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Elizabeth J. Murphy, MD, DPhilJune 15, 2020
What Diabetes Medicine Do I Use When?
I have no financial interests or relationships to disclose.
Today• Overview of the advantages and disadvantages of the different classes of drugs (thinking like an internist)
• Review the data (as of now) for cardiovascular and renal outcomes
• Practice critical review of diabetes drug comparator studies• Put some of it together? • Won’t cover:
– Insulins– Role of CGM and insulin pumps
Diabetes Care. Published online Oct 22, 2008
2008 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm
An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion.
Revised Consensus Algorithm - ADA and EASDDiabetes Care 31:173, 2008.
Diabetes Care, Diabetologia. 19 April 2012
Less Well‐Validated Buffet for DM2
ADA Standards of Medical Care in Diabetes 2017
Glucose-lowering medication in type 2 diabetes: overall approach.
Diabetes Care 2020;43:S98-S110
Decision cycle for patient‐centered glycemic management in type 2 diabetes. Davies MJ, D’Alessio
DA, Fradkin J, et al. Diabetes Care 2018;41:2669–2701.
Diabetes Complications in the US
Microvascular• Retinopathy, nephropathy, neuropathy• Leading cause of
– end stage renal disease– blindness – non‐traumatic amputations
Macrovascular• CAD, stroke, PVD • 2 x increase risk for CVD death• 2‐4 x increased risk of stroke• Prevalence of DM in patients
hospitalized for HF > 40% • DM is strongest risk factor for PVD
(OR 2.72)
Managing Complications
• Tight glucose control reduces microvascular complications– The lower you go the better– The earlier in the disease the better– Effects last long after tight control is over
• Tight glucose control early in the disease reduces macrovascular complications many years later
• BP control reduces micro and macrovascular complications• Lipid management reduces macrovascular complications
12
Tight Control Trials 1970s‐1990s
• United Kingdom Prospective Diabetes Study (UKPDS) ‐ Type 2 DM
• Diabetes Control and Complications Trial (DCCT) and follow on Epidemiology of Diabetes Interventions and Complications (EDIC) ‐ Type 1 DM
13
Tight Glucose vs Tight Blood Pressure Control in the UKPDS
StrokeAny Diabetic
EndpointDM
DeathsMicrovascularComplications
-50
-40
-30
-20
-10
0
% R
edu
ctio
n I
n R
elat
ive
Ris
k
Tight Glucose Control
32%
10%12%
5%
+ P < 0.05 compared to conventional rx*P <0.05 compared to glucose control Turner RC, et al. BMJ. 1998;317:703-713.
+
+
Tight BP Control+*
+*
37%
32%
24%
44%
+*+*
7% v. 7.9% A1C
Nathan D for the DCCT/EDIC Research Group Diabetes Care 2014;37:9‐1614
15JAMA 2003;290:2159‐2167.
DCCT/EDIC –T1DMTight Control A1C 7.2 v Usual Care 9.1%
Prevalence and Incidence of Albuminuria
EDIC Both Groups A1C 8%
N Engl J Med 2005;353:2643-2653
DCCT/EDIC ‐ Cumulative Incidence CVD Outcomes42% reduction in CVD risk57% reduction in risk of nonfatal MI, stroke or CVD death
8.0 v 8.1 % A1C[----------------------------------------------]
A1C 7.2 v 9.1%
At 30 y Follow up30% reduction in CVD risk32% reduction in risk of nonfatal MI, stroke or CVD death
1980s
9%
BeforeDCCT,UKPDS
SulfonylureaInsulin
1990s
8%
AfterDCCT
+ Metformin
1997
+ TZD
7%
AfterDCCT,UKPDS
Glycemic Targets Over the Years
Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Diabetes Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States,
1980–2008
http://www.cdc.gov/diabetes/statistics/esrd/fig7.htm
1980s
9%
BeforeDCCT,UKPDS
SulfonylureaInsulin
1990s
8%
AfterDCCT
+ Metformin
1997
+ TZD
7%
AfterDCCT,UKPDS
Glycemic Targets Over the Years
2006
+ Incretin
? 6% And focus on CVD prevention
1980s
9%
BeforeDCCT,UKPDS
