Non-adherence to non-insulin glucose-lowering drugs: Prevalence, predictors and impact on glycemic control and insulin initiation. A longitudinal cohort study in a large primary care database in Spain

Figures & data

Table 1. Sociodemographic characteristics of the patients included (n = 18,119).

Variable	Overall sample (n = 18,119)
Female sex, n (%)	7,343 (40.53)
Age (years), mean (SD)	63.44 (12.54)
Age (binary)
<80 Years old	16,205 (89.44)
≥80 Years old	1,914 (10.56)
Nationality, n (%)
Spain	15,068 (83.16)
European countries (excluding Spain)	807 (4.45)
Non-European countries	2,244 (12.38)
Occupational status, n (%)
Actively working	4,260 (28.37)
Retired	10,092 (67.21)
Unemployed	664 (4.42)
Social deprivation index (quintiles)*
1 (Less deprived)	3,743 (22.02)
2	4,515 (26.54)
3	4,462 (26.25)
4	2,911 (17.12)
5 (Most deprived)	1,373 (8.08)

*Social deprivation index (based on patient’s postal address) was computed according to six indicators: manual and temporary workers, unemployment, insufficient education overall and in young people (aged 16–29 years), and dwellings without access to the internet.

Table 2. Clinical characteristics of the patients included (n = 18,119).

Variable	Overall sample (n = 18,119)
Smoking, n (%)
Non-smoker	8,515 (50.08)
Former smoker	4,787 (28.15)
Smoker	3,701 (21.77)
Alcohol (regular consumption = yes), n (%)	2,529 (22.98)
Duration of diabetes (years), median (IQR)	3.74 (0.00–9.24)
Time of diagnosis of T2DM in relation to time of starting the index prescription, n (%)
Diagnosis of T2DM was concurrent to the prescription of the index GLD	4,273 (23.58)
Diagnosis of T2DM was previous to the prescription of the index GLD	13,846 (76.42)
Therapeutic group or the Index GLD, n (%)
Biguanides	6,774 (37.39)
Sulfonylureas	1,320 (7.29)
DPP4i	2,263 (12.49)
GLP-1	555 (3.06)
SGLT2i	1,721 (9.50)
Other	668 (3.69)
Combination biguanides and DPP4i	3,273 (18.06)
Combination biguanides and SGLT2i	1,545 (8.53)
Total number of drugs prescribed, mean (SD)	8.86 (5.81)
Taking concurrent GLD, n (%)	3,885 (21.44)
Number of concurrent GLD, mean (SD; range)	0.50 (1.16; 0–10.5)
Taking concurrent psychoactive drugs, n (%)	5,949 (32.83)
Number of concurrent psychoactive drugs, mean (SD; range)	0.53 (0.91; 0–8)
Clinical complexity (adjusted morbidity groups), n (%)
Low clinical complexity	5,364 (31.54)
Moderate clinical complexity	7,454 (43.83)
High clinical complexity	4,189 (24.63)
BMI (kg/m^2), mean (SD)
<25	506 (8.72)
25 to <30	1,828 (31.51)
≥30	3,468 (59.77)
HbA1c (%), mean (SD)	7.77 (1.58)
Hypertension, n (%)	9,278 (51.21)
Hypercholesterolaemia, n (%)	7,014 (38.71)
Asthma, n (%)	1,200 (6.62)
Cancer, n (%)	233 (1.29)
Heart disease, n (%)	807 (4.45)
Mental disease, n (%)	328 (1.81)
Osteoporosis, n (%)	371 (2.05)
Chronic kidney disease, n (%)	1,499 (8.27)
Obesity, n (%)	3,420 (18.88)
Retinopathy, n (%)	154 (0.85)
Adherence to previous chronic medication (excluding diabetes medication)*
Low adherence (MPR ≤80%)	1,278 (7.05)
High adherence (MPR >80%)	2,068 (11.41)
Not applicable (no previous medication)	1,4773 (81.53)
Adherence to previous diabetes medication
Low adherence (MPR ≤80%)	2,065 (11.40)
High adherence (MPR >80%)	3,587 (19.80)
Not applicable (no previous medication)	12,467 (68.81)

BMI: body mass index; DPP4i: dipeptidyl peptidase-4 inhibitors; GLD: glucose lowering drug; GLP-1: glucagon-like peptide-1 analogues; HbA1c: glycated haemoglobin; IQR: interquartile range; MPR: medication possession ratio; n: number of participants; T2DM: type 2 diabetes mellitus; SD: standard deviation; SGLT2i: sodium-glucose co-transporter 2 inhibitors.

