Treating Diabetes To Lower
Cardiovascular Disease Risk
Anne Peters, MD
Professor, USC Keck School of Medicine
Director, USC Clinical Diabetes Programs
Disclosure of Financial Relationships—
2013/2014
Consultantship
Abbott Diabetes Care
BD
Janssen
Lilly
Medscape
Medtronic Minimed
NovoNordisk
Sanofi
Takeda
Speakers Bureau
BMS/AstraZeneca
NovoNordisk
Gregg EW et al. N Engl J
Med 2014;370:1514-1523
LDL Cholesterol Targets in Diabetes
4S
LIPID
CARE
Clinical Event Rate
Post CABG
ASCOT
HPS
Risk Attributable
to LDL-C
CARDS
PROVE IT
Residual Risk of CVD
? Role of other lipid and non-lipid factors
60
80
100
120
140
160
LDL Cholesterol (mg/dl)
180
200
220
UKPDS: “Legacy Effect” of Insulin/Sulfonylurea
Therapy
Aggregate Endpoint
1997
2007
Any diabetes related endpoint
RRR:
P:
12%
0.029
9%
0.040
Microvascular disease
RRR:
P:
25%
0.009
24%
0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
After median 8.8 years post-trial followup
RRR = Relative Risk Reduction
P = Log Rank
Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589
UKPDS: “Legacy Effect” of Insulin/Sulfonylurea
vs Metformin Therapy
Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589
Meta-Analysis of Glycemic Control Trials
and Coronary Heart Disease
Ray KK, et al. Lancet. 2009;373:1765-1772.
Hyperglycemia and Coronary Heart Disease
(CHD)
• Possible reasons that individual trials failed to
show a beneficial effect on CHD
– Event rates were lower than expected
– Differences in glycemic control were not large enough
– The intervention or observation period was too short
– Need to start intervention earlier in natural history of
the disease
Mazzone T. Lancet. 2009. 23;373:1737-1738.
Hyperglycemia and CHD (cont’d)
• Conclusions
– Do not discount the benefits of managing
hyperglycemia
• Reduced microvascular disease well established
• Premature to conclude that glucose control plays no part in
CHD residual risk
• Benefits of glucose control will be less than BP and lipid control
– Additional studies needed to evaluate the effects of
controlling hyperglycemia on CHD risk
Mazzone T. Lancet. 2009. 23;373:1737-1738.
11
10
SGLT-2 I
Dopamine agonists
Renin inhibitors
Angiotensin II
Bile acid
receptor
sequestrants
blockers
DPP-4
ACE
inhibitors
Inhibitors
Ca+ channel
Amylinomimetics
blockers
GLP-1
peripheral
Receptor
-1 blockers
Agonists
HTN and DM: Drug Classes
in US Over Past Half Century
Number of Medication Classes
9
8
7
- blockers
6
5
4
3
2
‘Glinides
Thiazolidinediones
central
-2 agonists
-glucosidase
inhibitors
diuretics
adrenergic
neuronal
blockers
Biguanides
Biguanides
vasodilators Sulfonylureas
1
insulin
Slide from: Inzucchi S.