SulfonylureaInsulin
1990s
8%
AfterDCCT
+ Metformin
1997
+ TZD
7%
AfterDCCT,UKPDS
Glycemic Targets Over the Years
2006
+ Incretin
? 6%
Follow on Effects
• FDA mandated CV outcome trials for safety• Recognition that tight control in established CVD is likely not beneficial
1980s 1990s 1997
9%
BeforeDCCT,UKPDS
SulfonylureaInsulin
8%
AfterDCCT
+ Metformin + TZD
7%
AfterDCCT,UKPDS
Glycemic Targets Over the Years
2006
+ Incretin
? 6%
7%
AfterACCORD
2008+ Mortality
A1C Goal
Efficacy
ComorbiditiesComplications (CKD, obesity,
HF, CAD)
Adverse EffectsRisks/Hypoglycemia
PatientAcceptance
Cost
CardiovascularBenefit/Harm
A1C Targets• < 7% ‐ is appropriate for many nonpregnant adults. A• < 6.5% ‐might be reasonable for select patients C• < 8% (“less stringent A1C goals”) may be appropriate if: (B)
– h/o severe hypoglycemia– limited life expectancy– advanced micro or macrovascular complications– extensive comorbid conditions– longstanding DM and can’t get to goal despite trying really hard
ADA Diabetes Standards of Care 2020
25
A1C COST
Metformin 1-2% $4 $4Sulfonylurea 1-2% $5 $4Pioglitazone 0.5-1.5% $20 $11Exenatide 0.5-1.5% $450 $728Canagliflozin 0.5-1.0% $330 $520Sitagliptin 0.5-0.8% $320 $475Acarbose 0.5-0.8% $30 $19
Good Rx.com10/2014 6/2020
$498$731
$455
10/2019
Metformin
Advantages• Lowers A1C 1.5‐2%• Weight loss (0‐2 kg)• Lowers TG, LDLc; Increases HDLc• Data supports decrease in CVD
mortality and perhaps all cause mortality
• No hypoglycemia when used alone• Inexpensive
Disadvantages• Majority of patients with GI SE• Minimal risk of lactic acidosis• Impairs B12 absorption• Need to stop when GFR < 30
26
SulfonylureasAdvantages• Lowers A1C 1.5‐2%• Inexpensive
Disadvantages• Weight gain• Hypoglycemia
27
CVD???
MEDPAGE TODAY
Antonios Douros et al. BMJ 2018;362:bmj.k2693
Forest plot summarising the primary analysis and all sensitivity analyses
77,138Metformin Monotherapy Users
25,699Adding or switching to SU
13,217Adding SU
9,800Switching to SU
0.5 2.5 4.5 6.5 8.5
Myocardial InfarctionAdding SUSwitching to SU
Ischemic StrokeAdding SUSwitching to SU
CV DeathAdding SUSwitching to SU
All Cause MortalityAdding SUSwitching to SU
Adjusted HR(95% CI)
Adding a sulfonylurea to metformin does not increase the risk of cardiovascular disease but replacing metformin with a sulfonylurea does
MEDPAGE TODAY
SulfonylureasAdvantages• Lowers A1C 1.5‐2%• Inexpensive
Disadvantages• Weight gain• Hypoglycemia
35
CVD: The Jury’s Still Out
Thiazolidinediones (rosiglitazone, pioglitazone)
(PPAR‐γ Agonists)
Advantages• Lowers A1C 0.5‐1.5%• No hypoglycemia when used alone• Inexpensive• Likely benefit in fatty liver and NASH• Benefit shown in diabetes prevention
Disadvantages• Weight gain (2‐5 kg)• Increased fracture (osteoporosis) and
bladder cancer• Edema (up to 30% of patients)• Contraindicated in HF
36
Notes: ‐ Stop TZDs when insulin is started‐ Effectiveness is very patient dependent, stop if it’s not doing anything
Thiazolidinediones – CVDGood• Benefit post stent/revascularization• Benefit after stroke/TIA in insulin
resistant patients without diabetes1
• Some studies with decreased death, MI, Stroke2
Not So Good• Increases rates of serious HF• Some studies with increased mortality
37
1N Engl J Med 2016; 374:1321‐1331. 2JAMA 2007; 298: 1180‐1188
Preference for pioglitazone
The Incretins
Normal Control Subject
Insulin Response to Oral vs Intravenous Glucose
J Clin Invest 1967; 46:1954-1962
OralIntravenous
60
Insu
lin (
U/m
L)
30
00 60 120 18030 90 150
90
Minutes
GIP, GLP-1, CCK
Reduced in DM2
T1/2 2-5 minutes
Breakdown by DPPIV
DPPIV Inhibitors (gliptins)
Advantages• No hypoglycemia when used alone• ?
