What Follows Metformin James R Gavin III MD PhD CEO amp Chief Medical Officer Healing Our Village Inc Clinical Professor of Medicine Emory University School of Medicine Atlanta Georgia USA ID: 935760
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Slide1
Current Therapy in Type 2 Diabetes: What Follows Metformin?
James R. Gavin III, MD, PhDCEO & Chief Medical Officer, Healing Our Village, Inc.Clinical Professor of MedicineEmory University, School of MedicineAtlanta, Georgia USA
Slide2James R. Gavin III,
MD, PhD
Clinical Professor of Medicine
Emory University School of Medicine
Indiana University School of Medicine
Chief Medical Officer Healing Our Village, Inc. Atlanta, GA
Treatment After Metformin: Considerations for Therapy Selection
Slide3ObjectivesDescribe the pathophysiologic defects and natural history of type 2 diabetes Discuss the clinical and patient specific considerations for the selection of add-on therapy in patients not achieving glycemic control on metforminOutline the benefits and risks of various classes of antihyperglycemic agents including SGLT-2 inhibitorsDiscuss the importance of appropriate medication selection for patient medication adherence
Slide4Pre-Test Question 1What percentage increase in all-cause mortality is associated with each 1% increase in A1C?10%15%
20%25%30%
Slide5Pre-Test Question 2All of the following are important considerations for the selection of add-on therapy to metformin in a T2DM patient except:Clinical cardiovascular diseaseRenal disease (nephropathy)Duration of diabetes
Hepatic diseasePlanning pregnancy
Slide6Pre-Test Question 3Which of the following statements is CORRECT regarding the benefits and risks of SGLT-2 inhibitors?Increased risk of edemaHigh efficacy
Can be used in patients with renal dysfunction without dosage adjustmentAssociated with weight loss and low hypoglycemia risk
Slide7The Rising Tide of Global Diabetes: the Epidemic of Our Time
International Diabetes Federation. Diabetes prevalence. http://www.idf.org/diabetes-prevalence. Accessed August 10, 2009.
1985
2000
2007
2025
Slide8Natural History of Type 2 Diabetes Is Characterized by Progressive Loss of Beta Cell FunctionMacrovascular complications
Microvascular complications
Insulin resistance
Insulin secretion
Postprandial glucose
Fasting glucose
Progression of Dysglycemia
Prediabetes and Early Type 2 Diabetes: Generally
Asymptomatic
Diagnosis of Type 2 Diabetes Typically
Delayed
Years to Decades
Progression to Type 2 Diabetes Can be
Prevented or Delayed
Adapted from Ramlo-Halsted BA, Edelman SV.
Prim Care.
1999;26:771-789
Prediabetes
Type 2 Diabetes
Slide9Multiple Defects Contribute to the Pathophysiology of T2DM Necessitating Targeted Therapy*
hyperglycemia
β
α
Neurotransmitter dysfunction
*In addition to beta-cell changes over time, other organ systems in T2DM are also undergoing progressive change and worsening function.
DeFronzo RA.
Diabetes
. 2009;58(4):773-795
Incretin
effect
Glucose Uptake
Insulin secretion
Glucose
production
Glucagon
production
Lipolyisis
Glucose
reabsorption
Slide10Each 1% increase in A1C above 6.5% resulted in a
40% increase in the risk of events3
Each 1% increase in A1C above 7% resulted in a
38% increase
in the risk of events
3
Suboptimal Glycemic Control* May Lead to the Development or Worsening of Complications
CVD=cardiovascular disease.
*
Other cardiometabolic risk factors must likewise be targeted to reduce CVD outcomes.
a
Reasonable
A1C goal for many nonpregnant adults;
b
Based
on the results of a prospective study that evaluated the data collected from 4662 men aged 45–79 years.
1.
American Diabetes Association.
Diabetes Care
.
2018;41(
Suppl
1):S1-S159
.
2
.
Zoungas
S et al.
Diabetologia
.
2012;55(3):636-643. 3
. Khaw KT et al. BMJ. 2001;322(7277):15-18.
A large proportion of patients in the United States do not achieve recommended A1C targets despite initiation of antihyperglycemic therapy1
Suboptimal glycemic control may result in the development of complicationsMicrovascular
MacrovascularEach 1% increase in A1C was shown to increase the risk of all-cause mortality by 30% and CVD mortality by 40%3,b
A1Cup to 49%
fail to achieve recommended goal
of <7.0%
1,a
Slide11Long-term Complications of Diabetes(?Consequences of Sustained Hyperglycemia)
11
Diabetic
Retinopathy
Leading cause
of blindness
in working age
adults
Diabetic
Neuropathy
Leading cause of
nontraumatic
lower extremity amputations
Diabetic
Nephropathy
Leading cause of
end-stage renal disease
Stroke
Cardiovascular
Disease
2-fold to 4-fold
increase in
cardiovascular
events and mortality
National Diabetes Information Clearinghouse.
At: http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm.
Slide12Patient Case – Background JR is a 48 year-old Hispanic male. He had routine lab work and physical 2 weeks ago and a FPG of 201 mg/dL was noted. Repeat lab ordered for today’s visit shows an A1C 8.7%.
Medical history: 1. HTN 2. ObesityFamily history: Mother has diabetes Social history: Works as salesman; needs simple treatment plan; hectic life
Medications:
Lisinopril 10 mg daily
Physical exam: BMI 31 kg/m2 BP 132/80 mmHg HR 74 BPMLaboratory
: - A1C 8.7% - LDL-C 126 mg/dL
- HDL-C 41 mg/
dL
- eGFR 74 ml/min
Slide13Patient Case: Question 1 With an A1C goal of <7.0%, what is the most likely choice for treatment of his diabetes?Nothing. See him back in 2 weeks with glucose diary
Metformin 500 mg with meals and titrate gradually to 1000 mg BIDMetformin ER/SGLT2 inhibitor once dailyMetformin ER/DPP4 inhibitor once dailyMetformin 500 mg BID and GLP-1 RA injection once daily.
