Glucose Lowering Treatment

and Strategies

Dorte Lindqvist Hansen, MD, Ph.D.

 ADA 2016 Guidelines
Recommendations for Antihyperglycemic Therapy in Type
2 Diabetes
Lifestyle changes: healthy eating, weight control, increased physical activity, diabetes education

Monotherapy
Metformin

If A1C target not achieved after 3 months of monotherapy, proceed to:

Dual
Metformin +
therapy* Metformin + Metformin + Metformin + Metformin + Metformin +
SGLT2
Sulfonylurea TZD GLP-1 RA DPP-4 inhibitor Insulin (basal)
inhibitor
If A1C target not achieved after 3 months of dual therapy, proceed to:
Metformin + Metformin + Metformin + Metformin + Metformin + Metformin +
Triple TZD + SGLT2 + Insulin
therapy SU + GLP-1 RA + DPP-4
SU or SU or (basal) +
TZD or SU or inhibitor +
DPP-4 or DPP-4 or TZD or
DPP-4 or GLP-1 TZD or SU or
GLP-1 or TZD or DPP-4
or insulin‡ insulin‡ TZD or insulin‡
insulin‡ Insulin‡ or GLP-1
If A1C target not achieved after 3 months of triple therapy and patient (1) on oral combination, move
to injectables; (2) on GLP-1, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1
or mealtime insulin. Refractory patients: consider adding TZD or SGLT2.
Combination
injectable Basal insulin + Mealtime insulin or GLP-1 MET ?
therapy†
Risk of CVD is 2-fold increased in people with
type 2 diabetes
 Glucose control and CVD

Study Microvascular CVD Mortality

events

UKPDS1

ACCORD2

ADVANCE3

VADT4,5

Initial trial Follow-up

CVD=cardiovascular disease; RCT=randomized controlled trials.

1. Holman RR, et al. N Engl J Med. 2008;359:1577–1589; 2. Gerstein HC, et al. N Engl J Med. 2008;358:2545–2559;
3. Patel A, et al. N Engl J Med. 2008;358:2560–2572; 4. Duckworth W, et al. N Engl J Med. 2009;360:129–139;
5. Hayward RA, et al. N Engl J Med. 2015;372:2197–2206.
Danish T2DM treatment guidelines

 Launched April 2014

 Shared care perspective, based on a consensus
between
 Diabetologists
 GPs
 Evidence based
 Uses HbA1c as criteria for diabetes
 Based on patient education and self managesment
The Danish treatment algorithm
HbA1c target value is individual

HbA1c <48 mmol/mol (6.5%) in the first years, where hypos are of little
concern. Aims to reduce complications

HbA1c <53 mmol/mol (7.0%) in later phases, balancing between hypos and
the risk for microvascular complications

HbA1c <58 mmol/mol (7.5%) in long-term patients with hypos and

macrovascular complications (IHD, PAD and stroke)

HbA1c 58-75 mmol/mol (7.5 - 9.0%) in elderly patients in whom only

symptoms are treated
 ADA 2016 Guidelines
Recommendations for Antihyperglycemic Therapy in Type
2 Diabetes
Lifestyle changes: healthy eating, weight control, increased physical activity, diabetes education

Monotherapy
Metformin

If A1C target not achieved after 3

Dual
If A1C target not achieved after 3 months of monotherapy, proceed to:
Metformin +

months of monotherapy, proceed to:

therapy* Metformin + Metformin + Metformin + Metformin + Metformin +
SGLT2
Sulfonylurea TZD GLP-1 RA DPP-4 inhibitor Insulin (basal)
inhibitor
If A1C target not achieved after 3 months of dual therapy, proceed to:
Metformin + Metformin + Metformin + Metformin + Metformin + Metformin +
Triple TZD + SGLT2 + Insulin
therapy SU + GLP-1 RA + DPP-4
SU or SU or (basal) +
TZD or SU or inhibitor +
DPP-4 or DPP-4 or TZD or
DPP-4 or GLP-1 TZD or SU or
GLP-1 or TZD or DPP-4
or insulin‡ insulin‡ TZD or insulin‡
insulin‡ Insulin‡ or GLP-1
If A1C target not achieved after 3 months of triple therapy and patient (1) on oral combination, move
to injectables; (2) on GLP-1, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1
or mealtime insulin. Refractory patients: consider adding TZD or SGLT2.
Combination
injectable Basal insulin + Mealtime insulin or GLP-1 MET ?
therapy†
Traditionel stepwise type 2-diabetes treatment

 ADA/EASD guidelines recommends

sequentially intensified treatment
following the failure of existing
therapy

 This approach is unlikely to enable

maintenance of target HbA1c and may
result in prolonged periods of time
with poor control

Ref 1: Inzucchi SE, et al. Diabetes Care 2015;38:140–149; Ref 2: Del Prato S. Int J Clin Pract 2005;59:1345–55 Ref 3: www.endocrinology.dk
The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c
Metformin
ADA: “Metformin, if not contraindicated and if tolerated, is the
preferred initial agent in type 2 diabetes”.