1950
1960
1970
1980
1990
2000
2010
Management of Hyperglycemia in Type 2
Diabetes: A Patient-Centered Approach
Position Statement of the American Diabetes Association (ADA) and
the European Association for the Study of Diabetes (EASD)
Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596
The ADA/EASD Position Statement on Management of
Hyperglycemia in Type 2 Diabetes
ADA
Richard M. Bergenstal MD
Int’l Diabetes Center, Minneapolis, MN
EASD
Michaela Diamant MD, PhD
VU University, Amsterdam, The Netherlands
John B. Buse MD, PhD
Ele Ferrannini MD
Anne L. Peters MD
Michael Nauck MD
Richard Wender MD
Apostolos Tsapas MD, PhD
Silvio E. Inzucchi MD (co-chair)
David R. Matthews MD, Dphil
University of North Carolina, Chapel Hill, NC
Univ. of Southern California, Los Angeles, CA
Thomas Jefferson University, Philadelphia, PA
Yale University, New Haven, CT
University of Pisa, Pisa, Italy
Diabeteszentrum, Bad Lauterberg, Germany
Aristotle University, Thessaloniki, Greece
Oxford University, Oxford, UK
Impact of Intensive Therapy for Diabetes:
Summary of Major Clinical Trials
Study
Microvasc
UKPDS
 



DCCT /
EDIC*
 


 
ACCORD



ADVANCE
VADT
CVD
Mortality







Kendall DM, Bergenstal RM. © International Diabetes Center 2009
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)
Initial Trial
Long Term Follow-up
* in T1DM
Risk of CV Events and Death in Patients With Versus
Without Severe Hypoglycemia (ADVANCE)
Study inclusion criteria: T2DM + major vascular disease or ≥ 1 CV risk factor
Macrovascular events
3.45 (2.34-5.08); P < .001
Death—any cause
3.30 (2.31-4.72); P < .001
Death—CV cause
3.78 (2.34-6.11); P < .001
Death—non-CV cause
2.86 (1.67-4.90); P < .001
Decreased
risk
Adjusted Hazard Ratio (95% CI)
Increased
risk
Zoungas S, et al; ADVANCE Collaborative Group. N Engl J Med. 2010;363:1410-1418.
Lessons from Accord
Severe Hypoglycemia and Mortality Risk
ACCORD
ADVANCE
VADT
Severe Hypo
Intensive
Standard
Intensive
Standard
Intensive
Standard
(%/ year)
3.1%
1.1%
0.7%
0.4%
12.0%
4.0%
Annual mortality
5.0%
4.9%
4.0%
2.8%
3.0%
2.0%
1.0%
1.3%
1.0%
0.0%
Intensive
Standard
Bonds et al. BMJ 2010;340:b4909
Severe Hypoglycemia in ACCORD
• “Patients with type 2 diabetes who experience
symptomatic, severe hypoglycaemia are at
increased risk of death, regardless of the intensity of
glucose control.”
• “The increased risk of death seen in the ACCORD
trial among participants in the intensive glycaemia
control arm cannot be attributed to the increased
rate of severe hypoglycaemia in intensive arm
participants.”
Bonds et al. BMJ 2010;340:b4909
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
ANTI-HYPERGLYCEMIC THERAPY
•
Glycemic targets
-
HbA1c < 7.0% (mean PG ∼150-160 mg/dl [8.3-8.9 mmol/l])
-
Pre-prandial PG <130 mg/dl (7.2 mmol/l)
-
Post-prandial PG <180 mg/dl (10.0 mmol/l)
-
Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, comorbidities,
hypoglycemia prone, etc.
-
Avoidance of hypoglycemia
PG = plasma glucose
Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596
Figure 1
Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
1. Patient-Centered Approach
“...providing care that is respectful of and responsive to
individual patient preferences, needs, and values ensuring
that patient values guide all clinical decisions.”
• Gauge patient’s preferred level of involvement.
• Shared decision making – final decisions re: lifestyle
choices ultimately lies with the patient.
• Explore, where possible, therapeutic choices.
• Utilize decision aids.
Diabetes Care 2012;35:1364–
1379
Lifestyle: “Easy” Recommendations for Patients
• Eat breakfast
• Keep a regular eating schedule
• Don’t skip meals
• Identify and avoid stress triggers for eating
• Don’t take “seconds”
• Choose fruits for dessert
• Drink a lot of water (at least 8 glasses each day)
• No late-night eating
Metformin: The Only Choice in Type 2 DM?
• Most commonly used therapy for T2 DM (2/3rds of
patients)
• Clinical effects
• Lowers A1C 1-2% (especially at high baseline A1C), no weight gain
• Maximal clinical effect at 1500-2000 mg/day
• Possible side effects and precautions
• GI side effects common – less well tolerated by up to 10%
• Not advised if significant renal or liver disease, heart failure (~20%)
• Other features
• Lower CV risk in obese patients (UKPDS)
• Extensive clinical experience and lower cost
• ? Favorable impact on cancer risk and mortality
Sulfonylureas and the Secretagogues
How Do We Use Them Now?
