Controversies in DiabetesTargeting HbA1C versus

cardiovascular risk reductionin Type 2 DM!

!!

Dr Rob Skelly Consultant Endocrinology Salhiya Medical Pavilion

Nine risk factors represent 90.4% of the risk of AMI

• Current or former smoking • History of diabetes • History of hypertension • Abdominal obesity • Combined psychosocial stressors • Irregular consumption of fruits and vegetables • No alcohol intake • Avoidance of regular exercise • Raised plasma lipids

Yusuf S, et al. Lancet 2004; 364: 937–952.

Data from British Regional Heart Survey.

18 20 22 24 26 28 30 32 341.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

6.6

6.2

5.8

Total cholesterol

Triglycerides

HDL cholesterol

Body Mass Index (kg/m²)

0

10

20

30

40

50

60

mm

ol/l

SBP%

with high SB

P

Obesity: cardiovascular riskBritish Regional Heart Study.

Metabolic syndrome: International Diabetes Federation definition

• Abdominal obesity (Europids: ♂ WC >94 cm, ♀ WC >80 cm)

plus any two of (or treatment for) the following:

– Elevated TG: ≥1.7 mmol/l – Reduced HDL-cholesterol: <1.03 mmol/l (♂)

<1.29 mmol/l (♀) – Raised BP: ≥130/85 mmHg – Raised fasting plasma glucose: ≥5.6 mmol/l

IDF Guidelines, 2004. International Diabetes Federation www.idf.org

Focus on waist circumference

↑TG↑BP

↑CRP

↑ GlucoseInsulin

response

macrovascular disease

microvascular disease

Development of Type 2 diabetes 1

Insulin resistance

1. Beck-Nielsen H & The EGIR. Drugs 1999; 58 (Suppl 1): 7–10. Modified from Sattar N. Clin Lab International 2005; 29: 7–11.

Insulin secretion

Metabolic syndrome increases CV morbidity and mortality

21

9

4.85.5

2.1 1.40

5

10

15

20

25

CHD PreviousMI

Previousstroke

4.6

2.2

12

18

0

5

10

15

20

25

Totalmortality

CV mortality

Inci

denc

e (%

)

Pre

vale

nce

(%)

Metabolic syndrome present

Metabolic syndrome absent

Isomaa B, et al. Diabetes Care 2001; 24: 683–689.

p<0.001

p<0.001

p<0.001

p<0.001

p<0.001

Morbidity Mortality

High risk of cardiovascular eventsin type-2 diabetes

-MI no prior myocardial infarction + MI prior myocardial infarctionHaffner SM. N Engl J Med. 1998; 339:229-234

7-yearincidence of

cardiovascularevents (%)

-MI +MI -MI +MI -MI +MI -MI +MI -MI +MI -MI +MI

Myocardial infarction

Stroke Cardiovasculardeaths

05

101520253035404550

Non-diabetics Type-2 diabetics

β-ce

ll Fu

nctio

n (%

)

PostprandialhyperglycemiaIGT T2DM

DiagnosisT2DM

Phase II

T2DM Phase III25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14Years From Diagnosis

Lebovitz HE. Diabetes Rev. 1999;7:139-153.

Progressive β-cell Failure• 60% of patients on insulin 5

years post-diagnosis • β-cell loss at 5% per year

FBG

PPBG

Progressive Decline in Beta Cell Function

UKPDS 16. Diabetes 1995; 44: 1249-58

20

40

60

80

100

Conventional Sulphonylurea Metformin

Non overweight Overweight

Beta cell loss ~4% per year

HO

MA

%B

00 1 2 3 4 5 6 0 1 2 3 4 5 6

Years from randomisation

This has become accepted dogma !! BUT

Effects of duration of type 2 diabetes mellitus on insulin secretion.

Endocr Pract. 2006 Jul-Aug;12(4):388-93.

Zangeneh et al, Rizza

C-peptide concentrations were measured every 2 years before and after intravenous injection of 1 mg of glucagon in 89 patients with type 2 diabetes (51 men and 38 women) as part of the Rochester Diabetic Neuropathy Study in those subjects who participated in follow-up (median, 12 years; range, 6 to 14).

Although insulin secretion decreased over time (P<0.001) in the group as a whole, both the pattern and the rate of decline in C-peptide concentration differed considerably among the study subjects.

