# Presentation: 572097

## Macrovascular Outcomes with Antidiabetic Drugs:   Ongoing Studies

**Hertzel C. Gerstein MD MSc FRCPC**
- Professor & Population Health Institute Chair in Diabetes Research
- McMaster University & Hamilton Health Sciences
-  Hamilton, Ontario, CANADA

## Chronic Consequences of Type 2 DM

- Eye (cataracts, retina)
- Kidney (CRF, ON)
- Nerve (sensory, motor)
- Foot (pain, ulcer)
- Amputation (BKA)
- Ischemic Heart Disease
- Stroke
- Peripheral Vascular Disease
- Cirrhosis

- Early Death
- Cognitive Decline
- Depression
- Hip Fractures
- Imbalance & Frailty
- Connective Tissue (joint)
- Erectile Dysfunction
- Sexual Dysfunction
- Infertility/PCOS

## Outline

**What is the relationship between diabetes & CVD?**
- What is the relationship between glycemia & CVD in people with/without diabetes?
- Does glucose lowering reduce CVD outcomes?
- Do glucose-lowering drugs reduce CVD outcomes?

## Risk of Fatal CHD with Diabetes

**Huxley R et al. BMJ 2006:73**

**Risk of Fatal CHD with Diabetes**

## Outline

- What is the relationship between diabetes & CVD?
**What is the relationship between glycemia & CVD in people with/without diabetes?**
- Does glucose lowering reduce CVD outcomes?
- Do glucose-lowering drugs reduce CVD outcomes?

## Meta-Analysis: A1c & CV Risk- DMType 2 DM Studies: Selvin et al. Ann Int Med 2004: 421

**Cardiovascular Disease (CHD & Stroke)**

**18% (10%-26%) **
**per 1% Higher A1c**

## G & CV Events: Meta-Regression

**   ****@ 2 hr G = 140.......                            @ Fasting G = 110......**
**   ****RR=1.58 (1.19-2.10)                             RR=1.33  (1.06-1.67)**

**After remove any DM:****	*****P***** = 0.0006 for 2 h G**
**	*****P***** = 0.06 for FPG **

- Coutinho M, Gerstein HC et al. *Diabetes Care. *1999;22:233-240.

- RR

- RR

**72        108        144        180      198**

**72       90      108    126    144     163**

**2 h Glucose**

**Fasting Glucose**

## Usual Fasting Glucose vs. CVD Sex & Study Stratified; Age-adjusted

**Hazard Ratio (95% CI)**

**Risk: 21% (CI 18-24) rise per 1 mmol/L rise in glucose**

**Total Ischemic **
**Heart Disease**

**Asia Pacific Cohort Studies Collaboration. *****Diabetes Care*****. 2004;27: 2836-2842.**

**Usual Fasting Glucose vs. CVD ****Sex & Study Stratified; Age-adjusted**

**Total Stroke**

**4.0**

**2.0**

**1.0**

**0.5**

**CV Death**

**Risk: 23% (CI 19-27) rise per 1 mmol/L rise in glucose**

**Risk: 19% (CI 15-22) rise per 1 mmol/L rise in glucose**

## 2-hr Post 50g Blood G vs. CHD Death

**Brunner EJ, et al. *****Diabetes Care*****. 2006:29:26-31.**

**2-hr Post 50g Blood G vs. CHD Death**

_**Excluded New DM from Analysis; Threshold = 4.6 mM**_
**Age-adjusted HR: 1.22 (1.14-1.30)/1 mM 2 hr G rise >4.6**
**Multiple adjusted HR: 1.12 (1.04-1.19)/1 mM 2 hr G rise >4.6 **

**1.6 **–

**1.4 **–

**1.2 **–

**1.0 **–

**0.8 **–

**0.6 **–

**0.4 **–

**0.2 **–

**0 **–

**–****0.2 **–

**–****0.4 **–

**3.0**

**4.0**

**5.0**

**6.0**

**7.0**

**8.0**

**9.0**

**10.0**

**Log Hazard Ratio***

**Blood Glucose (mmol/L)**

## Cartoon: G & Risk of Problems

**Eye**

**CVD**

## Outline

- What is the relationship between diabetes & CVD?
- What is the relationship between glycemia & CVD in people with/without diabetes?
**Does glucose lowering reduce CVD outcomes?**
- Do glucose-lowering drugs reduce CVD outcomes?

