Denosumab improves glucose parameters in patients with impaired glucose tolerance: a systematic review and meta-analysis

Figures & data

Figure 1. Flow chart for literature review of studies to be included in the meta-analysis.

Table 1. Characteristics of the includes studies.

Study, Year	Type study	Country	Diagnostic	T2D	Sex	Age (years)^a	Denosumab^b (mg/month)	BMI (kg/m^2)^a	Vit. D^c	Calcium^d	DBL^e
Abe, 2019	Observational study	Japan	Osteoporosis	Yes	M/F	72.1 ± 7.2	60 mg/6 m (2)	23.6 ± 4.1	Yes	No	37
Lasco, 2016	Prospective study	Italy	Osteoporosis	No	F	57.9 ± 6.3	60 mg (1)	26.4 ± 2.3	Yes	No	35
Napoli, 2018 (T2D)	Randomized trial	FREEDOM study^f	Osteoporosis	Yes	F	73.5 ± 5.1	60 mg/6 m (6)	28.0 ± 4.7	Yes	Yes	39
Napoli, 2018 (PT2D)	Randomized trial	FREEDOM study^f	Osteoporosis	No	F	72.6 ± 5.4	60 mg/6 m (6)	27.0 ± 4.3	Yes	Yes	39
Passeri, 2015	Prospective study	Italy	Osteoporosis	No	F	67.1 ± 11.6	60 mg/6 m (1)	24.8 ± 3.7	Yes	Yes	34
Rossini, 2020	Prospective observational study	Italy	Breast cancer	No	F	68.1 ± 8.1	60 mg (1)	23.5 ± 4.6	Yes	No	38
Weivoda, 2020A	Randomized trial	USA	Post- menopausic	No	F	66.7 ± 4.9	60 mg (1)	27.0 ± 4.5	No	No	41
Weivoda, 2020B	Case–control study	USA	Osteoporosis	Yes	M/F	74.1 ± 10.0	Not stated	29.9 ± 8.6	No	No	37

BMI: body-mass index; DBL: Downs and Black Checklist; F: female; M: male; PT2D: persons with prediabetes; T2D: persons with type 2 diabetes; Vit D: vitamin D.

^aValues are mean ± standard deviation.

^bMost studies reported a dose regiment of 60 mg/6 months. In the parenthesis is the actual number of doses given.

^cArticles indicated that denosumab treatment was supplemented with vitamin D.

^dArticles indicated that denosumab treatment was supplemented with calcium.

^eDBL was used to determined study quality. Scores <14 denoted poor-quality studies [15].

^fParticipants of the FREEDOM study are from Western Europe, Eastern Europe, Latin America, North America, Australia, and New Zealand.

Table 2. Data used for analyses.

Study	Group	N^a	Duration (months)	Fasting plasma glucose (mg/dL)	Fasting plasma insulin (µU/mL)	HbA1c (%)	HOMA1-IR
Abe, 2019	T2D	20	Baseline	116.70 ± 21.50		6.52 ± 0.56	2.00 ± 1.21
			6	119.00 ± 22.00		6.48 ± 0.60	1.66 ± 0.98
			12	109.30 ± 18.50^b		6.32 ± 0.61^b	1.38 ± 0.76^b
Lasco, 2016	NGT	48	Baseline	93.69 ± 10.09^c	7.03 ± 3.61^c	5.60 ± 0.26	1.74 ± 1.22
			1	90.81 ± 12.07^c	5.52 ± 1.89^b,c		1.25 ± 0.54^b
			2			5.65 ± 0.37	1.60 ± 0.98
			3	93.15 ± 12.25^c	6.56 ± 2.97^b		1.56 ± 1.02
			6	91.89 ± 10.81^c	6.97 ± 3.08^b
Napoli, 2018	T2D	342	Baseline	136.90 ± 43.80
			36	131.30 ± 58.25
	PT2D	628	Baseline	106.30 ± 5.90
			36	102.20 ± 23.11
Passeri, 2015	NGT	14	Baseline	91.40 ± 10.10	9.50 ± 6.70	5.60 ± 2.60^c	2.20 ± 1.70
			1	89.60 ± 14.10	8.50 ± 5.50	5.60 ± 2.50^c	2.00 ± 1.40
			3	92.10 ± 15.30	10.50 ± 10.10	5.50 ± 2.70^c	2.70 ± 3.10
Rossini, 2020	NGT	14	Baseline	87.00 ± 8.70	9.10 ± 6.40	5.44 ± 2.36^c	2.00 ± 1.50
			1	83.80 ± 11.10	8.50 ± 4.80		1.80 ± 1.10
			5			5.77 ± 2.43^c
Weivoda, 2020A	NGT	22	Baseline	97.51 ± 10.48^c	7.65 ± 7.41		1.84 ± 1.80
			3	97.42 ± 8.46^c	4.80 ± 2.480		1.16 ± 0.62
Weivoda, 2020B	PT2D/T2D	115	Baseline	134.98 ± 55.86		6.73 ± 1.18
			6	(−7.91 ± 4.53)		(−0.10 ± 0.88)
			12	(−8.83 ± 4.06)		(−0.27 ± 0.85)