• Most common (traditional) 2nd agent in T2 DM
• Stimulate insulin release – during hyperglycemia and post-meal
• Clinical Use
• Inexpensive and commonly used, rapid glucose lowering
• Limited dose effect and limited “durability” of effect
• Side effects
• Associated with weight gain and risk of hypoglycemia
• Precautions and contraindications
(elderly, renal disease)
• Highest risk of hypoglycemia with GLYBURIDE
• May not be good for those at CVD risk (longstanding discussion)
• Associated with risk of severe hypoglycemia
Thiazolidinediones (TZDs)
Do We Target Insulin Resistance?
• Clinical application
• Targeted patients with clinical markers of insulin resistance
• Dyslipidemia, HTN, established CVD, central obesity
• May limit CVD risk and alter progression of diabetes
• Adverse effects and considerations
• Significant weight gain and increase risk of edema and HF
• Increased risk of long-bone fractures
• Macular edema
• Patient selection
• Higher CVD risk – particularly with dyslipidemia, est. CVD
• Those at lower risk for fracture and with central obesity, NASH
Grey A et al. J Clin Endocrinol Metab. 2007;92:1305-1310.
Summary Of Pioglitazone Clinical Trials
Center for Drug Evaluation & Research, July 30, 2007
PIO Meta-analysis
- without PROactive
0.75
#CV Events
# of Subjects
0.84
PROactive
PIO Meta-Analysis
plus PROactive
0.83
0.5
0.75
1.0
Hazard Ratio
PIO
COMP
375
8554
450
7836
Physiological Actions of GLP-1
Neuroprotection
Appetite
Cardioprotection
Cardiac output
Reduce BP
Gastric emptying
GLP-1
Glucagon secretion
Insulin secretion
Insulin biosynthesis
β cell proliferation
β cell apoptosis
Glucose production
Glucose disposal
Sodium excretion
Cardiovascular Effects of GLP-1-Based
Therapies
Improved weight, SBP, lipids
 Improved endothelial function
 Increased vasorelaxation
 Increased peripheral and coronary flow
 Increased ventricular function
 Decreased microvascular permeability
 Reduced inflammation
Effects in isolated vessels/hearts and GLP-1R
localization to CV tissues indicate some effects may
be direct

Okerson T, Chilton R. Cardiovasc Ther 30:e146-55, 2012
GLP-1 Secretion and Inactivation
Mixed
meal
Intestinal
GLP-1
release
GLP-1
active
GLP-1 Agonists
• A1c
reduction
Exenatide
• Weight
loss
Liraglutide
• Albiglutide
No hypos
• Injectable
Dulaglutide
• GI side effects
DPP-4
DPP-4 Inhibitors
• A1c
reduction
Sitagliptin
• Weight
neutral
Saxagliptin
DPP-4
inhibitor
GLP-1
inactive
• No
hypos
Linagliptin
• Alogliptin
Few SE’s/pill
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
DPP-4 Inhibitors: Sitagliptin (Januvia), Saxagliptin
(Onglyza), Linagliptin (Tradjenta) and Alopglitin (Nesina)
• Clinical Use
• Moderate effectiveness (A1C reduction ~0.5-0.8%)
• Use in both combo and mono therapy
• Unique Features
• Limited side effect profile, very well tolerated, pancreatitis?