*Chronic medications (codes C01, C02, C03, C04, C07, C08, C09, C10) were prescribed during the previous 13 months to the index GLD initiation, with a prescription being active for at least 6 months.

Table 3. Adherence to non-insulin glucose-lowering drugs (GLDs, overall and by treatment).

	Overall cohort (n = 18,119)
	MPR, median (IQR)	MPR, mean (SD)	MPR ≤80%, n (%)
All antidiabetic treatments	92.06 (71.79–98.37)	80.86 (24.35)	5,740 (31.68)
Biguanides	84 (58.14–95.64)	73.83 (26.84)	3,023 (44.63)
Sulfonylurea	95.12 (80.55–99.21)	85.28 (21.44)	327 (27.77)
DPP4 inhibitors	96.73 (87.75–99.73)	87.91 (20.57)	399 (17.63)
GLP-1 analogues	95.71 (85.71–100)	87.65 (19.69)	95 (17.12)
SGLT2 inhibitors	95.28 (83.67–99.18)	86.03 (21.31)	373 (21.67)
Other blood GLDs, excl. insulins*	91.57 (67.56–98.17)	78.31 (27.20)	227 (33.98)
Combination biguanides and DPP4	93.26 (77.12–98.66)	83.54 (21.86)	912 (27.86)
Combination biguanides and SGLT2	93.59 (80.32–98.44)	84.79 (20.61)	384 (24.85)

DPP4i: dipeptidyl peptidase-4 inhibitors; GLP-1: glucagon-like peptide-1 analogues; IQR: interquartile range; MPR: medication possession ratio; SD: standard deviation; SGLT2i: sodium-glucose co-transporter 2 inhibitors.

*Other blood GLDs included alpha-glucosidase inhibitors, thiazolidinedione, guar gum, glinides, and other combinations different from biguanides + DPP-4 inhibitors and biguanides + SGLT-2 inhibitors.

Table 4. Association between adherence to non-insulin GLDs (glucose-lowering drugs, overall and by type of drug) and HbA1c response after one year (multiple imputations for covariables*).

Drug	Number of participants n (%)	Number of participants with MPR ≤80% (%)	HbA1c (%) after 12 months for participants with MPR ≤80% (95% CI)	HbA1c (%) after 12 months for participants with MPR >80% (95% CI)	Difference between HbA1c (%) level after 12 months for participants with MPR ≤80% and MPR >80% (95% CI)	p
All treatments	9,025 (100)	2,453 (27.2)	7.15 (7.11; 7.20)	6.83 (6.80; 6.86)	−0.32 (−0.38; −0.27)	<0.001
Biguanides	3,145 (34.8)	1,272 (40.4.)	6.64 (6.58; 6.70)	6.43 (6.38; 6.47)	−0.21 (−0.29; −0.14)	<0.001
Sulfonylureas	694 (7.69)	133 (19.2)	7.55 (7.33; 7.78)	7.23 (7.12; 7.34)	−0.32 (−0.57; −0.07)	0.012
DPP-4i	1,187 (13.2)	176 (14.8)	7.21 (7.03; 7.40)	6.98 (6.91; 7.05)	−0.24 (−0.43; −0.04)	0.019
GLP-1	286 (3.17)	39 (13.6)	7.97 (7.50; 8.44)	6.95 (6.76; 7.13)	−1.02 (−1.54; −0.51)	<0.001
SGLT2i	912 (10.1)	183 (20.1)	7.74 (7.58; 7.90)	7.11 (7.03; 7.19)	−0.62 (−0.80; −0.44)	<0.001
Other blood GLDs (excl. insulin)**	336 (3.72)	105 (31.2)	7.24 (7.02; 7.46)	7.19 (7.04; 7.33)	−0.05 (−0.32; 0.21)	0.689
Combination 1 (biguanides + DPP4i)	1,699 (18.8)	391 (23.0)	7.43 (7.30; 7.55)	7.02 (6.95; 7.09)	−0.41 (−0.56; −0.26)	<0.001
Combination 2 (biguanides + SGLT2i)	766 (8.49)	154 (20.1)	7.44 (7.28; 7.60)	7.01 (6.93; 7.09)	−0.43 (−0.62; −0.25)	<0.001

DPP4i: dipeptidyl peptidase-4 inhibitors; GLD: glucose lowering drug; GLP-1: glucagon-like peptide-1 analogues; HbA1c: glycated haemoglobin; MPR: medication possession ratio; SGLT2i: sodium-glucose co-transporter 2 inhibitors; T2DM: type 2 diabetes mellitus.

