Intensive glycemic control and macrovascular, microvascular, hypoglycemia complications and mortality in older (age ≥60years) or frail adults with type 2 diabetes: a systematic review and meta-analysis from randomized controlled trial and observation studies

Figures & data

Table 1. A summary of the PICO (population, intervention, comparison, and outcome) model used for this systematic review and meta-analysis.

	Description
P (Population)	Adults aged ≥60 or with frailty AND a diagnosis of type 2 diabetes mellitus
I (Intervention)	Intensive glycemic control: as defined by HbA1c levels reduced to a pre-specified target level of at least ≤59 mmol/mol (≤7.5%), irrespective of treatment used
C (Comparison)	Standard care
O (Outcomes)	All-cause mortality Hypoglycemia Hospital admissions Macrovascular: rates of myocardial infarction or stroke Microvascular: rates of foot disease or amputation, nephropathy, neuropathy or retinopathy Cognition and memory: rates of dementia, other measures of cognitive decline including mini-mental state examinations Falls and fractures: rates of falls or fractures

Figure 1. Flow chart showing the systematic review process and the numbers excluded at each stage, with reasons where appropriate. Further detail can be found in Appendix 3.

Table 2. Study characteristics of the observational studies included in this review.

Study name or reference	Study design	Study region	Setting	Age or frailty	Treatments	Numbers of intensive control (n)/total (N)	Duration	HbA1c target Intensive vs Standard (mmol/mol)	Outcomes of interest
Anyanwagu et al. [13]*	Cohort	United Kingdom	Primary Care	Age>65	Any & on insulin	1,657/4,589	5 years	≤58 vs >58	Macrovascular Mortality
Davis et al. [33]‡^1	Cross-sectional	United Kingdom	Nursing homes	Age>65	Any & on insulin	n/583^1	n/a	<53 vs intervals up to >75	Hypoglycemia
GERODIAB [34]*	Cohort	France	Outpatient	Age>70	Any	178/987	5 years	≤50 vs >50	Mortality
Hamada et al. [35]*	Cohort	United Kingdom	Primary Care	Age>80	Any	11,826/25,966	Unclear	≤53 vs >53	Mortality
Huang et al. [36]*	Cohort	CA, USA	Outpatient	Age>60	Any	43,046/71,092	4 years	≤53 vs >53	Macrovascular Microvascular Mortality Hospitalisation^2
Lee et al. [37]	Cohort	USA	Outpatient	Age>65	Any	n/652,901^3	Unclear	<48 vs >58	Falls/Fracture
Ling et al. [38]	Cohort	UK	Primary care	Age>70	Insulin or sulphonylureas	6,288/22,857	Up to 17 years	≤53 vs >53	Mortality^4 Hypoglycemia
Oliver et al. [39]†^5	Cross-sectional	NY, USA	Outpatient	Dementia, Age>65	Any & on insulin^5	221/448	n/a	≤53 vs >53	Hospitalization
Puar et al. [40]‡^6	Cross-sectional	Singapore	Hospital	Frailty	Any	n/129^6	n/a	<48 reported	Falls/Fracture
Schwartz et al. [41]‡^7	Cohort	USA	Outpatient	Age>70	Insulin and non-insulin^7	n/2641^7	Unclear	<42 vs >64	Falls
van Hateren et al. [42]‡^8	Cohort	Netherlands	Primary Care	Age>75	Any	n/374^8	Unclear	≤53 vs >53	Hospitalization
Ying et al. [43]*‡	Case Control	Hong Kong	Primary Care	Age>65	Any	271/688	n/a	<48 vs 48–64	Mortality

*multiple subgroups pooled together to facilitate comparison; † Odds ratios calculated by hand using data extracted from the study (therefore narrative synthesis only); ‡ included in narrative synthesis only. 1. Number in each group not cited, results reported as rates per 100person/months; 2. Hospitalization due to hyperglycemic complications only; 3.Total number available, but data not clear on numbers with HbA1c <6.5%; 4. Separate reports for cardiovascular and non-cardiovascular mortality; 5. Only data for those on insulin was presented in a suitable format; 6. Study reported % of fractures with HbA1c <6.5%; 7. Numbers involved not clear and multiple models used; 8. Group sizes not reported for this result, which is a subanalysis of those with diabetes duration <5 years

Table 3. Study characteristics of the randomized controlled trials included in this review.

