Insulin therapy in type 2 diabetes: Insights into clinical efficacy, patient-reported outcomes, and adherence challenges

Table 1 Different types of insulin with their brand names and pharmacodynamic properties

Type of insulin	Brand name	Onset of action (min)		Peak time (h)		Duration of action (h)	Ref.
Short acting insulin
Human regular insulin	Humulin® R; Novolin® R; Actrapid®	30-60		2-4		6-8	[39]
Ultra-rapid insulin
Ultra-rapid aspart	Fiasp®	2		1-3		3-5	[40]
Ultra-rapid lispro	Lyumjev®	20		1-3		3-4	[41]
Rapid-acting insulin
Insulin lispro	Humalog®	20-30		1-2		≤ 5	[42]
Insulin aspart	Novolog®	15		1-3		3-5	[43]
Insulin glulisine	Apidra®	12-30		1.5		Approximately 4	[44]
Intermediate-acting insulin
NPH insulin	Humulin®; Novolin®	2-4		4-10		Up to 18	[45]
Long-acting insulin
Insulin glargine-100	Lantus®	N/A		No peak		24	[46]
Insulin detemir	Levemir®	N/A		No peak		14-24	[47]
Insulin glargine-300	Toujeo®	N/A		No peak		Up to 36	[48]
Insulin degludac	Tresiba®	N/A		No peak		> 40	[49]
Premixed insulins
Human insulin mix (70/30)	Mixtard® 30; Novolin® 70/30	30		2-10		Up to 24	[50]
Lispro mix (75/25) Lispro mix (50/50)	Humalog® Mix (75/25); Humalog® Mix (50/50)	5-20		1-2		Up to 24	[51]
Aspart mix (70/30)	NovoMix® 30	10-20		1-4		Up to 24	[52]
Degludec/Aspart	Ryzodeg®	15		2-4		> 24	[53]

N/A: Not applicable.

Table 2 Studies assess the effect of insulin therapy on satisfaction and quality of life

Effect on QOL	Comparison	PROMs	Result	Ref.
Negative	Insulin vs non-insulin users at baseline	SF-12v2; ADDQoL	Stable insulin treatment was associated with worse health status and QOL in comparison to non-insulin users	[123]
	Insulin vs non-insulin users at baseline and after 1 year	DHP; Rand-36	Insulin users had more significant problems in social functioning, pain and mental state than non-insulin users	[166]
	Insulin vs non-insulin users	SF-36v.2; WHOQOL-BREF	Insulin treated patients were associated with lower mental score than non-insulin users with no significant difference in other domains	[180]
	Insulin vs non-insulin users	DQOL; Rosser index	Individuals with established insulin therapy showed lower satisfaction and QOL	[123]
	Insulin vs non-insulin users	EQ5D; DTSQ	Insulin treatment was associated with lower HRQOL and treatment satisfaction scores than non-insulin treatment	[136]
	Insulin vs non-insulin users	SF-36	Insulin users had worse vitality and physical function domains than non-insulin users	[125]
	Insulin vs non-insulin users	EQ-5D	Insulin users had lower HRQOL scores than those not using any therapies	[126]
	Insulin vs non-insulin users	ADDQOL	Insulin therapy was associated with lower QOL scores	[181]
	Insulin vs non-insulin users	SF-12	Insulin was associated with significant lower HRQOL scores (especially mental composite scores)	[174]
	Insulin vs non-insulin users	SF-36; DHP	Insulin users showed lower scores in six domains of SF-36 questionnaire (physical functioning, social functioning, role physical, mental health, vitality, and general health) and in 2 domains of DHP-1 (barriers to activity and psychological distress) than non-insulin users	[175]
	Insulin vs non-insulin users	DQOLBCI; PDDT; QOL-VAS	Insulin therapy was associated with lower overall QOL scores (especially pain associated with treatment scale)	[182]
	Insulin vs non-insulin users	ADDQOL	Insulin use was associated with lower scores of QOL especially in younger patients	[131]
	Insulin vs non-insulin users	SF-36; HADS	Insulin therapy negatively affected emotional state, bodily pain, and physical state	[176]
	Insulin vs non-insulin users	ADDQOL-18	Insulin use was associated with negative impact on QOL	[183]
	Insulin vs non-insulin users	EQ-5D-5L; SF-12; EQ-5D-3L	Insulin users experienced more issues in self-care and usual activities, while individuals receiving combination therapy of insulin and oral drugs encountered greater difficulties in mobility, pain/discomfort, and anxiety/depression domains	[184]
	Insulin vs non-insulin users	SF-36; HADS; COPM; VAS-P; IPAQ	Insulin users exhibited more significant impairments in quality of life, functional capacity, and socialization, while also reporting higher levels of neuropathic pain and symptoms of anxiety and depression compared to non-insulin users	[127]
	Retrospective comparison	EQ-5D-5L	Longer duration of insulin use was associated with lower scores of QOL	[185]
Positive	Baseline vs follow up for 4 years of insulin therapy	SF-12v2; ADDQOL	Initiation of insulin therapy did not significantly affect health status or QOL during 4 years of follow up	[123]
	Baseline vs 4-8 wk short course of intensive insulin therapy	SF-36; DQOL; DSC-R	Early initiation of a short course of intensive insulin Therapy (IIT) associated with increased satisfaction and QOL	[129]
	Baseline vs one year of insulin treatment	DHP; Rand-36	Significant improvements in psychological distress and disinhibited eating scores of DHP questionnaire. Also, scores of vitality, physical function, social functioning and health change domain related to Rand-36 showed significant improvements	[166]
	Insulin vs non-insulin users	SF-36	Insulin users showed better quality of life in 2 domains (physical and emotional) out of 8 domains compared to non-insulin users	[167]
	Baseline vs 4 and 12 wk for insulin and non-insulin users	SF-36; DTSQ; GDS; GHQ-28	Insulin was associated with improvement in QOL, treatment satisfaction and mood reflected in different domains (Mental Health-Vitality-Social functioning-Role emotional and physical)	[133]
	Baseline vs 6 months of follow up	SF-36; DTSQ; HADS	Significant improvement in health status of Basal/Bolus group over time (7 domains) and in comparison, to oral medication group (vitality, social function, and mental health domains). Also, Basal/Bolus showed improvement in depression scores (first 3 months) and anxiety. Treatment satisfaction improved in all groups	[134]
	Baseline vs 6 months of follow up	HFS-w; DSC-R; WHO-5; ITAS	Significant improvement of well-being and QOL especially vitality and general mood	[168]
	Insulin (analog vs human) ± OAD vs OAD alone	DAWN QOL	Insulin users showed higher scores related to diet compliance and 3 subscales related to QOL measurements in comparison to non-insulin users	[169]
	Baseline vs 18 months of insulin initiation or switching	EQ-VAS; PITQ; EITQ	Improvement of the patients’ satisfaction to insulin and QOL scores in comparison to baseline	[170,171]
	Baseline vs one year of follow up	SF-36v2; DQOLCTQ	Scores of treatment satisfaction, diabetes impact and worry improved over time for each group with no significant difference between them	[172]
	Baseline vs 12 vs 24 wk for insulin users and non-insulin-users	DTSQ; ADDQOL	Significant improvement of treatment satisfaction and QOL for insulin group better than oral antidiabetic group	[135]
	Baseline vs 24 wk after insulin initiation or insulin switching	EQ-5D	Significant improvements in all measured 5 domains (Mobility- Pain/discomfort-Anxiety/depression-Self-Care-Usual activities) related to QOL for both insulin naïve and experienced patients	[164]
	Baseline vs 24 wk after insulin initiation or insulin switching	EQ-5D	Significant improvement in 3 domains (Mobility-Pain/discomfort-Anxiety/depression) out of 5 domains related to QOL for both insulin naïve and experienced patients	[165]