Slide14Patient Case – Continued It was decided to start him on metformin 500 mg once daily along with instructions to titrate as tolerated to 500 BID and up to 1000 mg twice daily. He is also scheduled to see the dietitian and participate in diabetes education classes. He is made aware that the success of this minimal medication regimen greatly depends on the success of lifestyle changes, including weight loss and dietary modifications.
Slide15Despite All We Know and Can Do: Ongoing Failures and Poor Outcomes Compel Us to Address a Range of Unmet NeedsFor better outcomes in T2DM, we urgently need to:Refresh our understanding of diabetes pathophysiology
Understand the many contributors to the dysmetabolism and CVD risk of T2DMUnderstand implications of its natural historyUnderstand implications of its heterogeneityUnderstand the urgency for individualization of therapyUnderstand the capabilities of current tools/treatmentsReconsider the optimal sequencing of T2DM treatmentUnderstand the shortcomings of current treatments--- in design, in composition, in timing, in consistency
Slide16Decreased post-prandial glucose--- one of the earliest defectsReduce/prevent progression of beta-cell failure/dysfunctionWeight loss --- up to 80% of patients with T2DM overweight/obeseLower A1C Decrease cardiovascular risk factors (blood pressure, lipids, hs-CRP) --- up to 70% of persons affected by HTN, etc.Lower rates of hypoglycemiaProtect essential major organs and their functions (i.e., heart, kidneys, brain)
Drucker DJ, Nauck MA. Lancet. 2006;368(9548):1696-1705; Baggio LL, Drucker DJ. Gastroenterology. 2007;132(6):2131-2157; American Diabetes Association. Diabetes Care. 2015;38(suppl MA.. 1):S41-S48.General Treatment Targets in T2DM Based on the Known Pathophysiology of the Disease and Its Known Progression
Slide17Prevalence of Meeting ABC Goals Among Adults Aged ≥20 Years With Diagnosed Diabetes, NHANES 2007–2010
Risk Factors for CVD Are Poorly Controlled in Patients With DiabetesStark Casagrande S, et al. Diabetes Care. 2013;36(8):2271-2279.
Percentage of patients
achieving target values
From 2007 to 2010, 81.2% of patients did not achieve the combined
ABC goal
ABC goals are A1C <
7%, BP <130/80 mm Hg, and LDL-C <100 mg/dL
Slide18Progressive Natural History of T2DM Associated With a Dynamic PathophysiologyThe progressive loss of β-cell function associated with T2DM results in the corresponding need for therapeutic intensification
2,3Other organ system contributions are also occurring (i.e. kidney, incretins, adipose tissue, inflammatory changes etc.)Many patients with T2DM will eventually need insulin or other injectable therapy2,3Progression to insulin/injectable therapy occurs at different rates in different study populationsORIGIN: 11.4% with IFG, IGT, or early T2DM in standard care arm used insulin within 7 years4TODAY: 46% of adolescents with newly diagnosed T2DM required rescue with insulin within 1 year51. Conget I. Rev Esp Cardiol. 2002;55:528-535; 2. Kahn SE. Diabetologia
. 2003;46:3-19; 3. Skyler JS.
Diabetes
. 2017:66:241-255; 4. Garber AJ, et al.
Endocr Pract. 2017;23:207-238; 5. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135.
T2DM
Normal
Glucose tolerance
Insulin sensitivity
Insulin secretion
Pancreatic
β
cell failure
Glucotoxicity
Lipotoxicity
Diabetogenic genes
Acquired factors
Hepatic glucose production
Insulin action
Insulin secretion
Obesity, adipose distribution
Diet, activity level, age, sex, lipids,
etc
Genes related to diabetes
Slide19General Considerations for Addressing the Current Sequence of T2DM TreatmentThe heterogeneity of T2DM encompasses many defectsThere is historical tyranny of the stepped-care approachCurrent practices reveal treatment by policy, not physiologyIndividual patient assessments should more frequently guide optimization of therapeutic choices in T2DM
Important to understand the complementary nature of T2DM treatmentsCurrent approaches compel urgency in deciding what will follow use of metformin, with occasional exceptions
Slide20Current Treatment Algorithms Include A Wide Array of Choices and Combinations to Achieve Glycemic Control– But are we sending the wrong message(s)?American Diabetes Association 2018American Association of Clinical Endocrinologists 2018
1. American Diabetes Association.
Diabetes Care
. 2018;41(Suppl. 1):S73–S85. 2. Garber AJ, et al.
Endocr
Pract. 2018;24(1):91-120.
Slide21Complementary Actions of Various Antihyperglycemic Agents1,2a
DPP-4 inhibitors increase endogenous GLP-1 ( 2-fold) and GLP-1 RAs increase exogenous GLP-1 ( 9-fold).31. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135. 2. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. 3. DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952. 4. Nauck MA, et al. Diabetes Obes
Metab
. 2017;19:200-207
.DPP-4 inhibitors and GLP-1 receptor agonists (RAs) both increase physiological levels of GLP-1 via a related mechanism of action3,a
; current evidence does not support their combined use.
4
Sulfonylureas (SUs);
Insulin
GLP-1
receptor agonists;
DPP-4 inhibitors
Metformin;
Thiazolidinediones (TZDs)
GLP-1
receptor agonists
SGLT2 inhibitors
GLP-1
receptor agonists
Slide22Metformin Has Its Metabolic Limitations
HGP = hepatic glucose production.1.