• Weight neutral, no significant weight loss, no hypoglycemia
• Variable clinical response (A1C reduction 0.2-1.1%)
• Reduced dosing in chronic kidney disease (except for
linagliptin)
• Saxagliptin increased risk of CHF in high risk
population
SAVOR-TIMI 53: No Impact of Saxagliptin on
Primary Outcome (MACE)
Scirica BM et al: N Engl J Med 369:1317-1326; 2013
EXAMINE: No Impact of Alogliptin on the
Primary Outcome (MACE)
White WB et al: N Engl J Med 369:1327-1335; 2013
SAVOR-TIMI 53: Prespecified
Clinical End Points
Scirica BM et al: N Engl J Med 369:1317-1326; 2013
SAVOR-TIMI 53: Safety End Points
Scirica BM et al: N Engl J Med 369:1317-1326; 2013
EXAMINE: Other Safety End Points
White WB et al: N Engl J Med 369:1327-1335; 2013
Newest Drugs on the US Market
GLP-1 RA
Daily
• Exenatide (BID) (Byetta)
• Liraglutide (Victoza)
Weekly
• Exenatide (Bydureon)
• Albiglutide (Tanzuem)
• Dulaglutide (Trulicity)
SGLT-2 Inhibitors
• Canagliflozin (Invokana)
• Dapagliflozin (Farxiga)
• Empagliflozin (Jardiance)
Structure of US Approved GLP-1 RAs
Diabetes Metab Syndr Obes. 2009 May 15;2:37
Albiglutide
GLP-1
H A E G T F
T S D V S S Y L
E G Q A A K E F
I
A W L
V K G R G
(7-37) amide
Site of proteolytic inactivation (DPP-4)
7
10
15
20
25
30
35
37
Albiglutide
H A E G T F
T S D V S S Y L
E G Q A A K E F
I
A W L
V K G R
H A E G T F
T S D V S S Y L
E G Q A A K E F
I
A W L
V K G R
Albumin
• 2 GLP-1 molecules in tandem
• Covalently bound to albumin
• DPP-4 resistant
• Half-life ~ 6-7 days
Drucker D, et al. Lancet. 2006;368:1696-1705. Bush M, et al. Diabetes Obesity Metabolism. 2008 (in press).
Pratley/Endo//14Jun13
Dulaglutide
Exenatide Added to Basal Glargine
0.5
OG + EXE BID (Baseline 8.3 ± 0.1%)
OG + PLB BID (Baseline 8.5 ± 0.1%)
A1C Change (%)
0
-0.5
7.41 ±
0.09%
-1
-1.5
-2
6.70 ±
0.09%
0%
18%
LS Weeks
mean ± SE
Buse JB, et al. Ann Intern Med. 2011;154(2):103-112.
30%
Exenatide Added to Basal Glargine
2
OG + EXE BID (Baseline 95.4 ± 1.7 kg)
Change in Body Weight (kg)
1.5
OG + PLB BID (Baseline 93.8 ± 1.8 kg)
1
0.5
0.96
0
*
-0.5
*
*
-1
*
-1.5
*
*
*
*
*
*
-2.0
1.78
-2.5
-3
0
2
4
6
8
10
14
Weeks
LS mean ± SE *P<.001 between-treatment comparison
Buse JB, et al. Ann Intern Med. 2011;154(2):103-112.
18
22
26
30
Effects of Liraglutide on Systolic BP With or
Without Concomitant Antihypertensive Agents
Meta-analysis of 6 × 26-week clinical trials (N = 3967)1
PBO
Change in SBP (mm Hg)
Overall
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
LIRA (1.8 mg)
With antihypertensive No antihypertensive
0.76
-0.19
-1.13
-2.03
-2.55
a
a
-3.07
a
Fonseca V, et al. 70th ADA Scientific Sessions. 2010:296-OR.
a
P < .05 vs PBO.
GLP-1 RAs Improve
Lipid Profiles in Patients With T2DM
EXN BID
0
LEAD-61
26 weeks
-10
-20
-30
-40
Significantly greater change vs EXN BID.
