Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options

Figures & data

Table 1 Categories of older people with type 2 diabetes in different guidelines

Guideline	Year	Category 1	Category 2	Category 3
CHCF^Citation19	2003	Relatively healthy	Frail, life expectancy <5 years	NA
VA/DoD^Citation20	2004	Life expectancy >15 years No or minimal microvascular complications	Life expectancy 5–15 years Moderate microvascular complications	Life expectancy <5 years Advanced microvascular complications, advanced age, severe comorbidity
VA/DoD^Citation21	2010	Life expectancy >10–15 years	DM duration >10 years, comorbid conditions	Life expectancy <5 years Advanced microvascular complications, advanced age, severe comorbidity
EDWPOP^Citation12	2011	Single system involvement Free of major comorbidities	Frail (dependent, multisystem disease, dementia, care home residents)	NA
ADA/AGS^Citation14	2012	Healthy (Few coexisting chronic illnesses, intact cognitive and functional status)	Complex/intermediate (Multiple coexisting chronic illnesses or ≥2 IADL impairments or mild to moderate cognitive impairment)	Very complex/poor health (Long-term care or end-stage chronic illnesses or ≥2 ADL dependences or moderate to severe cognitive impairments)
IDF^Citation10	2013	Functionally independent	Functionally dependent frailty or dementia	End-of-life care

Abbreviations: ADA, American Diabetes Association; ADL, activity of daily life; AGS, American Geriatric Society; CHCF, California HealthCare Foundation; EDWPOP, European Diabetes Working Party for Older People; IADL, instrumental activity of daily life; IAGG, International Association of Gerontology and Geriatrics; IDF, International Diabetes Federation; VA/DoD, Veterans Affairs/Department of Defense; NA, not applicable; DM, diabetes mellitus.

Table 2 Glycemic targets according to different categories indicated by guidelines worldwide

Guideline	Year	Category 1	Category 2	Category 3
CHCF^Citation19	2003	A1C ≤7% (53.0 mmol/mol)	A1C =8% (63.9 mmol/mol)	NA
VA/DoD^Citation20	2004	A1C <7% (53.0 mmol/mol)	A1C <8% (63.9 mmol/mol)	A1C <9% (74.9 mmol/mol), avoid symptomatic hyperglycemia
VA/DoD^Citation21	2010	A1C <7% (53.0 mmol/mol)	A1C <8% (63.9 mmol/mol)	A1C =8%–9% (63.9–74.9 mmol/mol)
EDWPOP^Citation12	2011	A1C =7%–7.5% (53.0–58.8 mmol/mol) FPG =6.5–7.5 mmol/L	A1C =7.6–8.5% (59.6–69.4 mmol/mol) FPG =7.6–9.0 mmol/L	NA
ADA/AGS^Citation14	2012	A1C <7.5% (58.5 mmol/mol) FPG =5–7.2 mmol/L Bedtime BG 5–8.3 mmol/L	A1C <8.0% (63.9 mmol/mol) FPG =5–8.3 mmol/L Bedtime BG 5.6–10 mmol/L	A1C <8.5% (69.4 mmol/mol) FPG =5.6–10 mmol/L Bedtime BG =6.1–11.1 mg/dL
IDF^Citation10	2013	A1C =7%–7.5% (53.0–58.8 mmol/mol)	A1C =7%–8% (53.0–63.9 mmol/mol) up to 8.5% (69.4 mmol/mol)	Avoid symptomatic hyperglycemia
Diabetes UK^Citation36	2011	Care home residents: A1C =7–8% (53.0–63.9 mmol/mol), FPG =7–8.5 mmol/L, random BG <9 mmol/L
IAGG/EDWPOP^Citation13	2012	In general, A1C =7%–7.5% (53.0–58.8 mmol/mol), avoid random BG >11 mmol/L
Canadian Diabetes Association^Citation15,Citation38	2013	Limited life expectancy, high level of functional dependency, advanced comorbidities: A1C 7.1%–8.5% (54.0–69 mmol/mol)
DCPNS/PATH, Canada^Citation16	2013	Frail older adults: A1C =8%–12% (63.9–107.7 mmol/mol), avoid symptomatic hyperglycemia

