Effects of glucose-lowering agents on cardiorespiratory fitness

Table 1 Effects of metformin on cardiorespiratory fitness in healthy individuals

Ref.	Study design	Subjects	Metformin dose and intervention	Results
Johnson et al[18], 2008	Randomized, double-blind, placebo-controlled, crossover study	11 healthy and active men	1000 mg/d	VO2max→, ventilator threshold→, maximal heart rate→, time to fatigue→
		Age: 29.9 ± 3.7 yr	Cycle ergometer at the mean intensity of 69 ± 5.5% of VO2max	Lactate↓, blood glucose concentrations↓
		Sex: All men
		BMI: 25.2 ± 2.8 kg/m2
Braun et al[19], 2008	Non-randomized, placebo-controlled study	18 healthy subjects	2000 mg/d	VO2peak↓, peak heart rate↓, peak ventilation↓, peak respiratory exchange ratio↓, exercise duration↓
		Age: 27.9 ± 3.3 yr	Treadmill or cycle ergometer	Rating of perceived exertion→
		Sex: 11 men and 7 women
		BMI: 24.1 ± 3.6 kg/m2
Malin et al[20], 2010	Non-randomized, double-blind, counterbalanced crossover study	15 healthy and active subjects	2000 mg/d	VO2→
		Age: 25 ± 4.4 yr	Cycle exercise at 5 submaximal cycle workloads	During exercise: Fat oxidation↑
		Sex: 7 men and 8 women		Postexercise: Fat oxidation↓
		BMI: 22.8 ± 2.7 kg/m2
Learsi et al[21], 2015	Randomized, placebo-controlled, counterbalanced study	10 healthy men	500 mg/d	VO2→, maximal accumulated oxygen deficit→, lactate concentrations→
		Age: 23.5 ± 3.6 yr	Cycle ergometer: An incremental test, 6 submaximal workload test at 40%–90% VO2max, 2 supramaximal tests at 110% VO2max	Time to exhaustion↑, VO2 recovery↑
		Sex: All men
		BMI: No description (height: 170.4 ± 4.8 cm, weight: 66.4 ± 6.5 kg)

BMI: Body mass index; VO₂: Oxygen consumption.

Table 2 Effects of metformin on cardiorespiratory fitness in patients with type 2 diabetes and metabolic syndrome

Ref.	Study design	Subjects	Metformin dose and intervention	Results
Boulé et al[22], 2011	Randomized, placebo-controlled, crossover study	10 patients with type 2 diabetes	2000 mg/d	VO2→, respiratory exchange ratio↓
		Age: 58 ± 6 yr	Exercise mode: Treadmill at three different submaximal intensities	Heart rate↑, lactate↑, rating of perceived exertion↑
		Sex: 8 men and 2 women	Study duration: 22 wk
		BMI: 28.6 ± 5.3 kg/m2
		HbA1c: 6.5 ± 0.6%
Boulé et al[23], 2013	Randomized controlled trial (Diabetes Aerobic and Resistance Exercise) trial	251 patients with type 2 diabetes (143 patients treated with metformin and 82 patients treated without metformin)	Approximately 1600 mg/d	VO2peak→
		Age: 54.9 ± 7.1 yr vs 53.1 ± 6.9 yr	Exercise mode: Aerobic training, resistance training, and combined aerobic and resistance training
		Sex (Men/Women): 100/43 vs 46/36	Study duration: 4 wk
		BMI: 33.3 ± 5.5 kg/m2 vs 33.3 ± 6.4 kg/m2
Cadeddu et al[25], 2014	Non-randomized, non-controlled trial	HbA1c: 7.78 ± 0.9% vs 7.47 ± 0.77%	1000 mg/d	VO2peak→
		75 patients with insulin resistance	30–50 min of cycle exercise at the intensity of 60%–80% of the heart rate reserve
		Age: 46.2 ± 11 yr
		Sex: 35 men and 40 women	Study duration: 12 wk
Paul et al[26], 2017	Prospective observational study	BMI: 29.8 ± 4.1 kg/m2	1000 mg/d	VO2max↓
		15 patients with metabolic syndrome	No intervention
		Age: No description	Study duration: 6 wk
		Sex: No description
		BMI: No description (weight: 75.4 ± 12.08 kg)

BMI: Body mass index; HbA1c: Hemoglobin A1c; VO₂: Oxygen consumption.