Disadvantages• Poor A1C lowering (0.5‐0.8%)• Expensive• Possibly higher rates of admission for
HF (worse with sitagliptin?), otherwise CV neutral
• Pancreatitis?• Joint pain?
40
Notes: ‐ Weight neutral‐ Stop when insulin is started‐ Don’t start if you are more than 0.8% from your A1C goal
41
CD26• Expressed on the surface of most cell types• T‐cell activation marker• 62 known substrates • Tumor suppressor role• Inhibitors inhibit T‐cell proliferation
• Good or evil: CD26 and HIV infection. J Derm Sci. 2000; 22:152‐60.
• Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008;13:2299‐310.
• Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci. 2008 13:2435‐43.
/DPPIV
DPPIV Inhibitors (gliptins)
Advantages• No hypoglycemia when used alone• ?
Disadvantages• Poor A1C lowering (0.5‐0.8%)• Expensive• Possibly higher rates of admission for
HF (worse with sitagliptin?), otherwise CV neutral
• Pancreatitis?• Joint pain?
42
Notes: ‐ Weight neutral‐ Stop when insulin is started‐ Don’t start if you are more than 0.8% from your A1C goal
‐ Immune modulating effects (good or bad?)‐ Be cautious in HIV disease
‐Glucosidase Inhibitors (acarbose)Advantages• No hypoglycemia when used alone• Weight loss or weight neutral• Inexpensive• Benefit shown in diabetes prevention
Disadvantages• Poor A1C lowering (0.5‐0.8%)• GI side effects (gas/bloating)
43
Notes: ‐ Limited data shows CVD neutral‐ Don’t start if more than 0.8% from A1C goal‐ Need glucose for hypoglycemia
GLP‐1 AnaloguesAdvantages• Good A1C lowering (0.5‐1.5%)• Excellent weight loss (2‐4 kg)• No hypoglycemia when used alone• Some require only once a week
injection
Disadvantages• GI side effects (nausea, vomiting,
diarrhea, abdominal pain)• Injectable except for oral semilgutide• Expensive• Pancreatitis? • Risk of C‐cell tumors (medullary thyroid
cancer – h/o other thyroid cancers not a contraindication)
44
Heloderma suspectumGila Monster
CVD AND RENAL OUTCOMES?
Liraglutide (Victoza GLP-1): CV outcomes
Marso SP et al. N Engl J Med 2016;375:311-322
CV DeathHR 0.78*
Marso SP et al. N Engl J Med 2016;375:311-322
1° OutcomeHR 0.87*
Nonfatal Stroke, NS
Nonfatal MI, NS
Marso SP et al. N Engl J Med 2016;375:311-322
Marso SP et al. N Engl J Med 2016;375:311-322
Liraglutide (Victoza): CV outcomes
DeathHR 0.85*
HF Hosp, NS
Mann et al. N Engl J Med 2017;377:839
Liraglutide (Victoza): Renal Outcomes
HR 0.78*
GLP‐1 Agonists and Renal Outcomes
• All analyses are secondary analysis and the majority of data is in high CVD risk folks
• Consistently suggest renal protective effect• Across the board 17% RR reduction• Driven primarily by decrease in urinary albumin excretion/new macroalbuminuria
• Need trials with primary endpoint of hard renal outcomes
GLP‐1Agonists Trade Name Indication Cost/month
(Good Rx.com 6 2020)
Abliglutide Tanzeum NA
exenatide Byetta/Bydureon 1. Glucose control $731/$691
dulaglutide Trulicity1. Glucose control2. Reduce risk of major CV events
in patients with established CVD or multiple CV risk factors
$693
liraglutide
(a) Victoza(b) Saxenda
1. Glucose control2. Reduce risk of major
cardiovascular events in patients with established CVD.
1b. Chronic weight management
$963
$1288
semaglutide Ozempic(b) Rybelsus
1. Glucose control1b. Glucose control
$808$770
lixisenatide Adlixin 1. Glucose control $645
GLP‐1 Agonists Indications in Adults (with DM2)
SGLT1
(180 L/day) (900 mg/L)=162 g/day
10%
Glucose
No Glucose
S1
S3
Renal Handling of Glucose
SGLT2
90%
Lots of Glucose
Canvas Trial
Neal et al, N Engl J Med 2017; 377:644‐657 DOI: 10.1056/NEJMoa1611925.