Cusi
K, et al.
J
Clin Endocrinol
Metab
.
1996;81(11):4059-67. 2.
DeFronzo RA, et al.
J Clin Endocrinol Metab
. 1991;73(6):1294-301.
Metformin Does Not Improve Insulin Sensitivity in T2DM Patients in the Absence of Weight Loss (n=20)
1
Effect of Metformin on Insulin Secretion in T2DM Patients (n=14): OGTT and Hyperglycemic Clamp
2
Slide23Metformin Has Its Metabolic Limitations (Continued)
HGP = hepatic glucose production.
1.
Cusi
K, et al.
J Clin Endocrinol Metab
. 1996;81(11):4059-67. 2. Brown JB, et al.
Diabetes Care
. 2004;27(7):1535-40.
Suppression of Basal HGP
is the Primary Mechanism via Which
Metfromin
Improves Glycemic Control
1
Effect of Metformin on A1C
2
Slide24A1C in UKPDS: Urgency for Progression from Monotherapy
Cross-sectional, Median values
0
6
7
8
9
0
3
6
9
12
15
HbA1c
(%)
Years from randomization
Conventional
Intensive
6.2% upper limit of normal range
UKPDS Group. Lancet. 1998;352(9131):837-53.
Slide25Standard Stepwise Management of T2DM Associated with Clinical Inertia
Slide26Drawbacks of the Stepwise ApproachEven short periods of hyperglycemia increase risk of complications1–3
A proactive approach is required to get patients to achieve their glycemic goals sooner
1.
JAMA
2003; 290:2159–2167. 2. EDIC Group.
JAMA
2002; 287:2563–2569. 3. Nathan DM,
et al
.
N
Engl
J Med
2003; 348:2294–2303.
Myocardial
infarction
Incidence per
1000 patient
-
years
Updated mean HbA
1c
(%)
20
40
60
80
5
6
7
8
9
10
11
0
0
Normal
HbA
1c
levels
Microvascular complications
Slide27Potential Impact of Clinical Inertia on Macrovascular Complications
Paul SK, et al.
Cardiovasc
Diabetol
. 2015;14:100.
Slide28General Considerations for Addressing the Current Sequence of T2DM TreatmentThe heterogeneity of T2DM encompasses many defectsThere is historical tyranny of the stepped-care approachCurrent practices reveal treatment by policy, not physiology
Individual patient assessments should more frequently guide optimization of therapeutic choices in T2DMImportant to understand the complementary nature of T2DM treatmentsCurrent approaches compel urgency in deciding what will follow use of metformin, with occasional exceptions
Slide29Our Conclusions, If Any, About Pathophysiology in T2DM Management Are Largely Clinical Deductions*WHEN WE OBSERVE:Long Duration T2DM ……….
Overweight/ Obesity ………..Increased FPG ………………Increased PPG ………………Abdominal Obesity ………….Hyperglycemia ………………
*
The real question is what defines the needs of our patient? What can we measure?
WE MOST LIKELY CONCLUDE:
Beta Cell Exhaustion
Insulin resistance, lipolysis
Excess HGP
Impaired Insulin Secretion
Decreased adiponectin; increased
resistin
; inflammation; NAFLD
Increased renal reabsorption
Slide30Patient Case – Continued JR is in the office for his 3 month appointment. He is currently on metformin 1000 mg twice daily and his A1C 7.2%. You recommend adding another agent but he asks you to wait since he is starting to exercise and improving his eating habits. You agree and will see him in 3 months.
He returns for his follow-up visit after 4 months and his A1C is 7.4%. Weight loss has been minimal. You ask him about his diet and exercise and he states that he has been exercising about 3 times a week but that it has been harder to change his diet.You discuss with him about getting better control of his diabetes and he agrees. However, he does not want to do injections at this time.
Slide31Patient Case: Question 2 Which of the following would you recommend for as add-on to metformin for treatment of his diabetes?Sulfonylurea
SGLT-2 inhibitorGLP-1 RADPP-4 inhibitorTZD
Slide32Diabetes Canada Clinical Practice Guidelines Expert Committee,
Lipscombe
L, et al. Can J Diabetes. 2018;42(
Suppl
1):S88–S103.
Considerations for Add-on Medication Selection
2018 Canadian Diabetes Guidelines
Add another agent
best suited to the individual by prioritizing patient characteristics
:
Other considerations:
Degree of hyperglycemia
Risk of hypoglycemia
Overweight or obesity
CV disease or multiple risk factors
Comorbidities (renal,
CHF
, hepatic)
Preferences & access to treatment
Planning pregnancy
Consider relative A1C lowering
Rare hypoglycemia
Weight loss or weight neutral
Effect on cardiovascular outcome
See therapeutic considerations; consider eGFR
See cost column; consider access
CLINICAL CONSIDERATIONS
CHOICE OF AGENT
Antihyperglycemic agent with
demonstrated CV benefit (
empa
, lira,
cana
)
PRIORITYClinical cardiovascular disease
No
clinical cardiovascular disease
Avoidance of hypoglycemia and/or weight gain with adequate glycemic efficacy
DPP-4 inhibitor, GLP-1 receptor agonist or SGLT2 inhibitor
Slide33Benefits and Risks of Antihyperlgycemic AgentsSulfonylureasGlyburide, glipizide, glimepiride
AdvantagesHigh efficacy; low costDisadvantagesHigh hypoglycemia risk; weight gainGlyburide not recommended in patients with renal diseaseAmerican Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.