ADDQOL: Audit of diabetes dependent quality of life;COPM: Canadian occupational performance measure; DAWN QOL: Diabetes attitudes, wishes, and needs quality of life; DHP: Diabetes health profile; DQOL: Diabetes quality of life questionnaire; DQOLBCI: Diabetes quality of life brief clinical inventory; DQOLCTQ: Diabetes quality of life clinical trial questionnaire; DSC-R: Diabetes symptom checklist-revised; DTSQ: Diabetes treatment satisfaction questionnaire; EITQ: Expectations about insulin therapy questionnaire; EQ-5D: Euro quality of life-5 dimension; EQ-5D-3L: Euro quality of life-5 dimension-3 levels; EQ-5D-5L: Euro quality of life-5 dimension-5 levels; EQ-VAS: Euro quality of life visual analogue scale; GHQ-28: General health questionnaire-28 items; GDS: Geriatric depression scale; HADS: Hospital anxiety and depression scale; HFS-W: Worry subscale of the hypoglycemia fear survey; HRQOL: Health-related quality of life; IPAQ: International physical activity questionnaire; ITAS: Insulin treatment appraisal scale; PDDT: Patient-perceived difficulties in diabetes treatment; PITQ: Patients' perceptions of insulin therapy questionnaire; PROMs: Patient-reported outcome measures; QOL-VAS: Quality of life-visual analogue scale; SF-12: Short form 12-items; SF-12v2: Short form 12 version 2; SF-36: Short form 36-items; SF-36v.2: Short form 36-items questionnaire version 2; VAS-P: Visual analogue scale of pain; WHO-5: World Health Organization-5 wellbeing index; WHOQOL-BREF: World Health Organization quality of life brief version.

