solely on non‐fatal MI, and, moreover, requires long‐term efforts before it is detected. (RRR in T1DM may be larger.)
4. Various diabetes drugs have been proposed to exert beneficial CV effects but, until recently, no individual agent has been conclusively shown to reduce events.
25 Years of Outcome Trials in Diabetes
3. There are some data to suggest an actual increased risk of CV mortality when overly stringent strategies are employed in high‐risk T2DM patients.
GLUCOSE
LIPIDS
OBESITY
INSULINRESISTANCE
INFLAMMATION
SMOKING
AGE
BP
MACROVASCULAR COMPLICATIONS
GENETICS
MICROVASCULAR COMPLICATIONS
BPGENETICS
The Puzzles of Diabetes & Its Complications
GLUCOSE
Fruchart JC. Circulation 2004;109:III15-III19Yau JW et al. Diabetes Care 2012;35:556-564MJ Fowler. Clin Diabetes 2008;26:77-82
++
‐‐
‐‐
peripheralglucose uptake
hepatic glucose production
pancreatic insulinsecretion
pancreatic glucagonsecretion
gutcarbohydratedelivery &absorption
incretineffect
HYPERGLYCEMIAHYPERGLYCEMIA?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Multiple Complex Pathophysiological Abnormalities in T2DM
renal glucose excretion
++
‐‐
‐‐
peripheralglucose uptake
hepatic glucose production
pancreatic insulinsecretion
pancreatic glucagonsecretion
gutcarbohydratedelivery &absorption
incretineffect
HYPERGLYCEMIAHYPERGLYCEMIA?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
ThiazolidinedionesMetformin
DPP-4 inhibitors
GLP-1Ragonists
Sulfonylureas
Insulin
Major Pathophysiologically‐Based Therapies for T2DM
UKPDS 34 Substudy: Metformin Improves CVD Outcomes vs. Standard Therapy
Myocardial Infarction
0
5
10
15
20
Inci
den
ce p
er 1
000
pat
ien
t ye
ars Coronary Deaths
0
2
4
6
8
10
Conventional /Diet
Insulinor
SU’s
Metformin
p=0.02
50%
Conventional /Diet
Metformin
p=0.01
39%
NS
UKPDS 34, Lancet 1998;352: 854-865N=951
Survival functions for the primary (lower pair of curves) and the secondary, macrovascular (upper pair of curves) end points. Metformin treatment was not associated with an improvement in the primary end point. It was, however, associated with a decreased risk of the secondary, macrovascular end point (hazard ratio, 0.61 [95% confidence interval, 0.40‐0.94; P = .02]). The number needed to treat to prevent 1 macrovascular end point was 16 (95% confidence interval, 9‐67).
Mean A1c: 7.5 vs. 7.9% Mean BMI: 31 vs. 30 kg/m2
Mean weight: 85 vs. 90 kgMean insulin dose: 67 vs. 84 units
Long‐term Effects of Metformin on Metabolism and Microvascular & Macrovascular Disease in Insulin‐treated Patients with T2DM
Kooy A et al. Arch Intern Med. 2009;16:616-625
HR 0.61 (0.40‐0.94) P=0.02
N=390
Only 16% on lipid‐lowering
therapy!
The “Common Soil” Hypothesis
Stern MP. Diabetes 1995; 44:369
Pioglitazone & MACE: Principal 2Endpoint from the PROactive trialKaplan-Meier event rate
N at risk: 5,238 5,102 4,991
Time from randomization (months)0 6 12 18 24 30 36
0.0
0.05
0.10
0.15
Pioglitazone
Placebo
N events:
301 / 2,605
358 / 2,633
3-year estimate:
12.3%
14.4%
4,877 4,752 4,651 786 (256)
HR 95% CI P
Pioglitazonevs. placebo
0.84 0.72, 0.98 0.027
Dormandy JA et al. Lancet 2005;366:1279-89. ( Primary Endpoint: HR 0.90 p=0.095 )
Hospitalization for heart failure:Pio 209 events in 149 pts (5.7%)
Placebo 152 events in 108 pts (4.1%)HR 1.41 (95% CI 1.10‐1.80)
p=0.007
- 57 events
+ 57 events
Heart Attack Risk Seen in Drug for Diabetes
Tuesday, May 22, 2007
Figure 2. Kaplan-Meier plots of time to the primary endpoint (cardiovascular death or cardiovascular hospitalisation).