DPP-4 inhibitors
Alogliptin, linagliptin, saxagliptin, sitagliptin
Advantages
No hypoglycemia risk; no weight gain; well tolerated
Disadvantages
Intermediate efficacy; may worsen heart failure (alogliptin, saxagliptin); reduce dose in renal disease (alogliptin, saxagliptin, sitagliptin)
Slide34Benefits and Risks of Antihyperlgycemic Agents (Continued)SGLT-2 inhibitorsCanagliflozin, dapagliflozin, empagliflozin, ertugliflozin,
AdvantagesNo hypoglycemia risk; weight loss, proven CV, CHF, and renal benefit (canagliflozin, empagliflozin)DisadvantagesIntermediate efficacy; GU infections; contraindicated in renal dysfunctionRisk of amputations & bone fractures (canagliflozin); risk of DKAGU = genitourinary.American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.
TZDs
Pioglitazone
Advantages
High efficacy; no hypoglycemia risk; low cost; potential CV benefit
Disadvantages
Weight gain; increase fracture risk; exacerbate heart failure; edema
Slide35Benefits and Risks of Antihyperlgycemic Agents (Continued)GLP-1 RAsDulaglutide, exenatide, liraglutide, lixisenatide, semaglutide
AdvantagesHigh efficacy; no hypoglycemia risk; weight loss; CV and renal benefit (liraglutide); proven CV safety (lixisenatide, exenatide ER)DisadvantagesInjection; not recommended in patients with eGFR <30 mL/min; GI side effects commonAmerican Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.
Insulin
Human insulin (i.e., NPH), analog insulin (i.e., glargine, detemir)
Advantages
Highest efficacy; can use in pregnancy and renal failure; proven CV safety (insulin glargine, degludec)
Disadvantages
Weight gain; increase hypoglycemia risk
Slide36Illustrative Examples of Individual Patient Assessments Required to Guide Choices
DSME = diabetes self-management education; TLC = therapeutic lifestyle changes; AGI = alpha-glucosidase inhibitor; BR-C = bromocriptine; CGM = continuous glucose monitoring;
RA-ins = ?; SOC = ?; SGM = ?.
Diabetes Canada Clinical Practice Guidelines Expert Committee,
Lipscombe
L, et al. Can J Diabetes. 2018;42(
Suppl 1):S88–S103.
Patient Clinical Characteristic
Desirable
Agent(s)
Less
Desirable Agent
Other
Important Considerations
Weight Loss
GLP-1
RA; SGLT-2i
SFUs;
TZDs; DPP-4i Insulin
Renal
function; Tolerance for Injection
Short
Duration of Diabetes
Incretin;
TZD; AGI
SFU;
Insulin
DSME; TLC
Elevated A1C (i.e. >8.0)
GLP-1
RA; SGLT-2i; insulin; Combo agent
AGI;
DPP-4i;BR-C
Stress importance of CGM
Established
CVD or CVD RFs
SGLT-2i;
Lira;
Sema
SFUs;
TZDs; Insulin
Rigorous SOC
Complex Lifestyle
QW agents; Co-formulations
Multi-dose agents; BBI
Non-invasive
SGM
Elevated A1C due to PPG
SA-GLP-1RA; DPP-4i;
RA-ins; BI/GLP-1; AGI
Basal
ins; Pre-mix ins; Met
SMBG
helpful to guide treatment
Slide37Complementary Actions of Various Antihyperglycemic Agents1,2
a DPP-4 inhibitors increase endogenous GLP-1 ( 2-fold) and GLP-1 RAs increase exogenous GLP-1 ( 9-fold).31. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135. 2. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. 3. DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952. 4. Nauck MA, et al. Diabetes Obes
Metab
. 2017;19:200-207
.DPP-4 inhibitors and GLP-1 receptor agonists (RAs) both increase physiological levels of GLP-1 via a related mechanism of action3,a
; current evidence does not support their combined use.
4
Sulfonylureas (SUs);
Insulin
GLP-1
receptor agonists;
DPP-4 inhibitors
Metformin;
Thiazolidinediones (TZDs)
GLP-1
receptor agonists
SGLT2 inhibitors
GLP-1
receptor agonists
Slide38The Need for Early Oral Combination Therapies in T2DM Matching Pharmacology with PathophysiologyUse of combination therapies with different mechanisms of action to address multiple metabolic defects associated with T2DM
DeFronzo
RA. Diabetes. 2009;58:773-795. American Diabetes Association. Diabetes Care. 2017;40(
suppl
1):S1-S135. Garber AJ, et al.
Endocr
Pract. 2017;23:207-238.
Slide39*Note: Major drawbacks with SFUs are weight gain and severe hypoglycemia.
DeFronzo
RA et al.
N
Engl
J Med.
1995;333:541-549
.
*
P
=0.001
N=632
Early Demonstration that Combo Therapy Works ---Metformin Effects on FPG in Glyburide-Treated Patients*
5
9
13
17
21
25
29
0
Mean Change from Baseline FPG (mg/
dL
)
-80
-60
-40
-20
0
20
40
Weeks
Continue
Glyburide
Switch to
Metformin
Add
Metformin
Slide40a P < .001 for measures listed in ORIGIN2 and ADVANCE3.; b P < .05 for all VADT4 measures.1. Bonds DE, et al. BMJ. 2010;340:b4909. 2. The ORIGIN Trial Investigators. Eur
Heart J. 2013; 34(40):3137-3144. 3. Zoungas S, et al; ADVANCE Collaborative Group. N Engl J Med. 2010;363:1410-1418. 4. Duckworth W, et al; VADT investigators. VA Diabetes Trial (VADT) Update. ADA 69th Scientific Sessions.SFU/Insulin Downside: Patients With T2DM and CVD Were at Increased Risk of Mortality If There was Severe Hypoglycemia
ACCORD
1
ORIGIN
2,a
Death—any cause
2.05 (1.65-2.55)
Death—CV cause
2.02 (1.52-2.69)
Death—arrhythmia
2.14 (1.43-3.18)
Macrovascular
events
1.77 (1.39-2.25)
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)
ADVANCE
3,a
Macrovascular events
3.45 (2.34-5.08)
Death—any cause
3.30 (2.31-4.72)
Death—CV cause
3.78 (2.34-6.11)
Death—non-CV cause
2.86 (1.67-4.90)
VADT
4,b
Macrovascular events
1.88 (1.03-3.34)
Death—any cause
6.37 (2.57-15.79)
Death—CV cause
3.73 (1.34-10.36)
Lower risk with SH Higher risk with SH
Lower risk with SH Higher risk with SH
Slide41Newer Antihypertensive and Antihyperglycemic Medications in the USCourtesy of Silvio Inzucchi, MD, Yale University.