Abbreviations. HOMA1-IR, Homeostatic Model Assessment of Insulin Resistance; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; PT2D, persons with prediabetes; T2D, persons with type 2 diabetes.

Values are mean or mean difference (in parenthesis) ± standard deviation.

^aNumber of patients in the study.

^bPublication’s authors reported a significant result.

^cWhen FPG levels were reported in mmol/L, a multiplication factor of 18.018 was used to convert to mg/dL. Likewise, when FPI levels were reported in pmol/L, a multiplication factor of 0.144 was used to convert to µIU/mL. Finally, when HbA1c was reported in the International Federation of Clinical Chemistry units (IFCC, mmol/mol), the value was converted to the National Glycohemoglobin Standardization Program (NGSP, percentage) by multiplying it by 0.0915 + 2.152.

Table 3. The effect of denosumab treatment on glucose metabolism, stratified by glucose tolerance.

		Heterogeneity^b			Association^c
Category	N^a	Q p-value	I^2 (%)	Model	SDM	95% CI	p-Value^d	p-Value^e
Fasting plasma glucose (mg/dL)
Overall	8	<.005	95.6	Random	−0.388	−0.705 to −0.070	.017*
NGT	4	.651	0.0	Fixed	−0.122	−0.301 to 0.056	.179	.263
IGT	4	<.005	98.1	Random	−0.636	−1.123 to −0.149	.010*
Fasting plasma insulin (µU/mL)^f
Overall	4	.310	16.3	Fixed	−0.094	−0.273 to 0.085	.303	N/A
HbA1c (%)
Overall	5	.026	63.7	Random	−0.075	−0.312 to −0.163	.538
NGT	3	.906	0.0	Fixed	0.133	−0.069 to 0.335	.197	.001*
IGT	2	.800	0.0	Fixed	−0.292	−0.446 to −0.138	<.005*
HOMA1-IR
Overall	5	.159	39.3	Fixed	−0.223	−0.388 to −0.058	.008*
NGT	4	.322	14.0	Fixed	−0.160	−0.339 to 0.020	.081	.078
IGT	1	1.000	0.0	Fixed	−0.573	−0.995 to −0.150	.008*

Abbreviations. 95%CI, 95% confidence interval; HOMA1-IR, Homeostatic Model Assessment of Insulin Resistance; I², Inconsistency Index; IGT, impaired glucose tolerance; N/A, not applicable; NGT, normal glucose tolerance; OR, Odds ratio.

^aN = number of studies included in analysis.

^bDepending on the level of heterogeneity, either random effects model or fixed effects model was used.

^cThe pooled effect was calculated using comprehensive meta-analysis software v2.

^dp-Value = assessment of the association.

^ep-Value = test for significance between IGT and NGT.

^fFor fasting plasma insulin, the group was only comprised of NGT.

*p-Value <.05 (two-tailed) were considered significant.

Figure 2. Time dependent effect of Denosumab treatment with respect to (A) Fasting plasma Glucose, (B) Fasting Plasma Insulin, (C) HbA1c, and (D) HOMA1-IR. The analysis was made with linear meta-regression using the method of moments by the comprehensive meta-analysis software V2. There was only a strong association between denosumab treatment and HbA1c (slope = −0.037, 95%CI: −0.059 to −0.015, p < .005).

Cantley J, Ashcroft FQA. Insulin secretion and type 2 diabetes: why do β-cells fail?. BMC Biol. 2015;13:33.

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Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files.