Home PD et al. Lancet 2009;373:2125-2135
RECORD Trial: CV Safety Trial of Rosiglitazone
N=4447
HR 0.99 (95% CI, 0.85‐1.16)
BARI-2D ResultsBypass Angioplasty Revascularization Investigation in T2DM (BARI‐2D)
Mortality: P=0.89
Insulin provision87.9%
MACE: P=0.13
Insulin provision75.4%
Insulin sensitization88.2%
Insulin sensitization77.7%
• 2368 T2DM patients with stable CAD• Pre-assigned to CABG vs. PCI strata by cardiologist• Subsequent comparison of 2 anti-hyperglycemic strategies:
“insulin sensitization” (met + rosi) vs. “insulin provision” (SU + insulinBARI-2D Investigators. N Engl J Med 2009; 360:2503
20.3%25.2%
P=0.059
18.7%26.0%
P=0.066
BARI-2D Investigators. N Engl J Med 2009; 360:2503
Bypass Angioplasty Revascularization Investigation in T2DM (BARI‐2D)
Courtesy, Darren McGuire, UTSW Medical Ctr, 2015
“…sponsors should demonstrate that the therapy will not result in an unacceptable increase in CV risk.”
• Meta-analysis strategy using Phase 2/3 data
• Blinded central adjudication of CVD events
• Inclusion of high-risk subjects: advanced CVD, elderly, CKD
• Minimum exposure of 2 years in large CVOT
• Approximately 15,000 pt-yrs
1.0Hazard Ratio
1.81.3
Pre-marketing AnalysesUpper CL of 95% CI <1.8For a HR=1.0 ≈122 events
Post-marketing AnalysesUpper CL of 95% CI <1.3For a HR=1.0 ≈611 events
Kim Y et al. Diabetes Metab Syndr Obes. 2012;5:313‐327.Inzucchi SE et al. Diabetes Care 2015;38:140‐159
• Genital mycotic infections • ? UTIs• Polyuria / Dehydration• Diabetic Ketoacidosis (DKA)• Reversible GFR • Small LDL‐C• ? Fractures
• HbA1c ~0.6‐0.9% (insulin‐independent, irrespective of disease duration)
• Low hypoglycemia risk• Modest weight• Modest BP• Albuminuria• Small TGs• Small HDL‐C
BENEFITS
RISKS
*not approved for weight loss; BMI, WC, BP, TG, albuminuria reduction; or to increase HDL‐C
* Before CV outcomes trial(s)
N Engl J Med 2016; 373:2117‐28.
EMPA-REG OUTCOME®
Trial design
• Study medication was given in addition to standard of care.• Primary outcome: 3-point MACE• Analysis: Placebo vs. pooled empagliflozin groups• Key inclusion criteria:
– Adults with type 2 diabetes and established CVD– BMI ≤45 kg/m2; HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD)
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)
14%
N=7020
Zinman B et al. N Engl J Med 2015;373:2117-28
CV death
HR 0.62(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
38%
Zinman B et al. N Engl J Med 2015;373:2117-28
Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value
Favours empagliflozin Favours placeboCox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI
Zinman B et al. N Engl J Med 2015;373:2117-28
Hospitalization for heart failure
Cumulative incidence function. HR, hazard ratio
35%
Zinman B et al. N Engl J Med 2015;373:2117-28
N=7020
HR 0.65(95% CI 0.50, 0.85)
p=0.0017
WeightVisceral adiposity
WeightVisceral adiposity
BPArterial stiffness
BPArterial stiffness
GlucoseInsulinGlucoseInsulin
AlbuminuriaAlbuminuria
Uric AcidUric Acid
Novel Pathways (?)
↑LDL-C
↑HDL-CTriglycerides
↑LDL-C
↑HDL-CTriglycerides
Oxidative stress
Oxidative stress
SNS activity(?)
Inzucchi SE et al. Diab Vasc Dis Res 2015;12:90-100
Potential pathways to CV impact of SGLT2-inhibitors, based on clinical and mechanistic studies
Ketonemia???
Osmotic Diuresis /
Natriuresis???
Sattar N et al. Diabetologia 2016Ferrannini E et al. Diabetes 2016Weir M. Postgrad Med 2016
• 75 subjects with T2DM (mean age 56 yrs, disease duration 6.3 yrs)• Randomized to placebo, dapagliflozin 10 mg, or HCTZ 25 mg QD x 12 weeks• Diuretic properties on BP, weight, plasma volume, eGFR
placebo dapa hctzBP: D>H>P
Weight: D>H>P
eGFR: D>H>P
N Engl J Med 2016; 374:1321‐31.