Insulin secretion, whether measured as fasting C-peptide, 6-minute C-peptide, or postglucagon increment in C-peptide concentrations, declined with increasing duration of diabetes in approximately half of the patients but either increased or remained essentially constant over time in the other half.

The decrease in insulin secretion was not associated with a deterioration in glycemic control because hemoglobin A1c also declined (P<0.005) during the same interval.

Primary Metformin Randomisation

Conventionalglucose control

policy n=411

Intensive glucose control policy with

metforminn=342

Main Randomisation >120% ideal body weight n=1704

UKPDS 34. Lancet 1998; 352: 837-853

Enrolledn=5102

Intensive glucose control policy with

SU or Insulinn=911

753 in total

! 32% 0.0023

39% 0.010

36% 0.011

29% 0.19

0.6% HbA1c difference achieved in overweight patients allocated metformin compared with conventional Rx

!Median follow up 10.7 years (range 6 to 20)

! ARR RRR p “Any diabetes-related endpoint” 13.5%

Myocardial infarction 7.0%

All cause mortality 7.1%

Microvascular disease 2.5%

UKPDS Metformin Study Results

UKPDS 34. Lancet 1998; 352: 837-853

UKPDS: METFORMIN

• 342 PATIENTS !

• 40% MORTALITY REDUCTION NOT GLYCAEMIC RELATED !

• CARDIOVASCULAR PROTECTION ? HOW

PIOGLITIZONE

• PROACTIVE • 10 % reduction in study secondary endpoint:

all cause mortality, nonfatal MI and stroke Did not achieve statistical significance for primary endpoint which was a composite of all cause mortality, ACS ,stroke,

revascularisation, above knee amputation

• Long-Term Results of the Kumamoto Study on Optimal Diabetes Control in Type 2 Diabetic Patients Motoaki Shichiri, MD, PHD Hideki Kishikawa, MD, PHDYasuo Ohkubo, MD, PH Nakayasu Wake, MD

• Diabetes Care 23 (Suppl. 2):B21–B29, 2000

There were 110 patients divided into two cohorts: the primary prevention cohort (no retinopathy and urinary albumin excretion rate <30 mg/24 h, n = 55) and the secondary intervention cohort (simple retinopathy and urinary albumin excretion rate <300 mg/24 h, n = 55). These patients were randomly assigned to either a conventional insulin injection therapy (CIT) group (n = 55) or a multiple insulin injection therapy (MIT) group (n = 55).

The goal of the MIT group was to maintain glycemic control, which meant having an FBG level close to <140 mg/dl, a 2-h postprandial blood glucose concentration <200 mg/dl, an HbA1c level <7.0%, and a mean amplitude of glycemic excursions (MAGE) <100 mg/dl

Kumamoto trial: intensive therapy reduced microvascular complications

Nephropathy: 74% risk reductionRetinopathy: 68% risk reduction

Pat

ient

s (%

)

30

3 4 6 85 71 20

40

0

20

10

60

50 ConventionalIntensive

Year of study

3 4 6 85 71 20

30

0

40

20

10

50

Adapted from: Diabetes Care 2000;23(suppl 2):B21–29

Kumamoto trial: intensive therapy did not increase severe hypoglycaemia

• No incidences of severe hypoglycaemia in either group

!• Mild hypoglycaemic events

occurred only 1.6 times more often with intensive than with conventional treatment

0

5

10

15

20

25

30

35

40

Intensive ConventionalMild

hyp

ogly

caem

ic e

vent

s

per 1

00 p

atie

nt y

ears

Kumamoto trial: Diabetes Care 2000;23(suppl 2):B21–29

Kumamoto trial: similar weight gain in both treatment groups

0

19

20

21

22

Baseline Trial end

Intensive

Conventional

BM

I (kg

/m2 )

Kumamoto trial: Diabetes Care 2000;23(suppl 2):B21–29

From this study, the glycemic threshold to prevent the onset and progression of diabetic microvascular complications was as follows: HbA1c <6.5%, fasting blood glucose concentration <110 mg/dl, and 2-h postprandial blood glucose concentration <180 mg/dl.

The dopamine hypothesis

Glucagon receptor knockout prevents insulin-deficient type 1

diabetes in mice.Lee et al Diabetes. 2011 Feb;

60(2):391-7..