1950 1960 1970 1980 1990 2000 2010 2015
9
8
7
6
5
4
3
2
1
Number of Medication Classes
10
11
Ca
2
+
channel blockers
Angiotensin II
receptor
blockers
ACE Inhibitors
β
-blockers
Diuretics
Central
α
-2 agonists
Peripheral
α
-1 blockers
Adrenergic
neuronal
blockers
Renin inhibitors
Vasodilators
12
Antihypertensives
Insulin
Sulfonylureas
Biguanides
SGLT2
inhibitors
-
glucosidase
inhibitors
Thiazolidinediones
Meglitinides
GLP-1 receptor agonists
DPP-4 inhibitors
Amylin
mimetics
Biguanides
Bile acid
sequestrants
Dopamine
agonists
Antihyperglycemics
(all approved on same basis!)
Slide42The Outcomes From Recent CVOTs Using Diabetes Drugs Are Changing USA Guidelines!DIABETES CARE---Clinical Guidelines Supplement (2017)Standards of Medical Care in Diabetes with a “new look”
Guidelines now include new recommendation to consider the use of empagliflozin or liraglutide in people with T2DM and established CVD to reduce the risk of cardiovascular death or events (Canadians have already included canagliflozin their guidelines)
Adoption of this recommendation has implications for future Clinical Guidelines in face of the emerging data from CVOTs
American Diabetes Association.
Diabetes Care
. 2017;40(Suppl. 1):S64–S74.
Slide43Rationale for Metformin/SGLT2 Inhibitor
MechanismEffectsMetforminImproves insulin sensitivityLowers hepatic glucose production
Weight neutral
Gastrointestinal
side effects
Contraindicated in renal failure (CrCl<30ml/min, Cr >1.5 (males), >1.4(females))
SGLT2 inhibitor
Inhibits the SGLT2 co-transporter, reducing renal glucose reabsorption and increases urinary glucose excretion
Weight loss
Low risk of hypoglycemia
UTI/genital
infections
Volume depletion risk
Ketoacidosis
Contraindicated with
CrCl
<30ml/min
Harris SB.
Expert Rev
Clin
Pharmacol
.
2016;9(11):1453-1462.
Slide44Proof of Concept: SGLT-2 Inhibitor/Metformin The glycemic efficacy of SGLT2 inhibitors + metformin is greater than that of monotherapy both in treatment naïve and patients uncontrolled on metformin alone.
Modest BP reductions: DAPA/MET: -3.3/-1.8 mmHg and ERTUG/MET: -5.2/-2.2 mmHg More effective for weight reduction and a low risk of hypoglycemiaAdjusted Mean Change in A1C (%) 95% CI
Weeks
Dapagliflozin/Metformin in Treatment Naïve Patients
LS Mean Change in
A1C (%)
Weeks
Ertugliflozin/Metformin in Patients Uncontrolled on Metformin
Henry RR, et al
.
Int
J
Clin
Pract
. 2012;66(5):446-56.
Rosenstock J, et al. Diabetes Obes Metab. 2018;20(3):520-529.
Slide45SGLT2 Inhibitor and DPP-4 InhibitorComplementary EffectsDey J. Postgrad Med
. 2017;129(4):409-420.
Slide46Proof of Concept: SGLT-2 Inhibitor/DPP-4 Inhibitor(In Patients Uncontrolled on Metformin)Pratley RE, et al. Diabetes Obes
Metab. 2018;20(5):1111-1120.Ertugliflozin/Sitagliptin
Ertugliflozin 5 mg
Ertugliflozin 15 mg +
Sitagliptin 100 mg
Ertugliflozin 15 mg
Sitagliptin 100 mg
Ertugliflozin 5 mg +
Sitagliptin 100 mg
Combination therapy achieved significantly greater A1C reduction and greater percent of patients achieving A1C <7%
Ertugliflozin 5 mg –
26.4%
Ertugliflozin 15 mg –
31.9%
Sitagliptin 100 mg –
32.8%
Ertug 5 mg/Sita 100 mg –
52.3%
Ertug 15 mg/Sita 100 mg –
49.2%
Combination therapy achieved greater reduction in SBP
-3.7 mmHg vs -0.7 mmHg
LS Mean Change From Baseline ±SE
Weeks
Slide47Rationale for Metformin/ DPP-4 Inhibitor
MechanismEffectsMetforminImproves insulin sensitivityLowers hepatic glucose production
Weight neutral
Gastrointestinal
side effects
Contraindicated in renal failure (CrCl<30ml/min, Cr >1.5 (males), >1.4(females))
DPP-4 inhibitor
Inhibits DPPIV preventing rapid
breakdown of incretins
- Increases insulin secretion and decreases glucagon secretion
Weight neutral
Low risk of hypoglycemia
Post prandial control
Avoid in history
of pancreatitis
Linagliptin
is safe in renal impairment, however its use in this population may be limited by metformin limitations.
Harris SB.
