Cardiovascular disease and intensive glucose control in type 2 diabetes mellitus: moving practice toward evidence-based strategies

Figures & data

Table 1 Comparison of four trials of intensive glycemic control and CVD outcomes

	ACCORD	ADVANCE	VADT	UKPDS post-trial
Clinical trials	NCT00000620	NCT00145925	NCT00032487	ISRCTN75451837
NIH listing	see website http://clinicaltrials.gov	see website http://clinicaltrials.gov	see website http://clinicaltrials.gov	see website http://controlled-trials.com
Design	RCT, AC, Phase III	RCT, PC, Phase III	RCT, AC, Phase III	RCT, AC, Phase III
Participant characteristics
n	10,251	11,140	1,791	3,277
Mean age (years)	62	66	60	63
Duration of diabetes (years)	10	8	11.5	17
Sex (% male/female)	39/61	42/58	97/3	SI:60/40; M:46/54
History of CVD (%)	35	32	40	None
BMI (kg/m^2)	32	28	31	SI:29; M:32
Mean baseline HbA1c (%)	8.1	7.5	9.4	SI:7.9; M:8,4
On insulin at baseline (%)	35	1.5	52	64
Protocol characteristics
HbA1c goals (%) (I vs S)^a	<6.0 vs 7.0–7.9	≤6.5 vs ‘based on local guidelines’	<6.0 (action if >6.5) vs planned separation of 1.5	Aiming for fasting plasma glucose <6 mmol/L
Protocol for glycemic control (I vs S)^a	Multiple drugs in both arms	Multiple drugs added to gliclizide vs multiple drugs with no gliclizide	Multiple drugs in both arms	Intensive therapy (either sulfonylurea or insulin/SI or, min overweight patients, metformin/M) vs corresponding conventional therapy group/C (dietary restriction)
Management of risk factors	Embedded BP and lipid trials	Embedded BP trial	Protocol for intensive treatment in both arms	None
On study characteristics
Median duration of follow-up (years)	3.5 (terminated early)	5	5.6	8.8
Achieved median HbA1c (%) (I vs S)^a	6.4 vs 7.5	6.4 vs 7.0	6.9 vs 8.5	SI:7.9 vs 7.9; M:8.1 vs 8.1
On insulin at study end (%) (I vs S)^a	77 vs 55^a	40 vs 24	89 vs 74	Data not shown
On TZD at study end (%) (I vs S)^a	91 vs 58^a	17 vs 11	53 vs 42	None
On statin at study end (%) (I vs S)^a	88 vs 88^a	46 vs 48	85 vs 83	Data not shown
On aspirin at study end (%) (I vs S)^a	76 vs 76^a	57 vs 55	88 vs 86	Data not shown
Smokers at study end (%)	10	8	8	Data not shown
Mean blood pressure at study end (mmHg)
Intensive glycemic control arm	126/67	136/74	127/68	Data not shown
Standard glycemic control arm	127/68	138/74	125/69	Data not shown
Weight changes (kg)
Intensive glycemic control arm	+3.5	−0.1	+7.8	SI: +1.0
Standard glycemic control arm	+0.4	−1.0	+3.4	M: −1.0
Severe hypoglycemia participants with 1 or more episodes during study (%)
Intensive glycemic control arm	16.2	2.7	21.2	Data not shown
Standard glycemic control arm	5.1	1.5	9.9	Data not shown
Outcomes
Definition of primary outcome	Nonfatal MI, nonfatal stroke, CVD death	Microvascular plus macrovascular (nonfatal MI, nonfatal stroke, CVD death) outcomes	Nonfatal MI, nonfatal stroke, CVD death, hospitalization for heart failure, revascularization	Any diabetes-related endpoint, diabetes-related death, death from any cause, MI, stroke, peripheral vascular disease, microvascular disease
HR for primary outcome (95% CI)	0.90 (0.78–1.04)	0.9 (0.82–0.98); macrovascular 0.94 (0.84–1.06)	0.88 (0.74–1.05)	SI:0.91 (0.83–0.99); M:0.79 (0.66–0.95)
HR for mortality findings (95% CI)	1.22 (1.01–1.46)	0.93 (0.83–1.06)	1.07 (0.81–1.42)	SI:0.87 (0.79–0.96); M:0.73 (0.59–0.89)

* Medication rates for ACCORD are for any use during the study.

Abbreviations: AC, active control; BMI, body mass index; BP, blood pressure; C, conventional therapy; CVD, cardiovascular disease; I, intensive glycemic control; M, metformin group; MI, myocardial infarction; PC, placebo control; RCT, randomized controlled trial; S, standard glycemic control; SI, sulfonylurea-insulin group; TZD, thiazolidinedione.

Figure 1 Evidence-based guideline for antihyperglycemic treatment in patients with T2DM (adopted from the German Diabetes Association [Deutsche Diabetes Gesellschaft/DDG] based on the data from the ACCORD, ADVANCE, VADT and UKPDS post-trial).

^aReduce HbA_1c level to ≤6.5% from ≤7% might be advantageous but only when:

– (severe) hypoglycemia is prevented

– weight gain does not occur

– use of multiple glucose-lowering drugs (>2) or additional insulin therapy can be avoided

HbA_1c should be measured every 3 months. Therapy should be intensified if/when the target level is missed. In contrast, pharmacological dechallenge and ‘step back’ can be performed if the individual HbA_1c remains stable over a longer time.