Reduced Incretin Effect in Type 2 Diabetic Patients

0

20

40

60

80

INSU

LIN

(mU

/L )

0 30 60 90 120 150 180TIME (min)

Control Subjects

Intravenous GlucoseOral Glucose

** * ** * *

0

20

40

60

80

INSU

LIN

(mU

/L )0 30 60 90 120 150 180

TIME (min)

Type 2 Diabetic Patients

**

*

Nauck M, et al. Diabetologia. 1986;29:46-52.

Incretin effect

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 Secretion and Inactivation

Intestinal GLP-1 release

GLP-1 (7-36) active

Mixed meal

GLP-1 (9-36) inactive

(>80% of pool)

DPP-4

T1/2 = 1 to 2 min

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 (9-36) inactive

Intestinal GLP-1 release

Mixed meal

GLP-1 (7-36) active

DPP-4

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

DPP-4 inhibitor

GLP-1 (7-36) active

Exenatide (Byetta)

♦ Synthetic exendin-4

♦ In clinical studies, exenatide exhibited actions that are similar to those of GLP-1:

♦ Stimulation of insulin secretion only when blood glucose concentrations are elevated

♦ Suppression of postprandial glucagon secretion

♦ Slowing of gastric emptying

Acute Meal Challenge Study:Postprandial Glucose and Glucagon Concentrations

Plas

ma

Glu

cago

n (p

g/m

L)

Plas

ma

Glu

cose

(mm

ol/L

)

0

5

10

15

20Exenatide or Placebo

Standardized Breakfast

0 60 120 180 240 300

Time (min)0 120 18030 9060 150

Time (min)

50

100

150

200

250Exenatide or Placebo

Standardized Breakfast

Placebo Exenatide 0.1 µg/kg

Placebo Exenatide 0.1 µg/kg

Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089

n=20 Mean ± SE

Effects of DPP-4 Inhibition

• ß-cell function • Glucagon secretion • Insulin sensitivity • ß-cell mass

Adapted from Ahrén B, et al. J Clin Endocrinol Metab. 2004;89:2078–2084.

Glycemic, Incretin, and Islet Cell Response to a Meal After 4 Weeks of Treatment With Vildagliptin

GlucagonGlucose

0

25

50

75

–30 0 30 60 90 120 150 180 210 240Time (min)

0

5

10

15

20

25

–30 0 30 60 90 120Time (min)

5.0

8.0

11.0

14.0

50

75

100

125

GLP

-1 [7

-36a

mid

e] (p

mol

/L)

Glu

cago

n (n

g/L)

Active GLP-1Insulin

Glu

cose

(mm

ol/L

)IR

I (µU

/mL)

PlaceboVildagliptin (100 mg qd)

GLP-1 = glucagon-like peptide–1

Normal Renal Glucose Physiology !

• 180 g of glucose is filtered each day !

• Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation !

• SGLT2 reabsorbs about 90% of the glucose !

• SGLT1 reabsorbs about 10% of the glucose !

• Virtually no glucose excreted in urine

The Kidneys Play an Important Role in Glucose Control

Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Targeting the Kidney

Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

Renal Glucose Transport

Effects of SGLT2 InhibitorsInhibition of renal tubular Na+- glucose cotransporter

reversal of hyperglycemia reversal of “glucotoxicity”

Insulin sensitivity in muscleGLUT4 translocation Insulin signaling

Insulin sensitivity in liverGlucose-6-phosphatase

GluconeogenesisDecreased Cori Cycle PEP carboxykinase

Improved beta cell function

DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14.

• Because of its effects in Na and glucose resorbtion reduces systolic BP as well as blood sugars and causes wt loss.

• In glucose clamp studies it has been noted that there is a ‘compensatory’ increased endogenous glucose production secondary to increased glucagon production that about 50% offsets the fall in blood sugar effected by the increased glycosuria .. It would seem logical to combine DDP-IV with SGL-T2 inhibitors to mitigate against this

Empagliflozin Safety Summary• In Phase 2b study !

- Reported adverse events were comparable among treatment groups ! !

- Urinary tract infection frequency was low (1.2%) and comparable to placebo (1.2%) and metformin (1.2%) !

- Incidence of genital infection was low: mycosis (0.8%) and pruritis (1.2%) with Empagliflozin versus none with metformin or placebo !

- Rates of hypoglycemia were similar between groups

Ferrannini E, et al. Abstract 877. EASD 2010.

• There is theoretical risk of hyponatremia greater with concomitant use of diuretics, watch in elderly.