Abbreviations: BG, blood glucose; DCPNS/PATH, Diabetes Care Program of Nova Scotia and the Palliative and Therapeutic Harmonization Program; FPG, fasting plasma glucose; ADA, American Diabetes Association; AGS, American Geriatric Society; CHCF, California HealthCare Foundation; EDWPOP, European Diabetes Working Party for Older People; IAGG, International Association of Gerontology and Geriatrics; IDF, International Diabetes Federation; VA/DoD, Veterans Affairs/Department of Defense; NA, not applicable; A1C, glycated hemoglobin.

Table 3 Comparisons of current options in glycemic control

Options	Hypoglycemia risks	Glycemic variability	Costs	Treatment complexity	Special considerations
Diet	Low	Reduced	Low	Variable	Balanced between glycemic control and nutrition status
Exercise	Low	Reduced	Low	Low	Individualized planning, muscle strengthening
BW reduction	Low	No data	Low	Variable	Not applicable to frail adults with or without malnutrition
Metformin	Low	No change	Low	Low	Be cautious in advanced CKD, CHF, frailty, malnutrition, and sarcopenia; preserve skeletal muscle
TZD	Low	No change	Moderate	Low	Preserve skeletal muscle; increased risk of fracture, CHF
SU	High	No change	Low	Variable	Avoid glyburide/glibenclamide
Meglitinides	Moderate	Reduced	Moderate	High	Should not combine with SU or AGI, drug interactions
DPP4-i	Low	Lowest	Moderate	Low	Effective with preserved β-cell function
GLP1-RA	Low	Lowest	High	Moderate	Effective with preserved β-cell function
AGI	Low	Reduced	Moderate	High	Gastrointestinal side effects, social problems
Insulin	High	Variable	Variable	Variable	Long-acting insulin analogs are suggested

Abbreviations: AGI, alpha glucosidase inhibitors; BW, body weight; CHF, congestive heart failure; CKD, chronic kidney disease; DPP4-i, dipeptidyl peptidase-4 inhibitors; GLP1-RA, glucagon-like peptide-1 receptor agonists; SU, sulfonylurea; TZD, thiazolidinediones.

Table 4 Comparisons of current options in glycemic control based on different categories

Options	Categories
	Functionally independent		Functionally dependent		End-of-life care
	Newly diagnosed	Long lasting	Frail	Dementia
Diet	Carbohydrates restriction	Carbohydrates restriction	Adequate calories, proteins	Adequate calories	Adequate calories
Exercise	Muscle strengthening	Muscle strengthening	Muscle strengthening	Activities	Activities
BW	Maintain healthy BW	Maintain healthy BW	Avoid BW loss	Avoid BW loss	Avoid BW loss
Metformin	First-line medication	First-line medication	Potentially beneficiala Potentially detrimentalb	First-line medication	May be considered
TZD	Second-line combination	Potentially beneficiala Potentially detrimentalc	Potentially beneficiala Potentially detrimentald	Potentially beneficiale Potentially detrimentalf	May be considered
SU	Second-line combination Start low, go slow	May be considered May not be effective	Alternative first lineg Potential detrimentalh	May be considered Once daily, start low	May be considered
Meglitinides	Second-line combination	May be considered May not be effective	May be considered	Potentially detrimentali	May be considered
DPP4-i	Second-line combination	May be considered May not be effective	May be considered	May be considered, once daily	May be considered
GLP1-RA	Second- or third-line combination	May be considered May not be effective	Potentially detrimentalb	May not be cost effective	May not be cost effective
AGI	Second-line combination	May be considered May not be effective	Potentially detrimentalb	May be considered	May be considered
Insulin	Second-line combination, long-acting analogs	May need prandial insulin	Long-acting analogs	Long-acting analogs	NPH may be enough

Notes:

a Potential muscle preservation is good for frail adults.