Table 3 Studies comparing premixed and basal-bolus regimens in term of patient-reported outcomes

Result	Type of insulin therapy	Study design	PROMs	Comment	Ref.
Favor basal bolus therapy	Glargine + glulisine (BB) vs lispromix or aspartmix (PM)	Comparative 12 wk intervention (crossover) phases	Validated generic and diabetes-specific modules of treatment satisfaction and QOL	The basal-bolus insulin regimen showed better outcomes in terms of treatment satisfaction and quality of life scores compared to premixed insulin regimens	[203]
	Premixed vs basal bolus	6 months observational prospective study	EQ-5D-3L	Basal-bolus regimen showed the most significant potential to increase HRQOL in comparison to other regimens	[204]
	Glargine + glulisine (BB) vs aspartmix (PM)	BB vs PM after 24 wk of treatment	DTSQ; ITSQ; ADDQOL; EQ-5D	The basal-bolus group showed significantly higher overall satisfaction with treatment, satisfaction with insulin, perceived frequency of hyperglycemia, and overall present quality of life	[137]
	Glargine + glulisine (BB) vs aspartmix (PM)	Baseline vs 60 wk follow up	PAIS-SR; EQ-5D; HFS; DQOL	The basal-bolus regimen showed superior outcomes compared to the premixed group in terms of QOL. The basal-bolus group experienced significant improvements in psychological adjustment to illness and less fear of hypoglycemia. The premixed group reported significant increases in hypoglycemic worry and a significant decline in general health related QOL	[205]
	Glargine + lispro (BB) vs lispromix (PM)	Baseline vs 24 wk follow up	DTSQ; EWITQ	No significant difference between the two groups in term of DTSQ and EWITQ scores except that premixed group showed significantly higher perceived frequency of hypoglycemia than basal-bolus group	[138]
Favor Premixed therapy	Glargine or NPH based BB regimen vs aspartmix (PM)	24 wk prospective study after switching to AspartMix	EQ-5D	Switching to AspartMix showed significant improvement in HRQOL	[206]
	Glargine + glulisine (BB) vs aspartmix (PM)	26 months randomized trial	EQ-5D; DQOL; WPAI	No significant difference of different scales for three questionnaires between two groups except for work missed for health which is significantly lower in BB group	[128]
	NPH + lispro (BB) vs lispromix (PM)	12 wk randomized comparative trial	ITR-QOL	The premixed group exhibited significantly higher scores in the total score and daily activities subscale score of ITR-QOL compared to the basal-bolus group	[207]
Undetectable difference	Glargine + glulisine (BB) vs lispromix or aspartmix (PM)	Patients switched from PM to BB with follow up for 16 wk	DTSQ	No significant difference in treatment satisfaction between two groups	[139]
	Detemir + aspart (BB) vs aspartmix (PM)	Baseline vs 50 wk of treatment	SF-36; DiabMedSat; DPM; TRIM-D	No statistically significant differences between premixed and basal-bolus group in term of patients’ satisfaction, productivity and quality of life	[130]
	Premixed vs basal bolus	Baseline vs 6 months Switching to basal bolus regimen	DQOL	No significant difference in satisfaction, impact of diabetes, social concern and concern related to diabetes after initiation of basal-bolus regimen	[101]
	Glargine + lispro (BB) vs lispromix (PM)	48 wk open label randomized study	EQ-5D; DHP-18	No significant difference of different scales for two questionnaires between two groups	[208]
	Glargine + lispro (BB) vs lispromix (PM)	Baseline vs 24 wk follow up	ITSQ; PAM-D21	No significant difference between the two groups in terms of ITSQ domain and total scores, and PAM-D21 questionnaires domain scores	[132]
	Glargine + lispro (BB) vs lispromix (PM)	Baseline vs 48 wk follow up	EQ-5D; DTSQ	No significant difference between the two groups	[140]
	Glargine + glulisine (BB) vs aspartmix (PM)	Baseline vs 24 wk follow up	DTSQ	No significant difference between the two groups in term of treatment satisfaction	[141]

ADDQOL: Audit of diabetes-dependent quality of life; BB: Basal-bolus; Basal-bolus: Includes both basal plus and full basal-bolus regimens; DHP-18: Diabetes health profile; DiabMedSat: Diabetes medication satisfaction; DPM: Diabetes productivity measure; DQOL: Diabetes quality of life questionnaire; DTSQ: Diabetes treatment satisfaction questionnaire; EQ-5D: Euro quality of life five-dimension; EQ-5D-3L: Euro quality of life -5-dimension 3-level; EWITQ: Experience with insulin therapy questionnaire; HFS: Hypoglycemia fear survey; HRQOL: Health-related quality of life; ITRQOL: Insulin therapy–related quality of life; ITSQ: Insulin treatment satisfaction questionnaire; NPH: Neutral protamine hagedorn; PAIS-SR: Psychosocial adjustment to illness state-self report; PAM-D21: Patients perceptions about medications for diabetes; PM: Premixed; PROMs: Patient-reported outcome measures; QOL: Quality of life; SF-36: Short-form 36 health survey; TRIM-D: Treatment-related impact measure-diabetes; WPAI: Work productivity and activity impairment.