EXN QW
DURATION-12
30 weeks
5
Δ Lipid Level (mg/dL)
Δ Lipid Level (mg/dL)
10
LIRA
a
0
-5
a
-10
-15
a
-20
-25
-30
1. Buse J, et al. Lancet. 2009;374:39-47;
2. Drucker DJ, et al. Lancet. 2008;372:1240-1250.
Anti-Inflammatory Effects of GLP-1 RAs in
Patients With T2DM
LIRA (1.9 mg, 1 X daily) vs PBO
14 weeks (N = 165)2
MCP-1
PAI-1
SAA
IL-6
60
40
20
0
-20
-40
-60
-15
a
-16
a
-22
a
Δ Inflammatory Markers
from BL (%, 95% CI)
Δ Inflammatory Markers
from BL (%± SE)
EXN (10 mcg, 2 X daily) vs PBO
12 weeks (N = 24)1
EXN BID also significantly reduced mononuclear cell
• Production of reactive oxygen species (ROS)
• NFκB activation
• TNFα and IL-1β expression
BL, baseline; BNP, B-type natriuretic peptide; MCP-1, monocyte
chemoattractant protein-1; PBO, placebo; SAA, serum amyloid A.
a P < .05 vs baseline and control; b P < .05 vs baseline.
BNP
IL-6
60
40
20
0
-20
-40
-60
-25
b
-2
-38
b
1. Chaudhuri A, et al. J Clin Endocrinol Metab. 2012;97:198-207.
2. Courrèges J, et al. Diabetic Med. 2008;25:1125-1131.
Incretin Cardiovascular Outcome Trials
Risk Factors
Stable CAD-CVD-PAD
ACS patients
EXAMINE Alogliptin n=5,400
SAVOR-TIMI 53 - Saxagliptin
n=16,500
TECOS - Sitagliptin
n=14,000
CARMELINA (vs pbo) - Linagliptin
n=8,300
CAROLINA (vs SU) - Linagliptin
n=6,000
September 2013
December 2014
January 2018
September 2018
ELIXA Lixisenatide
n=6,000
LEADER - Liraglutide n=9,340
SUSTAIN 6 - Semaglutide n=3,297
September 2013
January 2015
October 2015
January 2016
EXSCEL - Exenatide LAR n=14,000
April 2018
REWIND - Dulaglutide n=9,622
April 2019
SGLT-2 Inhibitors—Canagliflozin, Dapagliflozin, Empagliflozin
Clinical Effects
• Novel mechanism of action/oral agent
• Most will respond—action independent of beta-cell function
• A1C reduction ~1% with 2-3 kg weight loss
Possible Side Effects and Precautions
• Mycotic genital infections
• Findings due to volume depletion
• Don’t use if eGFR <45%
Other Features
• Lowers BP slightly
• Raises LDL cholesterol
Jacobsen LV, et al. Br J Clin Pharmacol. 2009;68:898-905. Linnebjerg H, et al. Br J Clin Pharmacol. 2007;64:317-327.
The Prospect of SGLT2 Inhibition
RENAL HANDLING OF GLUCOSE
(180 L/day) (900 mg/L) = 162 g/day
SGLT 2
S
G
L
T
1
90%
10%
NO
GLUCOSE
SGLT2 Inhibitors Lower Renal Threshold
for Glucose Excretion (RTG)
Urinary glucose excretion (g/day)
125
T2DM +
SGLT2
inhibition
100
75
Healthy
180 mg/dL
RTG
RTG
T2DM
240 mg/dL
RTG
50
SGLT2 inhibition
25
0
50
100
150
200
250
300
Plasma glucose (mg/dL)
Adapted with permission from Abdul-Ghani MA, DeFronzo RA.
T2DM = type 2 diabetes mellitus.
1. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 2. Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95(1):34-42.
Effect of Canagliflozin on A1C as Mono or
Combination Therapy
Canagliflozin Add-on1,2
Dual
Mono1
+Met
(N = 584) (N=1284)
7.94 7.95
+SU
(N=127)
+Met
+ SU
(N=469)
+Met
+ Pio
(N=342)
8.29 8.28
8.13 8.13
7.99 7.96
Older
subjects1-3
+Insulin
± AHAs* ± AHA
(N=1718) (N=714)
7.7
8.33 8.27
LS Mean Change From Baseline in
A1C (%)
Placebo-Subtracted Difference
Baseline A1C (%) 8.06 8.01
Triple
*Studies for combinations including SU or insulin were 18 weeks in duration; all others were 26 weeks in duration.