b Potential gastrointestinal upsets may be detrimental for malnourished adults with progressive BW loss.

c Limited use in some comorbidities, such as congestive heart failure.

d Potential fracture risk should be considered in frail adults with high risk of falling.

e Pioglitazone exhibited potential cognitive improvement in mild AD.

f Rosiglitazone is associated with cognitive decline.

g For elderly not eligible for metformin use, low dose initiated SU may be alternative first line medication.

h Risk of hypoglycemia and consequent falling may be detrimental for frail adults.

i For elderly with erratic eating habits, such kind of drug may result in higher risk of hypoglycemia.

Abbreviations: AGI, alpha glucosidase inhibitors; BW, body weight; DPP4-i, dipeptidyl peptidase-4 inhibitors; GLP1-RA, glucagon-like peptide-1 receptor agonists; SU, sulfonylurea; TZD, thiazolidinediones; NPH, neutral protamine Hagedorn.

Table 5 Drug interactions between antidiabetic agents and drugs used for the most common comorbidities in the elderly

Table 6 Comparisons of combination strategies in glycemic control

Study	n(D1/D2)	Age (years)	DM duration (years)	Preexisting drug(s)	Added-on drug 1 (D1)	Added-on drug 2 (D2)	Study period	A1C (%)	ΔA1C (%)	ΔBW (kg)	Hypoglycemia
Ferrannini et al^Citation180	1396/1393 Elderly 712	57.5	5.7	Metformin	Vildagliptin	Glimepiride	1 year	7.3	−0.44/−0.53	−0.2/+1.5*	0/10 events*
Matthews et al^Citation181	1562/1556 Elderly 789	57.5	5.7	Metformin	Vildagliptin	Glimepiride	2 years	7.3	−0.10/−0.10	−0.3/+1.2	2.3%/18.2% 2.1%/17.5%
Filozof and Gautier^Citation182	513/494 Elderly 390	59.5	6.6	Metformin	Vildagliptin	Gliclazide	1 year	8.5	−0.81/−0.85 −0.98/−0.91	+0.08/+1.36*	6/11 events
Göke et al^Citation183	428/430 Elderly 219	57.6	5.4	Metformin	Saxagliptin	Glipizide	1 year	7.7	−0.74/−0.80	−1.1/+1.1	3%/36.3%*
Gallwitz et al^Citation184	776/775 Elderly 506	59.8	Variable	Metformin	Linagliptin	Glimepiride	2 years	7.7	−0.16/−0.36	−1.4/+1.3	7%/36%
Arechavaleta et al^Citation206	516/519	56.3	6.8	Metformin	Sitagliptin	Glimepiride	30 weeks	7.5	−0.47/−0.54	−0.8/+1.2*	7%/22%*
Nauck et al^Citation186	588/584	56.7	6.3	Metformin	Sitagliptin	Glipizide	1 year	7.7	−0.67/−0.67	−1.5/+1.1*	5%/32%*
Takihata et al^Citation193	58/57	60.5	NA	Metformin and/or SU	Sitagliptin	Pioglitazone	24 weeks	7.4	−0.86/−0.58*	−0.3/+1.7*	3.4%/3.5%
Bolli et al^Citation194	295/281	56.6	6.4	Metformin	Vildagliptin	Pioglitazone	24 weeks	8.4	−0.88/−0.98	+0.3/+1.9*	1/0 episode
Bolli et al^Citation195	295/281	56.6	6.4	Metformin	Vildagliptin	Pioglitazone	1 year	8.4	−0.60/−0.60	+0.2/+2.6*	1/1 episode
Umpierrez et al^Citation196	96/107	53.7	5.4	Metformin	Glimepiride	Pioglitazone	26 weeks	8.4	−1.30/−1.23	+1.7/+1.8	33%/0.9%*