SGLT2‐Inhibitors
Advantages• Modest weight loss• Lower blood pressure• No hypoglycemia when used alone
Disadvantages• Modest A1C lowering (0.5‐1%)• Increased fractures• Increase in UTI and genital infections• Decreases GFR• Fournier’s Gangrene?• Euglycemic DKA
52
Laboratory Tests:
UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L Lactate 0.6 ABG: 7.20/23/90Lipase 369.
53
43 yo Hispanic man with history of IDDM, HTN, hyperTG and bumex treated heart failure presents with 2 days of epigastric abdominal pain and 1 day of nausea and vomiting.
138 96 103.5 14 0.72
167
Medications:NPH 50 units BIDAspart 25 units QAC Aspart correction 3:50 > 175Metformin 1 gm bidCanagliflozin 300 mg dailyAtorva 80 mg dailyFenofibrate 160 mg dailyOmega-3 FA 1 gm daily
A1C 8.9%
Laboratory Tests:
UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L Lactate 0.6 ABG: 7.20/23/90Lipase 369.
54
43 yo Hispanic man with history of IDDM, HTN, hyperTG and bumex treated heart failure presents with 2 days of epigastric abdominal pain and 1 day of nausea and vomiting.
138 96 103.5 14 0.72
167
Medications:NPH 50 units BIDAspart 25 units QAC Aspart correction 3:50 > 175Metformin 1 gm bidCanagliflozin 300 mg dailyAtorva 80 mg dailyFenofibrate 160 mg dailyOmega-3 FA 1 gm daily
A1C 8.9%
1997!!
Diabetes Subtypes
• Type 1 Diabetes• Type 2 Diabetes• Ketosis Prone Type 2 Diabetes• LADA: Latent Autoimmune Diabetes in Adults• Post pancreatitis diabetes.
Laboratory Tests:
UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L (0.4-0.5) Lactate 0.6 ABG: 7.20/23/90Lipase 369 Blood Lipemic
57
43 yo Hispanic man with history of IDDM, HTN, hyperTG and bumex treated heart failure presents with 2 days of epigastric abdominal pain and 1 day of nausea and vomiting.
138 96 103.5 14 0.72
167
Medications:NPH 50 units BIDAspart 25 units QAC Aspart correction 3:50 > 175Metformin 1 gm bidCanagliflozin 300 mg dailyAtorva 80 mg dailyFenofibrate 160 mg dailyOmega-3 FA 1 gm daily
TG 8807 mg/dL
A1C 8.9%
Laboratory Tests:
UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L (0.4-0.5) Lactate 0.6 ABG: 7.20/23/90Lipase 369 Blood Lipemic
58
43 yo Hispanic man with history of IDDM, HTN, hyperTG and bumex treated heart failure presents with 2 days of epigastric abdominal pain and 1 day of nausea and vomiting.
138 96 103.5 14 0.72
167
Medications:NPH 50 units BIDAspart 25 units QAC Aspart correction 3:50 > 175Metformin 1 gm bidCanagliflozin 300 mg dailyAtorva 80 mg dailyFenofibrate 160 mg dailyOmega-3 FA 1 gm daily
TG 8807 mg/dL
A1C 8.9%
Euglycemic KetoacidosisWhat we think we know
• Patients at increased risk for DKA are at increased risk of euglycemic ketoacidosis
• Reported precipitants are things that result in relative insulin deficiency OR promote ketones
• Reduction or stopping insulin• Severe acute illness/stress (e.g. surgery)• Dehydration• Extensive exercise• Low carbohydrate diets/poor PO intake/fasting• Excessive alcohol intake
Euglycemic KetoacidosisWhat we think we know
• Ketoacidosis can still occur several days after the SGLT2i is stopped
• Normal urine ketones might be misleading so check plasma ketones if concerned.
• Symptoms are similar to DKA with n/v, lethargy, abdominal pain but the glucose is relatively normal
• Treat with insulin and carbohydrates to correct relative insulin deficiency and dampen glucagon response
• For now would avoid use in hospital• More common in woman
SGLT2‐Inhibitors
Advantages• Modest weight loss• Lower blood pressure• No hypoglycemia when used alone
Disadvantages• Modest A1C lowering (0.5‐1%)• Increased fractures• Increase in UTI and genital infections
• Decreases GFR• Fournier’s Gangrene?• Euglycemic DKA
61
CVD AND RENAL OUTCOMES?
Zinman B et al. N Engl J Med 2015;373:2117‐2128.
Empagliflozin (SGLT2): CV and Mortality Benefit
Death – HR 0.68*
CV Death HR 0.62*
Hosp HF –HR 0.65*
Primary Outcome–HR 0.86*
V Perkovic et al. N Engl J Med 2019;380:2295‐2306.