*Linear regression adjusted for: age (continuous, in years), sex (categorical: men/women), smoking habit (categorical: non-smoker/former smoker/smoker), time with T2DM (continuous, in days), socioeconomic deprivation index (continuous), HbA1c baseline (continuous, in %), insulin or new GLD during follow-up (categorical: yes/no), treatment group (categorical: biguanides/sulfonylureas/DPP-4i/GLP-1/SGLT2i/other drugs/combination 1/combination 2; only for all treatments).

**Other blood GLDs included alpha-glucosidase inhibitors, thiazolidinedione, guar gum, glinides, and other combinations different from biguanides + DPP-4 inhibitors and biguanides + SGLT-2 inhibitors.

Table 5. Association between adherence and patient characteristics (predictors retained in the final multivariate logistic regression model).

	β (SE)	OR (95% CI)	p
Total number of drugs prescribed	0.02 (0.01)	1.02 (1.01–1.03)	<0.0001
Occupational status (currently working = 1)
Retired	0.39 (0.05)	1.48 (1.34–1.65)	<0.0001
Unemployed	0.12 (0.11)	1.13 (0.91–1.40)	0.281
Smoking (non-smoker = 1)
Former smoker	0.17 (0.06)	1.18 (1.05–1.32)	0.004
Smoker	−0.13 (0.06)	0.88 (0.79–0.98)	0.023
Male gender	−0.08 (0.05)	0.92 (0.84–1.01)	0.074
Age (> 80 years old = 1)
≤ 80 years old	−0.11 (0.08)	0.89 (0.76–1.05)	0.173
Therapeutic group of the index GLD (glucose lowering drug, biguanides = 1)
Sulfonylureas	0.61(0.10)	1.83 (1.52–2.21)	<0.0001
DPP4i	0.71 (0.09)	2.04 (1.71–2.41)	<0.0001
GLP-1	0.86 (0.15)	2.37 (1.76–3.19)	<0.0001
SGLT2i	0.73 (0.09)	2.07 (1.73–2.47)	<0.0001
Other	−0.24 (0.12)	0.78 (0.62–0.99)	0.039
Combination biguanides and DPP4	0.28 (0.07)	1.32 (1.14–1.52)	<0.0001
Combination biguanides and SGLT2	0.42 (0.10)	1.52 (1.26–1.83)	<0.0001
Hypertension (yes)	0.23 (0.04)	1.26 (1.15–1.37)	<0.0001
Obesity (yes)	0.10 (0.06)	1.10 (0.98–1.23)	0.081
Diagnosis of diabetes previous to the index prescription	0.12 (0.06)	1.14 (1.00–1.28)	0.034
Adherence to previous chronic medication (low adherence (MPR ≤80%) = 1)
High adherence (MPR > 80%)	0.98 (0.11)	2.67 (2.13–3.35)	<0.0001
Not applicable (no previous medication)	0.38 (0.08)	1.46 (1.24–1.72)	<0.0001
Adherence to previous diabetes medication (low adherence (MPR ≤ 80%)=1)
High adherence (MPR > 80%)	1.46 (0.09)	4.30 (3.58–5.18)	≤0.0001
Not applicable (no previous medication)	0.32 (0.07)	1.37 (1.19–1.59)	<0.0001
Duration of diabetes (years)	0.02 (0.01)	1.02 (1.00–1.03)	<0.0001
Nationality (Spain = 1)
European (excluding Spain)	−0.59 (0.10)	0.55 (0.46–0.67)	<0.0001
Non-European	−0.83 (0.06)	0.44 (0.39–0.49)	<0.0001

DPP4i: dipeptidyl peptidase-4 inhibitors; GLD: glucose lowering drugs; GLP-1, Glucagon-like peptide-1 analogues; MPR, medication possession ratio: SD, standard deviation; SE, standard error; SGLT2i, Sodium-glucose co-transporter 2 inhibitors.

Coefficients from full multivariate logistic regression model of predictors of non-adherence. β (SE) represents the log odds ratio of being non-adherent per unit increase in the predictor and its associated standard error, z is the test statistic (β/SE), OR (95% CI) is the odds ratio for being non-adherent per unit increase in the predict and the associated 95% confidence interval, P is the p value. Positive β coefficients and odds ratios >1 represent a higher likelihood of being adherent as the predictor increases.

Figure 1. Receiver-operating characteristic curve showing the discrimination between adherent (MPR >80%) and non-adherent (MPR ≤80%) patients for the index GLD when using predicted values from the full logistic regression model*. MPR: medication possession ratio. *Validation statistics: R squared (higher values indicate better discrimination) = 0.222 (95%CI = 0.186–0.258); ROC statistic (higher values indicate better discrimination) = 0.728 (95%CI = 0.706–0.737); Brier score (lower values indicate better performance) = 0.177 (95%CI = 0.171–0.183)