VECTOR• Comparison of the dipeptidyl peptidase-4

inhibitor Vildagliptin and the sulphonylurea gliclazide in combination with metformin, in Muslim patients with type 2 diabetes mellitus fasting during Ramadan: results of the VECTOR study !

• Authors: Mohamed Hassanein, Wasim Hanif, Waqar Malik, Ali Kamal, Parnia Geransar, Nicola Lister, Chris Andrews, Anthony Barnett

• Journal: Current Medical Research & Opinion* *Accepted article that has been peer-reviewed & approved for publication in Current Medical Research & Opinion

1. VECTOR. doi:10.1185/03007995.2011.579951

VECTOR: Background• The type of oral antidiabetes drug

administered can affect hypoglycaemia risk. • In a UK retrospective audit:

– Fewer patients experienced hypos with Vildagliptin plus metformin during Ramadan than those taking an SU plus metformin (7.7% vs 61.5%, p<0.001). 1

!• VECTOR is the first prospective study to

have compared treatments in this at-risk fasting Muslim population. 1. Devendra D et al. Int J Clin Pract 2009; 63 (10): 1446–1450.

VECTOR: AimVildagliptin Experience Compared To gliclazide Observed during Ramadan

• Main aim – To determine the incidence of hypoglycaemic events in Muslim patients with T2D

fasting during Ramadan, who are treated with dual therapy of: • metformin plus vildagliptin • metformin plus sulphonylurea (SU) !

• Study Design – Prospective, real-life, observational, non-interventional, two-cohort study of ≤16

weeks

VECTOR: ObjectivesVildagliptin Experience Compared To gliclazide Observed during Ramadan

• Primary objectives – the incidence of hypoglycaemic events defined as:

• Any reported symptoms by the patient and/or any blood glucose measurement of less than 3.9 mmol/L (also defined as mild or Grade 1 hypoglycaemia)

• The need for third party assistance (also defined as severe or Grade 2 hypoglycaemia); • Secondary objectives

– the change in weight; – the change in HbA1c levels; and – the treatment adherence during Ramadan.

VECTOR: Patient demographics and baseline characteristics

1

1. VECTOR. doi:10.1185/03007995.2011.579951

DOES TIGHTER METABOLIC CONTROL

INCREASE MORTALITY?

!• To determine whether CVD event rates

can be reduced in people with diabetes by intensively targeting three important CVD risk factors: hyperglycemia, dyslipidemia, and high blood pressure.

• Three trials in one research program –Double 2 by 2 factorial design

ACCORD Trial Overall Goal

Buse, JB, et al, AmJCard 2007 99:21i-33i.

!• In middle aged/older people with type 2 DM

at high risk for a CVD event, does a therapeutic strategy that targets an A1C < 6.0% reduce CVD event rates more than a strategy that targets an A1C between 7.0% & 7.9% (with the expectation of achieving a median level of 7.5%)?

Glycemia Trial Research Question

Buse, JB, et al, AmJCard 2007 99:21i-33i.

Intensive Glycemia (A1C<6%) 5128*

Standard Glycemia (A1C 7-7.9%) 5123*

LipidStatin + Masked Study Drug

Statin + Masked Study Drug

BPIntensive (SBP<120)

Standard (SBP<140)

2765*2753*2362* 2371*

1178 1193

11781184

1374

13911370

1383

10,251*Primary analyses compare the marginals for main effects

Double 2 X 2 Factorial Design

Buse, JB, et al, AmJCard 2007 99:21i-33i.

• Stable Type 2 Diabetes for 3+ months • A1C >7.5% AND <9% (more meds) OR <11% (fewer meds) • Age 40-79 + previous CVD events OR • Age 55-79 with:

– anatomical ASCVD, albuminuria, LVH OR – > 2 CVD risk factors (dyslipidemia, hypertension,

smoking, obesity) • BMI < 45; Cr < 1.5 (133 uM) • No frequent/recent serious hypoglycemia • Able/willing to take insulin, do glucose monitoring • Eligible for BP or Lipid Trial

Participant Eligibility

Buse, JB, et al, AmJCard 2007 99:21i-33i.

• Primary: – First occurrence of nonfatal MI OR Nonfatal Stroke OR

CV Death • Secondary/Other:

– Each component of 10 – Expanded CVD: 10 + Revasc & HF Hosp – Total mortality – Microvascular (nephropathy, neuropathy, eye) – Eye photo substudy (N = 3537) – HRQL (N = 2053); Cost (N = 4311) – MIND: cognition, brain volume (MRI) – Falls/Fractures/BMD

ACCORD Outcomes

Buse, JB, et al, AmJCard 2007 99:21i-33i.