Canagliflozin and Renal and Cardiovascular Outcomes
CV Death - HR 0.78* Death – HR 0.83
ESRD- HR 0.68* HD, Tx, Death HR 0.72*
V Perkovic et al. N Engl J Med 2019;380:2295‐2306.
Canagliflozin and Renal Outcomes
• Ejection fraction of 40% or less• 60% of enrolled WITHOUT Diabetes• ACE/ARB/ARNI 94%, beta‐blocker 96%, mineralocorticoid receptor antagonist 71%
McMurray et al., NEJM 2019; 381:1995‐2008
DAPA‐HF
Diabetes Medications and Heart Failure 66DapaHF N Engl J Med 2019; 381:1995‐2008 DOI: 10.1056/NEJMoa1911303
HF Hospitalization HR 0.70*
DeathHR 0.83*CV Death
HR 0.82*
SGLT2‐Inhibitors
Advantages• Modest weight loss• Lower blood pressure• No hypoglycemia when used alone
• Decreases GFR • Prevents death in patients with
established CVD• Prevents renal failure in patients with
renal disease
Disadvantages• Modest A1C lowering (0.5‐1%)• Increased fractures• Increase in UTI and genital infections• Fournier’s Gangrene?• Euglycemic DKA
67
BIG Advantages
SGLT2 Inhibitors ‐ Indications in Adults with DM2
SGL2 Inhibitors
Trade Name FDA Approved Indications
Cost/mth(Good rx.com
6/2020)
canagliflozin Invokana 1. Glucose control 2. Reduce risk of major CV adverse events in patients with
established CVD3. Reduce risk of ESRD, doubling of creatinine, CV death,
hospitalization for HF ‐ in patients with diabetic nephropathy with albuminuria
$520
dapagliflozin Farxiga*# 1. Glucose control2. Reduce risk of hospitalization for HF in patients with CVD or
CV risk factors$500
empagliflozin Jardiance 1. Glucose control 2. Reduce the risk of CV death in patients with established CVD $504
ertuglifozin Steglatro 1. Glucose control $300
*Forxiga is approved in Europe for DM1#Dapagliflozin now approved for the treatment of HF in patients without DM2
1980s
9%
BeforeDCCT,UKPDS
SulfonylureaInsulin
1990s
8%
AfterDCCT
+ Metformin
1997
+ TZD
7%
AfterDCCT,UKPDS
Glycemic Targets Over the Years
2006
+ Incretin
? 6%
7%
AfterACCORD
2008+ Mortality
2016
7-8%
After CV trials
+SGLT2
Putting it all Together?
WEIGHT IS A MAJOR ISSUE:‐ Beware with SU/TZD‐ Consider GLP‐1 first (more A1C
lowering and weight loss)‐ Consider SGLT2i second
FAR FROM A1C GOAL‐ Consider SU/TZD first for most effect‐ Avoid DPPIV, BAS, bromocriptine‐ SGLT2i okay for other reasons but not
for A1C lowering
HIGH ASCVD (Established or risk):‐ Consider GLP‐1 (with proven benefit) first
(more A1C lowering and weight loss)‐ Consider SGLT2i second
HIGH RISK FOR HYPOGLYCEMIA:‐ Avoid SU and insulin
HF OR CKD:‐ Consider SGLT2i (with proven benefit) first ‐ Consider GLP‐1 second especially if needed for
A1C lowering/renal benefit‐ Avoid TZD
Metformin
72
A1C COST
Metformin 1-2% $4 $4Sulfonylurea 1-2% $5 $4Pioglitazone 0.5-1.5% $20 $11Exenatide 0.5-1.5% $450 $728Canagliflozin 0.5-0.1% $330 $520Sitagliptin 0.5-0.8% $320 $475Acarbose 0.5-0.8% $30 $19
Good Rx.com10/2014 6/2020
$498$731
$455
10/2019
REFERENCES
ADA 2020 Standards of Care (Readers Digest version for Primary Care) https://clinical.diabetesjournals.org/content/38/1/10
In depth discussion of pharmacologic therapies. 2020https://care.diabetesjournals.org/content/43/Supplement_1/S98.full-text.pdf
Full supplement for ADA 2020 Standards of Carehttps://care.diabetesjournals.org/content/43/Supplement_1
Nice review of the data on renal effects of GLP‐1 Agonistshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136364/#Sec5title
73