RECORD

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Home PD, et al. "Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial". The Lancet. 2009. 373(9681):2125-2135.
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Clinical Question

In patients with type 2 diabetes mellitus (DM), does the addition of rosiglitazone to either metformin or sulfonylurea increase the rate of adverse cardiovascular (CV) outcomes as compared to the combination of metformin and sulfonylurea?

Bottom Line

In patients with T2DM, the addition of rosiglitazone did not increase the risk of CV hospitalization or mortality. However, a significant increase in the risk of heart failure and some fractures, especially in women, was noted.

Major Points

Several studies have raised concerns regarding the cardiovascular safety of thiazolidinediones (eg, pioglitazone, rosiglitazone).[1] In the PROactive, there was a higher rate of heart failure in the pioglitazone group as compared to placebo (11% vs 8%).[2] In 2003, the AHA/ADA published a consensus statement which emphasized the risk of edema and heart failure with thiazolidinedione use along with specific practice recommendations.[3]

The "Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD)" trial randomized 4,447 patients with T2DM on monotherapy with either metformin or sulfonylurea to receive additional rosiglitazone or to a combination of metformin and sulfonylurea.

The trial had limited statistical power as CV event rates were lower than predicted but non-inferiority for the primary endpoint (CV hospitalization or mortality) was achieved. The addition of rosiglitazone did not increase the risk of CV hospitalization or mortality. However, a significant increase in the risk of heart failure and some fractures, especially in women, was noted.

Guidelines

ADA Standards of Medical Care in Diabetes (2015, adapted)[4]

  • Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacological agent for type 2 diabetes. (Level of evidence: A)
  • If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target over 3 months, add a second oral agent, a GLP-1 receptor agonist, or basal insulin. (Level of evidence: A)
    • The choice of oral agents includes sulfonylurea, thiazolidinedione, DPP-4 inhibitors and SGLT2 inhibitors
  • A patient-centered approach should be used to guide the choice of pharmacological agents. Considerations include efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and patient preferences. (Level of evidence: E)

ACCF/AHA Guideline for the Management of Heart Failure (2013, adapted)[5]

  • Treatment with thiazolidinediones (eg, rosiglitazone) is associated with fluid retention in patients with heart failure and should be avoided in patients with NYHA class II through IV.
  • Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HFrEF are potentially harmful and should be avoided or withdrawn whenever possible (eg, most antiarrhythmic drugs, most calcium channel–blocking drugs [except amlodipine], NSAIDs, or thiazolidinediones). (Level of Evidence: B)

Design

  • Prospective, randomized, open-label trial
  • N=4,447
    • Rosigitazone+metformin or sulfonylurea (n=2,220)
    • Combination of metformin and sulfonylurea (n=2,227)
  • Setting: 364 centres in 25 countries in Europe and Australasia
  • Enrollment: 2001 to 2003
  • Mean follow-up: 5.5 years
  • Analysis: non-inferiority
  • Primary outcome: CV hospitalization or mortality

Population

Inclusion Criteria

=Published elsewhere.[6]

  • Patients with T2DM diagnosed according to the 1999 WHO criteria[7]
  • Age 40-75 years
  • BMI >25.0 kg/m2
  • HbA1c >7.0% and ≤9.0%
  • On maximum tolerated doses of monotherapy (metformin, glyburide/glibenclamide, gliclazide or glimepiride)
  • On oral glucose-lowering agents for ≥6 months and on current drug at the maximum tolerated dose for ≥2 months
  • For female patients, post-menopausal, sterilized or using effective contraceptive measures