†P<0.001 for reduction vs control.
1. INVOKANA™ [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 2. US Food and Drug Administration. Available
at:http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm33623
6.pdf. Accessed May 02, 2014. 3. Bode B, et al. Hosp Pract. 2013; 41:72-84.
Percent Change in Body Weight
LS mean
% change
–0.6%
(–0.5 kg)
–2.8%
(–2.5 kg)
–3.9%
(–3.4 kg)
0
6
12
18
26
Time point (wk)
PBO = placebo; CANA = canagliflozin; LS = least squares; SE = standard error
mITT = modified intent-to-treat; LOCF = last observation carried forward
Stenlöf et al, 2013.
–2.2%
(–1.9 kg)
P <0.001
–3.3%
(–2.9 kg)
P <0.001
Canagliflozin and Dapagliflozin Warnings and
Precautions
o Hypoglycemia: risk with secretagogues and/or
o
o
o
o
o
RxList, 2014.
insulin
Genital mycotic infections
Volume depletion/orthostatic changes
Hypersensitivity
Increased LDL
Bladder cancer: don’t use if active; use with
caution if prior history of bladder cancer
(dapagliflozin only)
Dapa/Cana/Empa in Patients with Renal
Impairment
Both dapagliflozin and canagliflozin are contraindicated in
patients with severe renal impairment, ESRD, or on dialysis:
Canagliflozin
– Contraindicated in patients with eGFR <45 ml/min/1.73 m2 and should
be discontinued in patients if eGFR falls to <45 ml/min/1.73 m2
– Dose is limited to 100 mg once daily in patients with eGFR
45-<60 ml/min/1.73 m2
Dapagliflozin
– Contraindicated in patients with eGFR <60 ml/min/1.73 m2 and should
be discontinued in patients if eGFR falls to <60 ml/min/1.73 m2
Empagliflozin
Contraindicated if eGFR <45 ml/min/1.73 m2
Drugs.com, 2014.
Bristol-Myers Squibb, 2014.
Volume Reductions Observed with Canagliflozin and
Dapagliflozin: Results from Clinical Trials
o SGLT2 inhibitors cause osmotic diuresis that may result in intravascular
volume reductions
Pool of 12 placebo
controlled studies*
Pool of 8 clinical trials†
Pool of 13 placebo
controlled studies*
Placebo
Dapa
5 mg
Dapa
10 mg
Placebo
Dapa 10 mg
Comparator
group**
Cana 100
mg
Cana 300
mg
Overall
population
0.4%
0.6%
0.8%
0.7%
1.1%
1.5%
2.3%
3.4%
Patients
on loop
diuretics
1.8%
0
9.7%
1.5%
2.5%
4.7%
3.2%
8.8%
eGFR ≥30
and <60
ml/min/1.7
3 m2
1.9%
0.9%
1.1%
1.5%
1.9%
2.5%
4.7%
8.1%
≥65-years
of age
0.4%
0.5%
1.5%
0.8%
1.7%
NR
NR
NR
NR
NR
NR
NR
NR
2.6%
4.9%
8.7%
≥75-years
of age
*Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.
**Includes placebo and active-comparator groups. † Patients could have more than 1 of the listed risk factors.
Farxiga.com, 2014.
Invokana.com, 2014.
When Goal is to Avoid Hypoglycemia
Reducing CVD Risk Treating T2DM
o Use statins, control BP, give aspirin
o Use diabetes drugs that don’t cause
o
o
o
o
o
RxList, 2014.
hypoglycemia
Improve control early and maintain it
Pioglitazone potentially beneficial based on
clinical trial data
GLP-1 RA’s and SGLT-2 I’s reduce BP
GLP-1 RA reduce inflammatory markers
TZD’s and ?DPP-IV increase CHF risk
Thank You
RxList, 2014.