Advantages Disadvantages
 Reduce HbA1c 15 mmol/mol  GI-Side effects up to 50%
(1.5%)  Reduced dose or
 Long clinical experience discontinuation in patients
 Inexpensive with reduced kidney function

 Reduce body weight

 May reduce cardiovascular
mortality?
Your patient with BMI of 31 is not Vote
satisfactory controlled on Metformin Now
- what will be your action?
1. Enhance strict diet and exercise

2. Add SU

3. Add Insulin

4. Refer to bariatric surgery

5. Add SGLT-2 inhibitors

6. Add DPP4-inhibitors

7. Add GLP-1 agonist

The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

contra-indications to Metformin

Sulfonyl Glitazones DPP-4

GLP-1 RA SGLT-2 Insulin
urea Acarbose inhibitors
The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

contra-indications to Metformin

Sulfonyl Glitazones DPP-4

GLP-1 RA SGLT-2 Insulin
urea Acarbose inhibitors

No major use in Denmark

- Glitazone: only in highly insulin resistant patients
- Acarbose: GI side effects and low impact on BG
The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

contra-indications to Metformin

Glitazones DPP-4
GLP-1 RA SGLT-2 Insulin
Sulfonyl Acarbose inhibitors
urea
Sulfonylurea as 2nd treatment

SU´s causes an
initial decrease in
HbA1c, but
thereafter there is a
progressive
increase in HbA1c
due to loss of beta-
cell function

Adapted from DeFronzo RA. Am J Med 2010; 123: S38-S48

SU increases body weight
to the same extent as insulin
Mortality and Cardiovascular Risk Associated with different Sulfunylurea
and insulin compared with metformin in type 2 diabetes -a nationwide
study
(n > 100.000 patients; 9600 with previous MI)

Schramm TK European Heart Journal (2011) 32, 1900–1908

Sulfonylurea

Advantages Disadvantages

 Reduce HbA1c 10-20  Hypoglycemia

mmol/mol (1-2%)  Weight gain
 Long clinical experience  Limited durability
 Inexpensive  Concerns about
cardiovascular safety
Sulfonylurea

Sulfonylurea should be used cautiously in

patients with cardiovascular complications and in
patients with an increased risk for hypoglycemia,
especially elderly patients or those who have
reduced kidney function
The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

contra-indications to Metformin

Sulfonyl Glitazones
urea SGLT-2 Insulin
Acarbose DPP-4
GLP-1 RA
inhibitors

Incretin
based
therapy
The Incretin Effect Demonstrates
the Response to Oral vs IV Glucose
Oral Glucose
IV Glucose

11 2.0
Venous Plasma Glucose (mmol/L)

C-peptide (nmol/L)
1.5 * *
* Incretin Effect
*
5.5 1.0 *

*
0.5

0 0.0
01 02 60 120 180 01 02 60 120 180
Time (min) Time (min)
GLP-1 Agonist and DPP-4 Inhibitors
 Active GLP-1 is rapidly
degraded by DPP-IV
Meal
Intestinal
GLP-1
release
Active
GLP-1

DPP-4

GLP-1
inactive
GLP-1 = Glucagon-Like Peptide-1; DPP-4= Dipeptidyl Peptidase-4
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
 DPP-4 Inhibitors Have Comparable Glycaemic
Efficacy to Sulphonylureas as Add-On to Metformin
7.8 7.4
7.2
7.4

HbA1c (% )
HbA1c (% )
7.0
7.0
6.8
6.6
6.6
6.2 Glipizide (up to 20 mg/day) + metformin 6.4 Glimepiride (up to 6 mg/day) + metformin
Sitagliptin (100 mg/day) + metformin Vildagliptin (50 mg bid) + metformin
5.8
0 12 24 38 52 60 78 1 104 -4 0 12 24 40 52 65 78 91 104 117
Weeks Weeks
8.0
7.75
Glimepiride (up to 4 mg/day) + metformin
HbA1c (% )

7.50 Linagliptin (5 mg bid) + metformin

HbA1c (% )
7.5
7.25 Glipizide (up to max 20 mg/day) + metformin
Saxagliptin (5 mg qd) + metformin
7.00
7.0
6.75

