AACE/ACE COMPREHENSIVE

TYPE 2 DIABETES
MANAGEMENT ALGORITHM
Sherwin D’Souza, MD, FACE
Prediabetes Treatment Algorithm
• Weight-loss agents orlistat, lorcaserin, and
phentermine/topiramate can prevent
progression to T2DM
– Improve BP, triglycerides, and insulin sensitivity
• Metformin and acarbose can reduce progression
to T2DM by 25% - 30%
– Use for prediabetes is off-label
– Both are safe, confer CVD risk benefit;
metformin is well tolerated
• TZDs prevented progression to T2DM in 60% -
75% of patients in clinical trials
– Associated with adverse outcomes
• GLP-1 receptor agonists may be as effective as
TZDs
T2DM = type 2 diabetes mellitus
BP = blood pressure
– Promote weight loss, but inadequate safety data
CVD = cardiovascular disease
TZD = thiazolidinedione
• TZDs and GLP-1 RAs reserved for patients not
GLP-1 RA= glucagon-like peptide-1 receptor agonist responding to conventional therapies or at
highest risk for T2DM
AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557.
 The Ticking Clock

Increased risk for both microvascular and

macrovascular disease begins early in the prediabetic
state
u -Insulin resistance is already present in patients with NGT who
later develop T2DM
u -Patients with prediabetes already have high insulin resistance
and significantly decreased beta-cell function
u -Both diabetic retinopathy, peripheral neuropathy, and
nephropathy occur in patients with prediabetes
u -Patients with prediabetes have a 2 to 3-fold increase in CHD risk,
similar to patients with diabetes

CHD = coronary heart disease; NGT = normal glucose tolerance; T2DM = type 2 diabetes mellitus
AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557;
DeFronzo RA et al. Am J Cardiol. 2011;108(3 Suppl):3B-24B
Risk of Hypoglycemia
u Plays a significant role in choice of agents in AACE
algorithm
u For patients at highest risk of hypoglycemia, may
consider close evaluation of agents chosen as well as
therapeutic goal
u Patients with type 2 diabetes at highest risk of low blood
glucose include those with:
u Diabetes duration >15 years
u Advanced macrovascular disease
u Hypoglycemia unawareness
u Limited life expectancy
u Severe comorbidities

AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557;

AACE Algorithm for Glycemic Control, Endocr Pract. 2009;15(6):540-59.
Clinical Considerations

u Combining therapeutic agents with different modes

of action may be advantageous
u Use insulin sensitizers such as metformin and/or
TZDs as part of the therapeutic regimen in most
patients (unless contraindicated or intolerance to
these agents has been demonstrated)
u Insulin and secretagogues are the only medications
that cause significant hypoglycemia
u Therefore, dosage of secretagogues or insulin should be
adjusted as blood glucose levels decline, when used in
combination with metformin, TZD, DPP-4 inhibitors, and/or
incretin mimetics (GLP-1 agonists)
TZD = thiazolidinediones; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1
AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557.
Sitagliptin [package insert]. Whitehouse Station, NJ; Merck Co. Inc.; 2010. Saxagliptin [package insert]. Princeton, NJ; Bristol Meyers Squibb;
2009; Linagliptin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals. 2011.
 Effect of Glucose-lowering Drugs
on Patient Weight
Therapeutic Options Weight

Sulfonylurea1,2

TZD3,4

Insulin5,6

Metformin7

DPP-4 inhibitor8

GLP-1 receptor agonist9

10
SGLT-2 Inhibitors
A1C = glycated hemoglobin; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SGLT-2 = sodium glucose co-transporter-2;
TZD = thiazolidinedione
1. Malone M. Ann Pharmacother. 2005;39:2046-2055. 2. Glipizide [package insert]. New York, NY; Pfizer; 2006. 3. Pioglitazone [package insert]. Deerfield,
IL: Takeda Pharmaceuticals America; 2007. 4. Rosiglitazone [package insert]. Research Triangle Park, NC; GlaxoSmithKline; 2007. 5. Nathan DM, et al. Diabetes Care.
2008;31(1):173-175. 6. Holman RR. NEJM. 2007;357(17):1716-1730. 7. Metformin[package insert]. Princeton NJ; Bristol Meyers Squibb; 2009. 8. Sitagliptin [package insert].
 -Metformin – 1st choice (if no contraindication)
-Consider drugs in the order suggested
-Order of medications represents a suggested hierarchy
of usage
-Length of line reflects strength of recommendation
-SFU’s are lowest on the list (Short-lived effect, strong risk of
hypoglycemia that may increase hospitalizations in elderly patients, may
increase MI risk, contraindicated for patients with renal failure)