Intensive N (%)

Standard N (%) HR (95% CI) P

Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16

Secondary

Mortality 257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04

Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004

Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74

CVD Death 135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02

CHF 152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17

Primary & Secondary Outcomes

ACCORD Study Group, NEJM 2008 358:2545-2549.

➢Among participants who never had a severe hypoglycemic event during follow-up, mortality was greater in the intensive group. However, among participants who had a hypoglycemic event, mortality was greater in the standard group

➢Participants who had experienced a severe hypoglycemic event were more likely to die "

• True for both treatment groups

Conclusions—I

ACCORD Study Group, NEJM 2008 358:2545-2549.

• We have not been able to identify a single agent, or combination, that accounts for the imbalance in mortality. – Exenatide ➔ less mortality, but used rarely and more often in

Intensive Glycemia group – Premixed Insulin ➔ greater mortality, but used more often in

Standard Glycemia group – Bolus Insulin ➔ greater mortality, but no difference in mortality

hazard ratios by randomized group and we don’t know if the relationship with mortality is a reflection of use or the participants to whom it was given

– Approximately a 20% increase in mortality associated with Intensive Glycemia even after controlling for participant characteristics and post-randomization use of glycemia medications.

Conclusions—II

ACCORD Study Group, NEJM 2008 358:2545-2549.

Never Experienced a

Hypoglycemic Event

Experienced Hypoglycemic Event

Overall Mortality Rates

1.2% / year 3.3% / year

Again, mortality is higher among participants who had experienced a Severe Hypoglycemic Event,

regardless of treatment strategy

Background: Mortality By Severe Hypoglycemia

Intensive Glycemia 1.3% / year 2.8% / year

Standard Glycemia 1.1% / year 4.9% / year

ACCORD Study Group, NEJM 2008 358:2545-2549.

ADVANCE: Study Design

ADVANCE Baseline Characteristic

Characteristic Standard (5569) Intensive ( 5571)

Mean age 66 years 66 years

Female 42.3% 42.6%

Mean A1c 7.52% 7.51%

Duration of DM 8.0 years 7.9 years

Mean BMI 28 kg/meter sq. 28 kg/meter sq.

ADVANCE Primary Outcomes

ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

ADVANCE: Primary Outcomes

ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

ADVANCE: Secondary Endpoints

• All-cause mortality: P = NS

• Total renal events 11% RR with intensive, P < 0.001

• Eye events: P = NS

• CHF, PVD, neuropathy: P = NS

ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

Differences Between ACCORD/ADVANCEBASELINE ACCORD ADVANCE # patients 10,251 11,140 duration DM (yrs) 10 8 Hx macrovasc. Dz (%) 35 32 Baseline A1C (%) 8.1 7.2 Intervention target A1C (%) <6 <6.5 insulin Rx (%) 77 vs. 55 41 vs. 24 TZD Rx (%) 92 vs. 58 17 vs. 11 Outcome (intensive vs. standard) Median A1C @ study end 6.4 vs. 7.5% 6.4 vs. 7.0% DEATH: any cause 5.0 vs. 4.0%* 8.9 vs. 9.6%

NEJM 2008;358, 2630 *P<0.05

VADT Study Background

• 1,791 patients no longer responsive to oral agents alone followed 5 to 7.5 years.

!• Primary endpoint was MACE (major

macrovascular events: AMI, CVA, CHF (new or worsened), amputations, invasive procedures (CAD, PVD), or death.

!• Randomized to either Intensive Rx. (A1c

=6.5%) versus Standard Rx. (A1c = 8.5%)

VADT Baseline Characteristics

Characteristic Standard Rx (899)

Intensive Rx (892)

Mean age 60.3 years 60.5 years

Female 3% 3%

Mean A1c 9.4% 9.4%

Duration DM 11.5 years 11.5 years

Mean BMI 31.2 31.3

VADT: Comparing Intensive With Standard Glucose Therapy, Change in Median A1C

VADT: Comparing Intensive With Standard Glucose Therapy, Primary Outcome

VADT: Comparing Intensive With Standard Glucose Therapy, Secondary Outcomes

Big Picture Message

• T2DM: patients with known CVD or long durations of DM may be harmed by meticulous control; although the mechanism(s) for this are not known, the leading candidate mechanism is hypoglycemia