6.50 6.5
BL 6 12 18 24 30 39 52 0 4 8 12 16 28 40 52 65 78 91 104
Weeks Weeks
Matthews et al, Diabetes Obes Metab 2010
Seck et al, Int J Clin Pract 2010 Gallwitz et al, ADA 2011 (Poster 39-LB)
Göke et al, Int J Clin Pract 2010
DPP-4 Inhibitors

Advantages Disadvantages
 Oral therapy  Modest reduction in
 No titration HbA1c 6mmol/mol (0.6%)

 Weight neutral  Expensive

 No hypoglycemia  risk heart falliure
hospitalisation?
 No difference between (saxigliptin)
agents
 Few side effects
 Vomiting

Diarrhoea
Nausea
Abdominal pain
Increasing plasma GLP-1
GLP-1 level during
treatment with
concentrations GLP-1 R agonists

Appetite
Food intake
Weight loss

Gastric emptying

Insulin secretion
Plasma glucose
Glucagon secretion

GLP-1 level during

GLP-1 effects treatment with
DPP-4 inhibitors
Madsbad. Lancet 2009; 373: 438-39
 26

LEADER TRIAL

 Aim: To investigate the effect on liraglutide 1.8mg as ad on to

standard therapy on cardiovascular outcome

 N=9340
 High risk individuals age >50 years with established cardiovascular
disease, or cardiovascular risk factor

 Primary outcome
 Cardiovascular death/non fatal myocardial infarction/non fatal stroke

N Engl J Med Volume 375(4):311-322 July 28, 2016

Leader Trial
Effect on HbA1c and Body Weight

Marso SP et al. N Engl J Med

 Primary and Exploratory Outcomes.
Leader Trial
CV-Outcome

Marso SP et al. N Engl J Med 2016;375:311-322

GLP-1 Agonist

Advantages Disadvantages
 Reduce HbA1c 10 mmol/mol  Expensive
(1%)  Injection
 Reduce body weight  GI-side effects
 Reduce cardiovascular
mortality?
 No hypoglycemia
The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

contra-indications to Metformin

Sulfonyl Glitazones DPP-4

GLP-1 RA Insulin
urea Acarbose inhibitors SGLT-2
SGLT2 I: Inhibition of sodium – glucose
reabsorption in the proximal tubules
SGLT2

Proximal tubule

SGLT2i
SGLT2 Glucosuria (~70 g/d; 280
Glucose kcal/d)
 SGLT-2 Inhibitors 32

EMPA-REG OUTCOME

 Aim; To examine the effect of empagliflzcin as ad on to

standard therapy on cardiovascular outcome

 N=7020
 Mean age 63 years and with established cardiovascular disease
 Primary outcome
 Cardiovascular death/myocardial infarction/stroke

Zinman B et al. N Engl J Med 2015;373:2117-2128

 EMPA-REG OUTCOME
Effect on HbA1c Levels.

Zinman B et al. N Engl J Med 2015;373:2117-2128

 EMPA-REG OUTCOME
Cardiovascular Outcomes and Death from Any Cause.

Zinman B et al. N Engl J Med 2015;373:2117-2128

SGLT-2 Inhibitors
Advantages
 Reduce HbA1c 10 mmol/mol
(1%)
 Insulin independent effect
 Reduce body weight
 No hypoglycemia
 May reduce cardiovascular
mortality
Disadvantages
 Genitourinary infections
 Expensive
 No effect in patents with
reduced kidney function
 DKA??
The Danish treatment algorithm

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

contra-indications to Metformin

Sulfonyl Glitazones DPP-4

urea GLP-1 RA SGLT-2
Acarbose inhibitors Insulin
Insulin treatment of T2DM
Fix fasting first * continue metformin * no insulin of choice
Biphasic insulin Basal insulin
morning and/or morning and/or
evening evening

Biphasic insulin Basal insulin x 1-2

X3 Plus bolus insulin x 1-2

Basal insulin x 1-2

Plus bolus insulin x3
> 40 IU, split dose in morning and evening
> 40-60 IU in one dose, use two injections
Conclusion

T2DM Lifestyle changes: diet, stop smoking, exercise

diagnosed Metformin 850-1000 mg x 2 irrespective of HbA1c

Failure to reach target, side effects, or

If HbA1c target is not achievedcontra-indications
or maintained toover 3 months,
Metformin
intensified treatment is necessary
Sulfonyl Glitazones DPP-4
GLP-1 RA SGLT-2 Insulin
urea Acarbose inhibitors
The 2nd and 3rd drug of choice depends on
• Patient’s wishes
• Weight
• Co-morbidities
• Efficacy and side-effects
• Risk of hypoglycemia
• Cost and accessibility of the drugs
Thank You for Your Attention
Questions?

There are limits what you can do to an old car!