Table 3 Effects of thiazolidinediones on cardiorespiratory fitness in patients with type 2 diabetes and metabolic syndrome

Ref.	Study design	Subjects	Thiazolidinedione dose	Results
Regensteiner et al[33], 2005	Randomized controlled trial	20 patients with type 2 diabetes (10 patients received rosiglitazone and 10 patients received a placebo)	Rosiglitazone, 4 mg/d	VO2↑, insulin sensitivity↑, endothelial function↑
		Age: 55 ± 7 yr vs 56 ± 1 yr
		Sex (Men/Women): 5/5 vs 5/5
		BMI: 32.2 ± 5.6 kg/m2vs 30.4 ± 5.8 kg/m2
		HbA1c: 7.2 ± 1.1% vs 7.2 ± 1.0%
Kadoglou et al[36], 2008	Randomized controlled trial	70 patients with type 2 diabetes (35 patients received rosiglitazone and 35 patients received a placebo)	Rosiglitazone, 8 mg/d	VO2peak↑, duration of the exercise test↑, oxygen pulse↑
		Age: 63.8 ± 7.3 yr vs 66.7 ± 9.6 yr		Insulin resistance↓, diastolic blood pressure↓
		Sex (Men/Women): 14/21 vs 16/19
		BMI: 29.5 ± 3.8 kg/m2vs 29.9 ± 4.3 kg/m2
		HbA1c: 8.2 ± 1.2% vs 8 ± 0.8%
Yokota et al[37], 2017	Before-after study	14 patients with metabolic syndrome	Pioglitazone, 15 mg/d	VO2peak↑, anaerobic threshold↑
		Age: 52 ± 11 yr		Intramyocellular lipid content↓, muscle phosphocreatinine loss during exercise↓
		Sex: All men
		BMI: 26.6 ± 3.3 kg/m2
		HbA1c: 5.7 ± 0.6%

BMI: Body mass index; HbA1c: Hemoglobin A1c; VO₂: Oxygen consumption.

Table 4 Effects of sodium–glucose cotransporter 2 inihibitors on cardiorespiratory fitness in patients with type 2 diabetes

Ref.	Study design	Subjects	SGLT2 inhibitors dose	Results
Núñez et al[45], 2017	Before-after study	19 patients with type 2 diabetes and heart failure	Empagliflozin, 10 mg/d	VO2peak↑, ventilatory efficiency during exercise↑, 6-minute walking distance↑, ↓antigen carbohydrate 125
		Age (median): 72 yr
		Sex: 14 men and 5 women
		BMI: 30.6 ± 5.5 kg/m2
		HbA1c: No description
Carbone et al[46], 2018	Before-after study	15 patients with type 2 diabetes and heart failure	Empagliflozin, 10 mg/d	VO2peak↑ in patients using loop diuretics
		Age (median): 60 yr		VO2peak↓ in patients without loop diuretics
		Sex: 7 men and 8 women
		BMI (median): 34 kg/m2
		HbA1c (median): 7.8%

SGLT2: Sodium–glucose cotransporter 2; BMI: Body mass index; HbA1c: Hemoglobin A1c; VO₂: Oxygen consumption.

Table 5 Effect of glucose-lowering agents on cardiorespiratory fitness

Glucose-lowering agents	Cardiorespiratory fitness
Metformin	→ or ↓
Thiazolidinediones	↑
DPP-4 inhibitors	Unknown
	(↑ in mice with heart failure)
GLP-1 receptor agonists	↑ in patients with heart failure
	→ in patients with type 2 diabetes
SGLT2 inhibitors	↑ in patients treated with loop diuretics

DPP-4: Dipeptidyl peptidase-4; GLP-1: Glucagon-like peptide-l; SGLT2: Sodium–glucose cotransporter 2.