Matthews et al^Citation197	313/317	56.5	5.7	Metformin	Gliclazide	Pioglitazone	1 year	8.6	−1.01/−0.99	+1.4/+1.5	11.2%/1.3%*
Charbonnel et al^Citation198	313/317	56.5	5.7	Metformin	Gliclazide	Pioglitazone	2 years	8.6	−0.76/−1.07*	+1.1/+2.3	11.5%/2.2%*
Ceriello et al^Citation207	62/54	56.3	7.4	Metformin	Gliclazide	Pioglitazone	1 year	8.5	−1.00/−0.80	+0.6/+1.3	NA
Pfützner et al^Citation208	288	59.0	6.1	Metformin	Glimepiride	Pioglitazone	24 weeks	7.3	−1.00/−0.80	+0.7/+0.7	5/2 events
Wang et al^Citation114	28/23	53.8	6.8	Metformin	Acarbose	Glibenclamide	24 weeks	8.4	−0.70/−1.20	−1.5/+0.8	0/3 events
Cefalu et al^Citation199	483/482 485/482	56.3 56.1	6.6 6.7	Metformin Metformin	Canaglifozin 100 mg Canaglifozin 300 mg	Glimepiride Glimepiride	1 year 1 year	7.8 7.8	−0.82/−0.81 −0.93/−0.81*	−3.7/+0.7* −4.0/+0.7*	6%/34%* 5%/34%*
Lavalle-González et al^Citation200	368/366 367/366	55.5 55.4	6.7 6.9	Metformin Metformin	Canaglifozin 100 mg Canaglifozin 300 mg	Sitagliptin Sitagliptin	1 year 1 year	7.9 7.9	−0.73/−0.73 −0.88/−0.73*	−3.3/−1.2* −3.7/−1.2*	4.2%/4.7% 5.0%/4.7%
Aschner et al^Citation185	227/253	53.6	4.5	Metformin	Insulin glargine	Sitagliptin	24 weeks	8.5	−1.72/−1.13*	+0.44/−1.08*	46%/13%*
Charbonnel et al^Citation209	285/262	57.3	7.8	Metformin	Sitagliptin ± SU	Liraglutide	26 weeks	8.2	−1.30/−1.40	−0.4/−2.8*	12.0%/4.0%*
Kim et al^Citation112	28/30	56.9	9.6	Insulin glargine	Acarbose	Nateglinide	2 weeks	8.3	NA	NA	3%/5%
Triple combination
Schernthaner et al^Citation201	378/377	56.7	9.6	Metformin, SU	Canaglifozin 300 mg	Sitagliptin	1 year	8.1	−1.03/−0.66*	−2.5%/+0.3%*	43.2%/40.7%
Derosa et al^Citation202	52/51	54.0	3.5	Metformin, SU	Acarbose	Repaglinide	15 weeks	8.1	−1.4/−1.1	−1.9%/+2.3%	0/1 events
Derosa et al^Citation203	175/178	56.0	1.1	Metformin, SU	Acarbose	Pioglitazone	24 weeks	8.6	−1.5/−2.1*	−1.2/+1.4	2/3 events
Derosa et al^Citation204	225/228	NA	NA	Metformin, pioglitazone	Sitagliptin	Glibenclamide	1 year	7.2	−0.7/−1.1	−2.5/+4.5*	NA
Osonoi et al^Citation205	14/15	64.4	Variable	Metformin, acarbose	Sitagliptin	Mitiglinide	4 weeks	7.0	−0.39/−0.18	NA	0.4%/0.9%a

Notes:

* Reached significance, P<0.05.

a Assessed by continuous glucose monitoring, percentage of blood glucose levels <70 mg/dL.

Abbreviations: BW, body weight; DM, diabetes mellitus; n, number of patients; NA, not available; SU, sulfonylurea; A1C, glycated hemoglobin.

Figure 1 Comparison of combination therapies, studies including two drugs combination, and three drugs combination.

Abbreviations: AGI, alpha glucosidase inhibitors; DPP4-i, dipeptidyl peptidase-4 inhibitors; SU, sulfonylurea; TZD, thiazolidinediones; SGLT2i, sodium glucose co-transporter 2 inhibitor; MET, metformin.

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