## Intensive Insulin & CVD: Type 1 DM DCCT/EDIC NEJM 2005;353:2643

**Primary CV Composite**
**RRR= 42% (9-63)**

**RRR after adj. for updated GHb until end of DCCT (or CV event during DCCT): ****16% (-64 – 57) P=0.61**

## G Lowering to Prevent CVD Trials in People with Dysglycemia

**G Lowering to Prevent CVD ****Trials in People with Dysglycemia**

**Yrs from Dx ******

**0**

**5**

**-10**

**-5**

**10**

**15**

**ACCORD**

**VADT **

**Eye, Kidney, Nerve Disease**

**CVD**

***Dysglycemia - - - - - - - - - - - - - - - - - - - - - - - *********

**      ****ORIGIN**

**ADVANCE**

## Research Question:

-    In middle aged or older adults with type 2 DM at high risk for a CVD event because of _***existing CVD or additional CVD risk factors***_**,** does a _***therapeutic strategy***_ that targets A1C <6.0% reduce the rate of CVD events more than a strategy that targets A1C 7.0% to 7.9%?
- Participant baseline characteristics:
- Age: average 62 years
- Known DM duration:  average 10 years
- Existing CVD:  in 35%
- BMI:  average 32
- A1C:  mean 8.3%; median 8.1%
- On insulin therapy:  35%

**NEJM 2008;358:2545**

## Slide 15

## Slide 16

|  | 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 |

## 1.41%/yr

**1.41%/yr**

**1.14%/yr**

**HR = 1.22 (1.01-1.46)**
**P = 0.04**

## 2.29%/yr

**2.29%/yr**

**2.11%/yr**

**HR = 0.90(0.78-1.04)**
**P = 0.16**

## ADVANCE RCT – Glycemic QuestionAction in Diabetes and Vascular Disease

***Participants***
- N = 11,140; Type 2 DM
***Eligibility***
- Age _>_ 55; DM Dx after age 30; High CV Risk
***Intervention***
- G Question: 	Gliclazide based glucose lowering vs. 				Standard Care; Added Rx  A1c _<_ 6.5%
***Primary Outcome****** ***
- Micro or CVD events
***Power Issues***
- F/U – 5 yrs; 90% power for 16% RRR

- Diabetes Care 2004;27:1647

## ADVANCE Results: HbA1c 

**NEJM 2008;358:2560**

**NEJM 2008;358:2560**

## G Lowering to Prevent CVD Trials in People with Dysglycemia

**G Lowering to Prevent CVD ****Trials in People with Dysglycemia**

**Yrs from Dx ******

**0**

**5**

**-10**

**-5**

**10**

**15**

**ACCORD**

**VADT **

**Eye, Kidney, Nerve Disease**

**CVD**

***Dysglycemia - - - - - - - - - - - - - - - - - - - - - - - *********

**      ****ORIGIN**

**ADVANCE**

## Glucose Lowering Trials & CVD

**ORIGIN: Am Heart J 2008;155:26**

## Glucose Lowering Trials & CVD

**ORIGIN: Am Heart J 2008;155:26**

## Outline

- What is the relationship between diabetes & CVD?
- What is the relationship between glycemia & CVD in people with/without diabetes?
- Does glucose lowering reduce CVD outcomes?
**Do glucose-lowering drugs reduce CVD outcomes?**