-If unsuccessful, move to dual oral rx

Metformin still cornerstone of therapy
(If contraindicated, consider TZD as foundation of rx)

• Road Map to Achieve Glycemic Goals A1c < 7.5%

Dual therapy
with
If dual oral Rx is
metformin
successful,
provides
consider triple
superior
therapy
glycemic
control
over
metformin If triple oral rx fails to
alone. achieve A1C goal,
initiate insulin

AA Glycemic Goals
A1c 7.5-9% Road Map to Achieve
 Algorithm to Achieve Glycemic Goals
Baseline A1C > 9.0%

If patient is asymptomatic with

recent onset of disease and drug
naïve, may consider starting
with dual or triple oral If symptomatic,
regimens start insulin

Once A1C has improved to <7.5%, consider

initiation of dual oral therapy with tapering
and possible discontinuation of insulin rx
AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557.
UKPDS: Benefits of Glycemic Control

Every 1% decrease in A1C led to significant

reductions in diabetes-related complications

14%
21%
37%
43%
Risk of
myocardial
infarction Risk of diabetes-
related death Risk of
microvascular
complications
Risk of
amputation or
PVD Death

Decrease was statistically significant for all comparisons shown

Stratton IM et al. BMJ. 2000;321:405-412.

Landmark Glycemia Trials

u Action to Control Cardiovascular Risk in Diabetes (ACCORD)

u Action in Diabetes and Vascular Disease Preterax and
Diamicron MR Controlled Evaluation (ADVANCE)
u Veterans Affairs Diabetes Trial (VADT)
u All conducted in:
u “Older” patients (≥60 years of age)
u Patients with cardiovascular disease (CVD; 1/3 to 1/2 of
cohorts)
or
u ≥1 CVD risk factors

Ray et al. Lancet. 2009;373:1765–72.

 Probability of All-cause Mortality with
Intensive Glucose-lowering vs. Standard
Treatment

All-cause mortality

Ray et al. Lancet. 2009;373:1765–72.

EMPA –REG(empagliflozin)

u Empagliflozin is the first SGLT2 inhibitor to report CV

benefit
u 14% reduction in the hazard of MACE in over 7000
patients with T2DM + CVD
u 38% reduction in CV mortality
u Heart failure hospitalization was reduced by 38%
u Also shown to have renal benefits: 39% decrease in pre
specified end points(progression to macroalbuminuria,
doubling of serum Cr, worsening nephropathy, initiation
of renal replacement therapy).
LEADER-Trial (Liraglutide)

u Liraglutide is the second Drug to show CV benefits

u 13% lower risk of primary composite MACE outcome
u 22% lower risk of CV mortality
u 15% lower risk of all cause mortality
u 15% lower risk of microvascular (renal events-driven
mainly by reduction in macroalbuminuria)
CVOT’s-Summary

u Empagliflozin has an FDA indication to reduce the risk of

cardiovascular death in adult patients with type 2 diabetes
mellitus and cardiovascular disease.
u On 8/25/17, FDA approved a new indication for
Victoza® (liraglutide) to reduce the risk of major adverse
cardiovascular (CV) events, heart attack, stroke and CV
death, in adults with type 2 diabetes and established CV
disease
u Weigh the risk vs benefits of all antihyperglycemic agents
before prescribing.
u ADA 2017 and AACE/ACE 2017 guidelines now include
recommendations for considerations of empagliflozin or
liraglutide in patients with T2 DM not at goal and
established atherosclerotic CVD.
CVOT’s and Diabetes in 2017-
some takeaways..
u Based on recent CVOT’s, the manner in which glucose is
lowered is more important than the degree of glucose
lowering.
u Should we be using therapies proven to reduce CV
events in those with pre-existing CVD?
u In those without CVD and mild hyperglycemia, DPP-4
inhibitors may be reasonable options.
u Pioglitazone has limited use but can be considered in
the very insulin resistant patient with no major risks of
HF
CVOTs and Diabetes in 2017-
any takeaways?
u Sulfonylureas could be used selectively in those with
intact renal function possibly third line in those not
able to use the other agents(avoid in elderly)
u If the HbA1c is very high, insulin therapy remains the
most efficacious therapy as long as the dose is
appropriately titrated.
u COST remains the major issue with branded medications
and of course this aspect must be taken into account.
Thanks for your attention!