Exclusion Criteria

  • Using other glucose-lowering therapies
  • Use of a combination of two or more oral glucose-lowering agents within 6 months
  • Use of insulin, except for pregnancy, inter-current illness or stabilization
  • Previous use of any PPAR-γ agonist
  • Hospitalization for a major CV event in the last 3 months, scheduled major CV intervention, or gangrene
  • Diagnosed or receiving medication specifically for heart failure (except diuretics alone)
  • Systolic or diastolic blood pressure >180/105 mmHg, on therapy if used
  • Fasting serum triglycerides >12.0 mmol/l
  • Serum creatinine >130 μmol/l (>1.47 mg/dl)
  • ALT, AST, total bilirubin or alkaline phosphatase ≥2.5 times the upper limit of normal
  • Haemoglobin <11.0 g/dl for males or <10.0 g/dl for females or haemoglobinopathy interfering with valid HbA1c assay
  • Contraindication/intolerance to metformin, glyburide, gliclazide or glimepiride
  • Pre-existing medical condition judged to preclude safe participation in the study
  • Abuse of alcohol or drugs, or presence of any condition that may lead to poor adherence to study protocols
  • Recent use of an investigational drug
  • Pregnancy, breast feeding or planning pregnancy

Baseline Characteristics

From the Rosiglitazone+Metformin group

  • Demographics: Age 57 years, 53.8% male, 98·9% white race
  • BMI: 32.8±5.0 kg/m2
  • BP: Systolic 140±16 mmHg, diastolic 84±9 mmHg
  • LDL-C : 3·2±0·9 mmol/L; HDL-C: 1·2±0·3 mmol/L; triglyceride: 2·3±1·3 mmol/L
  • PMH: IHD 15·3%, heart failure: 0·4%, active smoker 17·8%
  • Duration of diabetes : 6·1±4.2 years
  • HbA1c: 7·8±0·7 %

From the Rosiglitazone+Sulfonylurea group

  • Demographics: Age 59·8 years, 49·0% male, 99·3% white race
  • BMI: 30·3±4·1 kg/m2
  • BP: Systolic 138±15, diastolic 82±8
  • LDL-C: 3·4±0·9 mmol/L; HDL-C: 1·2±0·3 mmol/L; triglyceride: 2·3±1·7 mmol/L
  • PMH: IHD 19·2%, heart failure 0·7%, active smoker 14·9%
  • Duration of diabetes: 7·9±5·5 years
  • HbA1c: 8.0±0.7 %

Interventions

All participants entered a 4-week run-in period during which they receive lifestyle education and continued their usual oral glucose-lowering drug (metformin or sulfonylurea). Next, participants were randomized to two groups as listed below. The target HbA1c was 7.0% throughout the study.

  • Rosiglitazone+Metformin/Sulphonylurea
    • Rosiglitazone was started at 4 mg per day, and titrated to 8 mg after 8 weeks of therapy, if not teaching target HbA1c
    • If HbA1c ≥8.5%, a third oral agent would bed added. If this fails, rosiglitazone would be stopped and substituted with insulin therapy
  • Metformin+Sulfonylurea
    • If HbA1c ≥8.5%, treatment with metformin+sulfonylurea would be stopped and changed to insulin.

Outcomes

Comparisons are rosiglitazone+metformin/sulfonylurea vs. metformin+sulfonylurea

Primary Outcomes

CV hospitalization or mortality
321 vs. 323 cases (HR 0.99; 95% CI 0.85-1.16; P=0.93)

Secondary Outcomes

CV mortality
60 vs. 71 cases (HR 0.84; 95% CI 0.59-1.18; P=0.032)
CV mortality, MI, or stroke
154 vs. 165 cases (HR 0.93; 95% CI 0.74-1.15; P=0.05)

Subgroup Analysis

  • For patients on rosiglitazone+metformin/sulfonylurea, there was a higher risk of CV events in patients with IHD but this failed to reach statistical significance (P=0.055).
  • There were also no significant interactions in other pre-specified subgroup analyses (gender, age, duration of diabetes, BMI at baseline, use of ACE-inhibitor, statin or nitrates).
  • The relative risk of bone fractures in women was higher than in men but this was not statistically significant (RR 1·82; 95% CI 1·37–2·41 vs. RR 1·23; 95% CI 0·85–1·77; interaction P=0·10).