Expert Rev
Clin
Pharmacol
. 2016;9(11):1453-1462.
Slide48Proof of Concept: Metformin/DPP-4 Inhibitor (In Treatment Naive Patients)
Adjusted Mean Change in A1C (%) 95% CIWeeks
Saxagliptin
/Metformin
Weeks
A1C (%)
Sitagliptin/Metformin
Greater efficacy compared with monotherapy
Greater efficacy achieved with lower doses and a corresponding lower rate of adverse reactions
Haak
T.
Clin
Med Insights
Endocrinol
Diabetes
. 2015;8:1-6.
Pfützner
A, et al.
Diabetes
Obes
Metab
. 2011;13(6):567-76.
Williams-Herman D, et al.
Diabetes Obes Metab
. 2010;12(5):442-51.
Slide49There Are Compelling Physiological and Practical Clinical Reasons That Justify the Use of Incretin Therapy Following Metformin in T2DMDPP-4 inhibitors should be considered the secretagogues of the 21st century, displacing SFUs in the majority of patients with T2DM
GLP-1 RAs provide more robust incretin effects, with broader mix of secondary benefits, i.e. weight loss, BP effects, appetite suppression
Slide50Guideline Recommendations for What Follows Metformin in T2DM TreatmentaThe
others are basal insulin, DPP-4 inhibitor, SGLT2 inhibitor SU, TZD; bUse with caution. 1. ADA. Diabetes Care. 2018;41(suppl 1):S1-S159. 2. Garber AJ, et al. Endocr
Pract
. 2018;24:91-120
.
Monotherapy
Metformin
GLP-1 RA
SGLT2 inhibitor
DPP-4 inhibitor
TZD
b
SU
b
Dual Therapy: first line agent plus…
GLP-1 RA
SGLT2 inhibitor
DPP-4 inhibitor
TZD
b
Basal
insulin
b
SU
b
Triple Therapy: 2 agents plus…
GLP-1 RA
SGLT2 inhibitor
TZD
b
Basal
insulin
b
DPP-4 inhibitor
SU
b
Suggested Hierarchy for Major Agents -AACE/ACE Algorithm
2
GLP-1 and SGLT-2i show good efficacy, actions complement other agents, low hypoglycemia risk, weight loss
1,2
ADA: among 6 preferred
options
a
, GLP-1 after metformin; most-preferred option in patients with CVD
1
AACE/ACE: high in suggested treatment hierarchy across disease progression
2
Alternatives to metformin when it is contraindicated or not tolerated
1,2
Alternatives for intensifying basal insulin (GLP-1 RAs preferred over DPP-4 inhibitors)
1,2
GLP-1 RAs should not be used in combination with DPP-4 inhibitors
1
Slide51Patient Case – Continued You add a SGLT-2 inhibitor to JR’s regimen and after 3 month his A1C is 6.8%. He is happy his diabetes in under control and is continuing to exercise.
Slide52Decreased post-prandial glucose--- one of the earliest defectsReduce/prevent progression of beta-cell failure/dysfunctionWeight loss --- up to 80% of patients with T2DM overweight/obeseLower HbA1c Decrease cardiovascular risk factors (blood pressure, lipids, hs-CRP) --- up to 70% of persons affected by HTN, etc.Lower rates of hypoglycemia
Protect essential major organs and their functions (i.e., heart, kidneys, brain)Drucker DJ, Nauck MA. Lancet. 2006;368(9548):1696-1705; Baggio LL, Drucker DJ. Gastroenterology. 2007;132(6):2131-2157; American Diabetes Association. Diabetes Care. 2015;38(suppl MA.. 1):S41-S48.General Treatment Targets in T2DM Based on the Known Pathophysiology of the Disease and Its Known Progression*
*
While the GLP-1 RA s satisfy these requirements with more efficacy, they are hampered by injectable delivery requirements and a greater AE profile, posing logistical barriers to more widespread use. This increases the potential increased adoption of
fixed oral combination therapies
.
Slide53Metformin Fixed-Dose Combination TherapyMETFORMIN
SULFONYLUREAGLITAZONESDPP-4 INHIBITORS
SGLT2 INHIBITORS
ACARBOSE
Slide54METFORMIN FIXED DOSE COMBINATION THERAPYMETFORMIN
SULFONYLUREAGLITAZONESDPP-4 INHIBITORS
SGLT2 INHIBITORS
ACARBOSE
Slide55Combination Pills With a DPP4 Inhibitor*
Generic NameTrade
Name
Daily Dose Range (mg)
Recommended
Frequency
Sitagliptin/metformin
Janumet
50/500, 50/1000
Twice with meals
Sitagliptin/ertugliflozin
Steglujan
100/5, 100/15
Once daily
Saxagliptin
/metformin ER
Kombiglyze
XR
5/500, 2.5/1000, 5/1000
Once daily with evening meal
Linagliptin/metformin
Jentadueto
2.5/500, 2.5/850, 2.5/1000
Twice with meals
Linagliptin
/
empagliflozin
Glyxambi
5/10, 5/25
Once daily
Alogliptin
/pioglitazone
Oseni
25/15, 25/30, 25/45, 12.5/15, 12.5/30, 12.5/45
Once
Alogliptin
/metformin
Kazano
12.5/500, 12.5 mg/1000
Twice with meals
Edelman SV, Henry RR. Diagnosis and management of type 2 diabetes. 12
th
Edition. Professional Communications, Inc., Greenwich, CT. 288 pages, 2014.
*
In each case, for H2H studies, the combos have
greater efficacy
than monotherapy
Slide56Fixed-Dose Combinations Improves AdherencePatients are more adherent to glyburide/metformin compared to glyburide + metformin. Fixed-dose combinations (FDC) may enhance adherence rates by approximately 13% when compared to a 2-pill regimen
Blonde L, et al. Diabetes Obes Metab. 2003;5(6):424-31.