Eligibility: Recent TIA or Ischemic StrokeNon-DiabeticInsulin Resistant (HOMA > 3.0)No CHF
IRIS Trial Design
RN=3895*
Placebo
Pioglitazone15mg→45 mg
Fatal/non-fatal MIFatal/non-fatal stroke
5 years
5 years
*90% power to detect a 20% RRR from 27% in the placebo group to 22% in the pioglitazone group at an alpha level of 0.05
ClinicalTrials.gov Identifier:NCT00091949Viscoli CM et al. Am Heart J 2014 Dec;168:823
IRIS Baseline FeaturesPioglitazone
(N=1939)Placebo(N=1937)
Age, mean years 63.5 63.5
Male sex 67% 64%
Black race 11% 12%
Mean BMI, mean kg/m2 29.9 ±5.6 30.0 ±5.3
Fasting glucose (mg/dl) 98 ±10 98 ±10
Impaired Fasting Glucose (IFG) - ADA 42% 41%
HbA1c (%) 5.8 ±0.4 5.8 ±0.4
Elevated HbA1c (≥5.7%) 65% 64%
HOMA-IR (mean) 5.5 ±2.8 5.4 ±2.7
Statin therapy 82.5% 82.4%
Anti-platelet therapy 92.0% 92.3%
SBP/DBP 133 ±18 / 79 ±11 133 ±17 / 79 ±11
IRIS Primary Outcome
80%
85%
90%
95%
100%
‐ 20 40 60
Months in Trial
CumulativeEvent-Free
SurvivalProbability HR 0.76
95% CI 0.62, 0.93; P=0.007RRR 24%, ARR 2.9%
Pioglitazone
Placebo
11.8%
9.0%
0
IRIS Secondary Outcomes
Pioglitazone (N=1939)
Placebo (N=1937)
Outcome* % (No.) % (No.)Hazard Ratio
(95% CI) P
Stroke 6.5 (127) 8.0 (154) 0.82 0.19
ACS 5.0 (96) 6.6 (128) 0.75 0.11
Stroke/MI/HF 10.6 (206) 12.9 (249) 0.82 0.11
DM 3.8 (73) 7.7(149
)0.48 <.0001
Death 7.0 (136) 7.5 (146) 0.93 0.52
*ACS=Acute coronary syndrome (unstable angina or MI). *HF=heart failure
IRIS Serious Adverse Events
# Participants
Pioglitazone(N=1939)
Placebo(N=1937)
Event % (N) P
Bone fracture† 5.1 (99) 3.2 (66) <0.01
Heart failure† 2.6 (51) 2.2 (42) 0.35
Incident cancer 6.9 (133) 7.7 (150) 0.29
†Previously reported to be associated with pioglitazone or drugs in its class.
This article was published on June 13, 2016, at NEJM.org.
DOI: 10.1056/NEJMoa1603827
Primary outcomeCV death, non-fatal MI, or non-fatal stroke
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatalmyocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and thehazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because lessthan 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.
Presented at the American Diabetes Association 76th Scientific Sessions, June 13 2016, New Orleans, LA
Primary and secondary CV outcomes*
*Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.†The primary composite outcome in the time-to-event analysis consisted of the first occurrence of death from cardiovascular causes (181 patients in the liraglutide group vs. 227 in the placebo group), non-fatal (including silent) myocardial infarction (275 vs. 304), or non-fatal stroke (152 vs. 163). The p-value is for superiority. ‡The expanded composite outcome included death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure. §This analysis was not prespecified. CI: confidence interval; CV: cardiovascular; UAP: unstable angina pectoris.
Presented at the American Diabetes Association 76th Scientific Sessions, June 13 2016, New Orleans, LA
3-point MACE 0.87 (0.78-0.97)
CV death 0.78 (0.66-0.93)
Nonfatal MI 0.88 (0.75-1.03)
Nonfatal stroke 0.89 (0.72-1.11)
HF hospitalization 0.87 (0.73-1.05)
Semaglutide & Cardiovascular Outcomesin Patients with Type 2 Diabetes
Marso SP et al. N Engl J Med. Sep 16, 2016; DOI: 10.1056/NEJMoa1607141
Metformin high low risk neutral/loss GI / lactic acidosis low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
high low risk gain edema, HF, fxs
low
Thiazolidine- dione
intermediate low risk neutral rare
high
DPP-4 inhibitor
highest high risk gain hypoglycemia variable
Insulin (basal)
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
Sulfonylurea
+ TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-dione +
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
or
or
or
GLP-1-RA
high low risk loss GI
high
GLP-1 receptor agonist
Sulfonylurea
high moderate risk gain hypoglycemia low
SGLT2 inhibitor intermediate low risk loss GU, dehydration high
SU
TZD
Insulin§
GLP-1 receptor agonist +
SGLT-2 Inhibitor +
SU
TZD
Insulin§
Metformin +
Metformin +
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono- therapy
Efficacy* Hypo risk Weight Side effects Costs
Dual therapy†
Efficacy* Hypo risk Weight Side effects Costs
Triple therapy
or
or
DPP-4 Inhibitor +
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Insulin (basal)
+
ADA‐EASD Position Statement: Managing Hyperglycemia in T2DM (2015 Update)
Diabetes Care 2015;38:140
• Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes. A
• If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target after 3 months, add a second oral agent, a glucagon‐like peptide 1 receptor agonist, or basal insulin. A
• In patients with long‐standing suboptimally controlled type 2 diabetes and established atherosclerotic cardiovascular disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all‐cause mortality when added to standard care. Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes. B