Adverse events

Heart failure
3.7% vs. 1.9% (P=0.0003)
MI
3.3% vs. 3.0% (P=0.59)
Participant-reported bone fractures of all types
185 vs. 118 cases (RR 1.57; 95% CI 1.26-1.97; P<0.0001)
Malignancies (prostate, breast, colon, pancreatic and bladder)
5.7% vs. 6.6% (P=0.32)
Pancreatic cancer
0.09% vs. 0.6% (P=0.0074)
Bladder cancer
0.3% vs. 0.2% (P=0.99)
Hypoglycemia
0.7% vs. 0.3% (P=0.076)
Hyperglycemia
1.2% vs 2.5% (P=0.0027)
Mean change in LDL cholesterol (mmol/L)

Comparisons are metformin+rosiglitazone vs. metformin+sulfonylurea

-0.33(±0.04) vs. −0·50 (±0·03) (P=0.0001)

Comparisons are sulfonylurea+rosiglitazone vs. sulfonylurea+metformin

−0·22 (±0·04) vs. −0·53 (±0·03) (P<0.0001)
Mean change in HDL cholesterol (mmol/L)

Comparisons are metformin+rosiglitazone vs. metformin+sulfonylurea

0.12 (±0.01) vs. 0·04 (±0·01) (P<0.0001)

Comparisons are sulfonylurea+rosiglitazone vs. sulfonylurea+metformin

0.11(±0.01) vs. 0·07 (±0·01) (P=0.002)

Criticisms

  • Low rate of statin use at 5 years in both rosiglitazone (55.2%) and control groups (46.0%) in the study.[8]
  • Open-label study design
  • Limited statistical power as CV event rates were much lower than expected. This might have precluded statistical confirmation of risk.[9]
  • Patient population is relatively young and healthy, therefore results may not be applicable to high-risk patients.[10]
  • The effect of rosiglitazone on MI rates is still unclear. In this study, there is a non-significant increase in MI rate in the rosiglitazone group.[10]
  • It is important to note that more patients who took rosiglitazone required additional glucose-lowering therapy. This conflicts previous study findings supporting a greater glycemic durability of the drug.[11]

Funding

GlaxoSmithKline plc, UK

Further Reading

  1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-71
  2. [http://www.ncbi.nlm.nih.gov/pubmed/16214598 Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary
    prevention of macrovascular events in patients with type 2 diabetes
    in the PROactive Study (PROspective pioglitAzone Clinical Trial In
    macroVascular Events): a randomised controlled trial. Lancet 2005;
    366: 1279–89.]
  3. Nesto RW, Bell D, Bonow RO et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27: 256–263
  4. American Diabetes Association. 7. Approaches to Glycemic Treatment. Diabetes Care. 2015. 1;38(Supplement 1):S41–8.
  5. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr. DE, Drazner MH, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013 Oct 15;62(16):e147–239.
  6. PD Home, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005. 48(1726–1735)
  7. World Health Organization. Dept. of Noncommunicable Disease Surveillance. Definition, diagnosis and classification of diabetes mellitus and its complications : report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus. 1999 [cited 2015 Oct 5; Available from http://apps.who.int/iris/handle/10665/66040]
  8. McCall AL. When is evidence of lack of harm enough? Has the rosiglitazone controversy ended? Curr Diab Rep. 2009 Sep 29;9(5):325–8.
  9. Retnakaran R, Zinman B. Thiazolidinediones and clinical outcomes in type 2 diabetes. Lancet. 2009 Jun 26;373(9681):2088–90.
  10. 10.0 10.1 Rosiglitazone was non-inferior to metformin plus sulphonylurea for CV events but increased risk of HF and fractures in type 2 diabetes. Evid Based Med. 2009 Dec 1;14(6):168–168.
  11. Lipscombe LL. Rosiglitazone was noninferior to metformin plus sulfonylurea for CV events but increased risk for HF and fractures in type 2 diabetes. Ann Intern Med. 2009 Oct 20;151(8):JC4–8.