Study name or reference	Study region	Setting	Numbers of intensive control (n)/total (N)	Duration	HbA1c target Intensive vs Standard (mmol/mol)	Outcomes of interest
ACCORD [9,10,22, 44–46]	North America	Outpatients	Age >65: 1,732/3,475	3.7 years	<42 vs 53–64	Macrovascular Microvascular (neuropathy only) Mortality Hypoglycemia Falls^1
ADVANCE [8,32,47]	Global	Outpatients	Age >65: 3,296/6,A613	5 years	≤48 vs >48	Macrovascular Microvascular Memory Mortality Hypoglycemia
Chen et al. [48].‡	China	Outpatients	30/60^2	3 years	≤53 vs “usual care”	Memory Hypoglycemia

‡Included in narrative synthesis only due to small numbers unclear design. 1. Falls outcomes include patient aged <60 year, but due to paucity of other data this has been extracted for discussion 2. n = 30 in intermediate group excluded, comparisons between “usual care” and tight glycemic control arm

Figure 2. Forest plot showing individual study and pooled hazard ratios (subgroup and overall) for the effect of intensive glycemic control versus standard control on the risk of mortality in frail and/or elderly patients with type 2 diabetes.

Figure 3. Forest plot showing individual study and pooled hazard ratios (subgroup and overall) for the effect of intensive glycemic control versus standard control on the risk of severe hypoglycemia in frail and/or elderly patients with type 2 diabetes.

Figure 4. Forest plot showing individual study and pooled hazard ratios (subgroup and overall) for the effect of intensive glycemic control versus standard control on the risk of a) macrovascular complications b) microvascular complications in frail and/or elderly patients with type 2 diabetes.

Table 4. Table summarizing the results of the systematic review for each outcome including numbers of observational or randomized controlled trials (RCT) included, pooled hazard ratios (HRs), assessments of heterogeneity and bias, and overall conclusions.

Outcome	Observational studies	RCTs	Pooled HR (95% CI)	I^2 heterogeneity	Assessment of bias	Conclusions
All-cause mortality	6 (1)*	2	0.96 (0.90–1.03)	00.0% – Low	Potential high risk of bias in some of the concluded studies.	No convincing evidence that favors intensive glycemic control in reducing mortality
Severe hypoglycemia	2 (1)*	3 (1)*	2.30 (1.71–3.09)	82.2% – High	Significant heterogeneity. Included studies relatively free from bias. Clear signal from pooled HR	Current evidence favors standard glycemic control in reducing severe hypoglycemia
Hospital admission	3*	0	n/a	n/a	Relatively unbiased studies, significant difference in study design.	Conflicting results from small number of available studies means no conclusion can be drawn
Macrovascular	2	2	0.88 (0.77–1.02)	64.25 – Moderate	Included studies show little evidence of bias	Three of the studies show consistent results and meta-analysis of all four studies is in favor of intensive glycemic control to reduce the risks of macrovascular complications
Microvascular	1	2 (1)*	0.78 (0.69–1.02)	88.6% – High	Included studies show little evidence of bias but heterogeneity is large.	Reduced rates of microvascular complications in all studies, as further evidence by pooled HR. Favors intensive glycemic control. Effect seemingly greater than for macrovascular.
Cognition	0	2*	n/a	n/a	Significant potential bias in one of the studies. Significant differences in study design, one with very small numbers	Conclusions difficult to draw given paucity of evidence. Probable neutral to beneficial effect of intensive control but more high-quality studies are needed
Falls/Fractures	2*	1*	n/a	n/a	Significant heterogeneity in design and reporting	Conclusions cannot be drawn. From available data effect of intensive control likely neutral or increased risk of falls and fractures

*number not suitable for meta-analysis in brackets otherwise no studies identified suitable for meta-analysis

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