## G Lowering Drugs to Prevent CVD Trials in People with Dysglycemia

**G Lowering Drugs to Prevent CVD ****Trials in People with Dysglycemia**

**Yrs from Dx ******

**0**

**5**

**-10**

**-5**

**10**

**15**

**PROACTIVE**

**RECORD**

**NAVIGATOR**

**Eye, Kidney, Nerve Disease**

**CVD**

***Dysglycemia - - - - - - - - - - - - - - - - - - - - - - - *********

**BARI 2D**

**ACE**

**HEART 2D**

## PROactive RCTPROspective PioglitAzone Clinical Trial In MacroVascular Events

***Participants***
- N = 5238; Type 2 DM X 9.5 yrs; 19 countries; Age=62
***Eligibility***
- A1c _>_ 6.5: 35-75 yrs; high CV risk
- No: CHF (NYHA > 2); insulin mono-Rx; ALT>2.5X ULN
***Intervention***
- Pioglitazone titrated from 15-45 mg over 3 mo. vs. placebo
***Primary Outcome****** ***
- Death, Non-fatal MI, ACS, revascularization, stroke, leg amputation (above the ankle) or revascularisation
***Follow-up & Power***
- 2.9 years; 90% power for 20% RRR

**Diabetes Care 2004;27:1647 **

**Lancet 2005: 366:1279**

**NB: HbA1c Contrast 0.6%**
**       ****SBP Contrast 3 mm **

## Interim Results of RECORDRosiglitazone Evaluated for Cardiac Outcomes & Regulation of Glycemia in Diabetes

**Question****: **Is rosi + either MET or SU non-inferior 				(upper CI of HR _<_1.2) to SU + MET re CVD?
**Design****:****	**Open label, blinded outcome ascertainment        **	****	**No difference in glucose levels by group
**Pts:****	**N=4447; HbA1c 7-9% on max MET or SU
**Contrast:****	**Rosi + MET/SU, vs. SU + MET; HbA1c target 		           for both groups was the same (< 7%**)****	**
**Outcome: **CV hosp (includes CHF) or CV death
**F/U Plan:****	**Median of 6 yrs: *UNPLANNED PUB 3.75 yrs*
**Power:****	**99% to detect noninferiority assuming a 			           control event rate 11%/yr (3%/yr CV death & 		           8%/yr CV hospitalization)

**Home P et al. N Engl J Med**

## Interim Results of RECORDRosiglitazone Evaluated for Cardiac Outcomes & Regulation of Glycemia in Diabetes

| Outcome | Rosi
N=2220 | Met/SU
N=2227 | HR (CI) | P |
| --- | --- | --- | --- | --- |
| CV Hosp/CV Dth | 217 (9.8) | 202 (9.1) | 1.08 (0.89-1.31) | 0.43 |
| CV Death | 29 (1.3) | 35 (1.6) | 0.83 (0.51-1.36) | 0.46 |
| Any Death | 74 (3.3) | 80 (3.6) | 0.93 (0.67-1.27) | 0.63 |
| Acute MI | 43 (1.9) | 37 (1.7) | 1.16 (0.75-1.81) | 0.50 |
| CHF | 38 (1.7) | 17 (0.76) | 2.24 (1.27-3.97) | 0.006 |
| MI/Stroke/CV Death | 93 (4.2) | 96 (4.3) | 0.97 (0.73-1.29) | 0.83 |

**Home P et al. N Engl J Med 2007 online**

## Conclusions

- Diabetes & non-diabetic dysglycemia may be present for decades and are strong risk factors for CVD; a key determinant of this risk is the elevated glucose
- Despite trends, reported trials of intensive glucose lowering strategies have not detected CVD benefits in advanced DM
- If there is a benefit in such people it will be modest (15-20%) initially, and require _>_ 5 years to clearly emerge
- Trials of antidiabetic agents/strategies need to be long enough (at least 5 years) and large enough to allow any beneficial effect to emerge or to establish non-inferiority
- Short trials may miss benefits & only detect adverse effects

## Conclusions

- Whether glucose lowering (or prevention of its rise) by an antidiabetic agent reduces CVD in people with early diabetes or prediabetes remains unknown & is being tested
- Whether most specific antidiabetic agents reduce CVD or other clinical outcomes remains unknown and needs testing
- If such an agent is effective it may either be due to the agent, and/or its effects on glucose, BP,  etc....
- The only antidiabetic agent shown to reduce CVD in a 10 year trial is metformin (not replicated)

## Final Conclusions

- Diabetes increases the risk of many serious diseases; CVD is not the only clinically important outcome
- Antidiabetic agents that will make a difference are those that will be proven to reduce clinically important outcomes, and not just glucose levels
- These outcomes may include CVD but do not necessarily have to include CVD

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