. 2016 May 26;8(6):321. doi: 10.3390/nu8060321

Table 4.

Effect of regular cocoa consumption on inflammation in patients with type 2 diabetes or impaired glucose tolerance—results from randomized, controlled trials.

Study (Reference)	n	Participants	Intervention	EC (mg)	IP (d)	Study Design	Sample	Parameter	Results	Annotations
Balzer et al., 2008 [63]	41	Type 2 diabetes, stably-treated, NS Age: 64 ± 1 BMI: 31.6 ± 0.8 CRP: 4.9 ± 1.1	I: Flavanol-rich cocoa drink, with CocoaPro cocoa powder (Mars), 750 mL/day	I: 203	30	Double-blind, parallel group	Plasma	CRP	I: o C: o	No dietary restrictions, dietary intake not determined, compliance: empty cocoa sachets, epicatechin in plasma
Balzer et al., 2008 [63]	41		C: Flavanol-poor cocoa drink with CocoaPro cocoa powder (Mars), similar in taste, matched for energy and macro-, micronutrient composition, 750 mL/day	C: 17	30	Double-blind, parallel group	Plasma	CRP	I: o C: o
Grassi et al., 2008 [61]	19	Impaired glucose tolerance, untreated stage I hypertension, NS Age: 45 ± 1 BMI: 26.5 ± 0.3 CRP: n.d.	I: Flavanol-rich chocolate (Cuorenero, Sugar Company), 100 g/day	I: 111	15	Crossover	Serum	CRP ^a	I: o C: o	No flavonoid-rich food, 1 week cocoa-free run-in and washout, food records daily
Grassi et al., 2008 [61]	19		C: White chocolate (Milka, Kraft Foods), 100 g/day	C: 0	15	Crossover	Serum	CRP ^a	I: o C: o
Monagas et al., 2009 [64]	42	Diabetes or ≥3 cardiovascular disease risk factors (smoking, hypertension, hypercholesterolemia, obesity, family history of premature coronary heart disease) Age: 70 ± 2 BMI: 27.6 ± 0.8 CRP: 0.5 ± 0.3	I: Cocoa drink, prepared with cocoa powder (Nutrexpa) and skim milk, 500 mL/day	I: 46	28	Crossover	Serum or plasma	CRP ^a	I: o C: o	Flavonoid-rich food limited, 3 × 3 days food records, ompliance: patient reports and epicatechin metabolites in plasma and urine, 2 weeks run-in, no washout-period
			C: Skim milk, 500 mL/day	C: 0				P-selectin	I: ↓ C: o I < C (d28)
								E-selectin	I: o C: o
								ICAM-1	I: ↓ C: o I < C (d28)
								VCAM-1	I: o C: o
								MCP-1	I: o C: o
								IL-6	I: o C: o
							Monocytes	LFA-1	I: o C: o
								Mac-1	I: o C: o
								VLA-4	I: ↓ C: o I < C (d28)
								SLe^x	I: o C: o
								CD36	I: ↓ C: o I < C (d28)
								CD40	I: ↓ C: o I < C (d28)
							T cells	LFA-1	I: o C: o
								VLA-4	I: o C: o
								SLe^x	I: o C: o
								CD40	I: o C: o
Mellor et al., 2010 [65]	12	Type 2 diabetes, no steroids, no changes in chronic medication Age: 68 (median); 42–71 (range) BMI: n.d. CRP: 2.8 ± 0.5	I: Polyphenol-rich chocolate (Nestlé), 45 g/day	I: 17	56	Double-blind, crossover	Serum or plasma	CRP ^a	I: o C: o	4 weeks washout, compliance: empty wrappers: 93.8%, no changes in diet and lifestyle, dietary recalls
Mellor et al., 2010 [65]	12		C: Polyphenol-free chocolate (Nestlé), 45 g/day, matched for energy and macronutrients	C: <2	56	Double-blind, crossover	Serum or plasma	CRP ^a	I: o C: o
Stote et al., 2012 [66]	19	Impaired or normal glucose tolerance, obese, NS Age: 46 ± 1 BMI: 36.8 ± 0.2 CRP: n.d.	I: Cocoa drink with 28 g cocoa (different flavanol content, Mars), water, 300 mL/day	I_1: 184 I₂: 72 I₃: 34	5	Single-blind, crossover	Serum or plasma (0, 0.5, 1, 1.5, 2.0 h after an oral 75-g-glucose load)	CRP ^a	↓ by dose	10 days washout, no dietary changes
								ICAM-1	o by dose
								IL-6	↓ by dose
			C: Flavanol-poor drink with water (Mars), 300 mL/day, matched for energy, macro-, micronutrients	C: 4				IL-6	↓ by dose
Parsaeyan et al., 2014 [67]	100	Type 2 diabetes Age: 54 ± 1 BMI: 28 ± 0.5 CRP: n.d.	I:_Cocoa drink (10 g cocoa, 10 g milk powder, 250 mL water), 2 drinks/day	n.d.	42	Parallel group	Serum	CRP^a	I: ↓ C: o	Dietary records, no restrictions
								IL-6	I: ↓ C: o
								TNF-α	I: ↓ C: o
			C: Cocoa-free drink (10 g milk powder, 250 mL water), 2 drinks/day	n.d.				TNF-α	I: ↓ C: o
Rostami et al., 2015 [68]	60	Type 2 diabetes, blood pressure ≥140/90 mm Hg, stable medication, NS Age: 60 ± 1 BMI: 29.8 ± 0.6 CRP: unclear	I: Dark chocolate (Farmand), 25 g/day	n.d.	56	Placebo-controlled, double-blind, parallel group	Serum	CRP ^a	I: ↓ C: o; No effect by ANCOVA adjusted for age, sex, energy intake	No further chocolate, 3 days food records
Rostami et al., 2015 [68]	60		C: White chocolate (Farmand), 25 g/day, isocaloric, same color and shape, identically wrapped	n.d.	56	Placebo-controlled, double-blind, parallel group	Serum	CRP ^a		No further chocolate, 3 days food records

^a determined by high-sensitivity test kits for C-reactive protein. BMI: body mass index; C: control; d: days; CRP: C-reactive protein; EC: epicatechin; I: cocoa intervention; ICAM-1: intercellular adhesion molecule-1; IL-6: interleukin-6; IP: intervention period; LFA-1: lymphocyte function-associated antigen-1; MCP-1: monocyte chemoattractant protein; n.d.: no data available; SLe^x: sialil Lewis X, CD15s; VCAM-1: vascular cell adhesion molecule-1; VLA-4: very late activation antigen-4; ↓: decrease; o: no changes; Δ difference pre- vs. post-consumption values. Data on age (years), BMI (kg/m²), and CRP (mg/L) are means ± SEM if not indicated otherwise. Means were calculated as weighted means from the data of individual groups if not provided by the authors. Missing SEMs were calculated by SDs, of individual groups. n refers to the number of participants for whom data on inflammatory markers were available.