Slide57Medication Nonadherence a Major Barrier to Glycemic Control in DiabetesAdherence is estimated to range between 46%-87% for OADs and 54%-81% for insulin1
Optimizing medication selection can improve adherenceDrug regimens that minimize the number of drugs and frequency of doses2Regimens associated with weight loss and the avoidance of hypoglycemia3Selecting medications that patients prefer (patient-centered care)4
1. Salas M, et al. Value Health. 2009;12(6):915-22. 2.
http://www.medpagetoday.com/resource-center/diabetes/Strategies-Improved-Treatment-Adherence-Type-2-Diabetes/a/31638. Accessed April 27, 2017. 3.
Gordon J, et al.
BMJ Open Diabetes Res Care
. 2018;6(1):e000512. 4.
Robinson JH, et al. J Am
Acad
Nurse
Pract
. 2008;20(12):600-7.
Slide58Pathophysiologic-Based (DeFronzo) Algorithm---How Soon To Add-on?
Lifestyle +
TRIPLE COMBINATION:
PIO + Metformin
+ GLP-1 Receptor Agonist
HbA
1c
< 6.5%
DeFronzo
RA, et al.
Diabetes Care
. 2013;36
Suppl
2:S127-38. Abdul-Ghani MA, et al.
Diabetes
Obes
Metab
. 2015;17(3):268-75.
Slide59Time-Related Change in A1C in Triple and Conventional Therapy Groups After 36 Months
(Consider the additional role of the SGLT-2 inhibitors)
HbA1c (%)
8 -
7 -
9 -
6
0
12
18
24
6 -
Time (months)
Triple
Therapy
5 -
30
36
Conventional
Therapy
HbA1c = 6.71%
HbA1c = 5.80%
*
*
*
*
*
*
*
*
*
*
P<0.0001
Abdul-Ghani MA, et al.
Diabetes
Obes
Metab
. 2015;17(3):268-75.
Slide60Beta Cell Function (ΔCP/ΔG ÷IR) in Triple and Conventional Therapy Groups at Baseline and at 36 Months
36 mo
Conventional Therapy
BL
BL
Triple Therapy
36 mo
P<0.0001
Beta Cell Function
(ΔCP/ΔG
0-120
÷IR)
150 -
100 -
200 -
0 -
50 -
ΔCP = change in plasma C-peptide; ΔG = change in plasma glucose; IR = insulin resistance.
Abdul-Ghani MA, et al.
Diabetes
Obes
Metab
. 2015;17(3):268-75.
Slide61Effect of Combo Therapy on A1C in QATAR Study (EQW + Pio versus BBI on Background of Met + SFU)
7.1%
6.2%
P<0.0001
9 -
8 -
6 -
7 -
0
10 -
# P<0.05
* P<0.0001
3
6
9
Months
HbA1c (%)
12
15
18
-
-
-
-
-
-
-
Insulin
Therapy
Combination
Therapy
#
*
*
*
*
*
*
EQW =
exenatide
weekly; PIO = pioglitazone; BBI = basal bolus insulin.
Abdul-Ghani M, et al.
Diabetes Care.
2017;40(3):325-331.
Slide62Proactive Management of Glycemia in T2DM:When and How to Move Beyond Metformin
OAD
+
multiple daily insulin injections/GLP-1RA
ACTION POINT:
HbA
1c
= 7%
HbA
1c
= 6.5%
OAD + basal insulin/GLP-1
Diet
and
exercise
OAD*
monotherapy
OAD
combinations
OAD
up-titrations
Duration of Diabetes
7
6
9
8
HbA
1c
(%)
10
*OAD = oral antidiabetic
Slide63The Urgency for Rational Approach to Combination Therapy Beyond Metformin in T2DM! – SOME CLOSING THOUGHTSWe have amassed abundant evidence that T2DM is a progressive, physiologically complex and heterogeneous diseaseIn the absence of adequate disease control (beginning with glucose), the long-term complications are serious, widespread, and expensive
Current treatment guidelines for glucose control rely heavily on a policy-driven, historical, metformin-driven, stepwise approach that is largely unreliable and indifferent to pathophysiology
Slide64The Urgency for Rational Approach to Combination Therapy Beyond Metformin in T2DM! – SOME CLOSING THOUGHTS (Cont’d)We have amassed multiple glucose-lowering drugs that have targeted actions and are complementary in their actions with other agentsThere is abundant evidence that combination therapy is superior to monotherapy in achieving (and maintaining) glucose targets
CONSIDER FIRST THE INDIVIDUAL PATIENT NEEDS TO GUIDE CHOICE!Renal or cardiovascular disease Weight loss, hypoglycemia riskSide effectsOral or injection
Slide65HOW I SEE IT TRENDING AFTER ALL THESE YEARS – MY THREE CENTS!The combined benefits of oral forms, available coformulations, weight loss, potential renoprotection, and CV benefits will likely lead to more widespread use of SGLT-2i’s as first choice beyond metformin
The wider spectrum of benefit from GLP-1 RAs will compel broader use of this class after metformin, especially given its benefits in beta cell preservation and easier long-term dosing approaches (may ultimately be the real game-changer in which follows metformin!)Future “core therapy” for the vast majority of T2DM will combine Metformin/GLP-1 RA/SGLT-2i/+ Pio (low dose)
Slide66Post-Test Question 1What percentage increase in all-cause mortality is associated with each 1% increase in A1C?10%15%
20%25%30%
Slide67Post-Test Question 2All of the following are important considerations for the selection of add-on therapy to metformin in a T2DM patient except:Clinical cardiovascular diseaseRenal disease (nephropathy)Duration of diabetes
Hepatic diseasePlanning pregnancy
Slide68Post-Test Question 3Which of the following statements is CORRECT regarding the benefits and risks of SGLT-2 inhibitors?Increased risk of edemaHigh efficacy
Can be used in patients with renal dysfunction without dosage adjustmentAssociated with weight loss and low hypoglycemia risk
Slide69Backup Slides
Slide70Current Treatment Algorithms Include A Wide Array of Choices and Combinations to Achieve Glycemic Control– But are we sending the wrong message(s)?1. ADA. Diabetes Care. 2017;40(
suppl 1):S1-S135. 2. Garber AJ, et al. Endocr Pract. 2017;23:207-238.American Diabetes Association 2017American Association of Clinical Endocrinologists 2017
Slide71Proof of Concept: SAXAGLIPTIN/ METFORMIN (In Treatment Naive Patients)Greater efficacy compared with monotherapy
Greater efficacy achieved with lower doses and a corresponding lower rate of adverse reactionsHaak T. Clin Med Insights Endocrinol Diabetes. 2015;8:1-6. Pfützner A, et al. Diabetes Obes
Metab
. 2011;13(6):567-76.
Slide72Proof of Concept: DAPAGLIFLOZIN/ METFORMIN (In Treatment Naive Patients)Henry RR, et al
. Int J Clin Pract. 2012;66(5):446-56.The glycemic efficacy of SGLT2 inhibitors + metformin is greater than that of monotherapy (in treatment naïve patients).
Modest blood pressure reductions: systolic -3.3, diastolic -1.8mmHg
More effective for weight reduction and a low risk of hypoglycemia
1.98%
Slide7352 year old centrally obese male with: 1-year history of T2DM, dyslipidemia, and hypertension. Family History: Both Parents had type 2 diabetes, HTN and CADNotes: BMI 37 (1yr ago it was 34, 2
yrs ago it was 31)Metformin 1000 mg BIDCurrent A1c 8.3% (7.5% 6 months ago, 7.2% at diagnosis)Creatinine 1.3 mg/dL,
eGFR
65
LDL 112 mg/
dL, Triglycerides 256 mg/dL, HDL 29 mg/
dL
Case 1: Clarence
Slide74The scope of likely underlying pathophysiologic contributors to his T2DM include at least:beta cell dysfunctionalpha cell dysfunctionIncretin dysfunction
adipose tissue contribution to insulin resistance Increased renal glucose reabsorptionHGP excessNeurotransmitter/CNS dysfunction How many defects covered by metformin? Current treatment is indifferent to pathophysiology
.
Our practical challenge on a day-to-day basis is just what do we do next regarding Clarence’s treatment plan?
Case 1: Clarence (Continued)
Slide75Implicated Determinants of Cardiovascular Disease in DiabetesInsulin resistanceHyperglycemiaDyslipidemiaHypertensionOxidative stressAngiotensin II
Inflammation Endothelial dysfunctionImpaired fibrinolysisProcoagulationHomocysteinemiaSmoking
Agmon
Y, et al.
Circulation.
2000;102:2087-2093.
Feener
EP, King GL.
Lancet
. 1997;350(
suppl
1):SI9-SI13.
Tribouilloy
CM, et al.
Chest.
2000;118:1685-1689.
Atherosclerosis and vulnerable plaque
Slide76The Urgency for Rational Approach to Combination Therapy Beyond Metformin in T2DM! – SOME CLOSING THOUGHTS (Cont’d)We have amassed multiple glucose-lowering drugs that have targeted actions and are complementary in their actions with other agentsThere is abundant evidence that combination therapy is superior to monotherapy in achieving (and maintaining) glucose targets
Evidence is strong/practical for addition of SGLT-2i after metforminThe greatest flexibility and the capacity for the greatest efficacy derives from the use of incretins added to metformin, especially GLP-1 RAsCONSIDER FIRST THE INDIVIDUAL PATIENT NEEDS TO GUIDE CHOICE!
Slide77GLP-1 Has Numerous Physiological ActionsBaggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.
neuroprotection
appetite
Adipose
tissue
Pancreas
Brain
Intestine
cardioprotection
cardiac function
Stomach
glucose uptake
and storage
β
-cell apoptosis
β
-cell proliferation
glucagon secretion
insulin biosynthesis
insulin secretion
Heart
insulin
sensitivity
glucose production
Liver
Muscle
gastric emptying
Slide78American Diabetes Association. Diabetes Care. 2018;41(Suppl 1):S1-S159; Garber AJ, et al. Endocr Pract. 2018;24:91-120.
GLP-1 RAs Address Multiple Aspects of Pathophysiology and Complement the Actions of Other Antihyperglycemic Agents
GLP-1 RAs, DPP-4 inhibitors
↑ incretin effect
↑ insulin
↓ FPG
↓ PPG
↓ glucagon
↓ PPG
↑ satiety
↓ weight
SGLT2 inhibitors
↑ glucose excretion
TZD
↑ insulin sensitivity
Metformin, insulin
↓ hepatic glucose
Insulin, SU
↑ insulin
GLP-1 RAs can be combined with any other class of agents for T2DM (
except DPP-4 inhibitors
)
Combination therapy is often necessary in T2DM: agents with complementary actions should be used
Less risk of hypoglycemia
with glucose-dependent action
Unique to GLP-1 RAs
In addition to reducing glucose levels, GLP-1 RAs reduce the risk of weight gain, with a low risk of hypoglycemia
Slide79GLP-1 RA Meta-analysis: CV Mortality -Clearly It’s More Than About Glucose Control!Bethel MA, et al.
Lancet Diabetes Endocrinol. 2018;6(2):105-113.