Table 1.

Summary of Trials Reporting Impact of Glucose Control on DSP Measures

Type 1 Diabetes Observational Studies
Study Name Author/year	DSP Measures	Study Population N/age	Intervention	Follow-up	HbA1c	Outcomes
Ziegler et al. 1991(36)	NCS measured by EMG and thermal discrimination threshold by Marstock stimulator	N=32 Mean age 20 years	N/A Group 1: Mean HbAIc<8.3 % Group 2: Mean HbAIc>8.3 %	5 years	Baseline Group 1: 10.6 % Group 2: 11.6 % Follow-up Group 1: 7 % Group 2: 10 %	Prevalence of DSP
							Group 1	Group 2
						Baseline	0	3.5 %
						24 month	5.6 %	14.6 %
						48 months	2.6 %	22 %
						60 months	6.1 %	21 %
						P <0.05
Pittsburg Epidemiology of Diabetic Complications (EDC) Study Maser RE et al./1989 (37)	Two or more of the following: symptoms, sensory and/or motor signs, and/or absent tendon reflexes.	N=400 DSP+= 135 DSP −=228 Mean age 28 years	N/A	N/A	DSP + : 10.2 % DSP − : 9.8 %	OR for DSP HbA1c 10 vs. 9 %=1.36 (1.16–1.61) P <0.05
Seattle Prospective Diabetic Foot Study Adler et al./1997(60)	Monofilament testing	N=775 DSP+= 388 DSP−=387 Mean age 62 years	N/A	2.5 years	Baseline DSP+= 11.6 % DSP-=10.9 % Follow-up DSP+ : 8.8 % DSP− : 8.3 %	OR for DSP per 1 % HbA1c =1.06 (1.01–1.11) P=0.03
EURODIAB IDDM Complications Study. Tesfaye S et al./ 1996 (57)	Neuropathic symptoms and physical signs, vibration perception threshold, abnormal autonomic function	N=3250 Mean age 32 years	N/A	7.3 years	Baseline : 6.7 % Follow -up : 8.3 %	Prevalence of DSP: Overall Prevalence: 28 % DSP Prevalence by HbA1c
						HbA1c	DSP
						<5.4	15 %
						5.4–6.4	26 %
						6.5–7.7	30 %
						>7.8	40 %
						OR=2.48 (1.50– 4.11) P<0.001
Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) study Klein R et al. /1996 (39)	Loss of tactile sensation or temperature sensitivity	N=1210 mean age 29 years	N/A	10 years	Baseline : 10.8 % Follow- up: 10.1 %;	2 % change in HbA1c from baseline to 4 years results in 19 % decrease in the 10-year incidence of loss of tactile sensation P <0.005
Randomized Controlled Trials
Study Name Author/year	DSP Measures	Study Population N/age	Intervention	Follow-up	HbA1c	Outcomes
Reichard et al./1993(61)	Composite of symptoms of neuropathy and NCS	N=102 Mean age 31 years	INT N=48 Intensified insulin therapy, individual education, tutoring and home glucose monitoring CON N=54 Standard insulin therapy, routine diabetes care	7.5 years.	Baseline INT: 9.5 % CON : 9.4 % Follow-up INT : 7.1 % CON: 8.5 %	Prevalence of DSP at follow-up INT : 14 % CON : 28 % P=NS
Oslo study Amthor et al./1994(62)	Motor and sensory NCS	N=45 Mean age 26 years	INT N=33 c Continuous insulin infusion/ multiple injections (4–6 daily) CON N =12 Twice daily insulin therapy	8 years	Baseline :11.2 % Follow-up : 9.5 %	Every 1 % change in HbA1c resulted in a 1.3 m/s change in nerve conduction velocity during 8 years. Change in peroneal NCS from baseline to 8 years by mean HbA1c groups
						HbA1c	NCS
						< 9 %=	−2.2 m/s
						9.1–10 %=	−0.2 m/s
						> 10 %=	−4.8 m/s
						P <0.01
Diabetes Control and Complications Trial (DCCT) DCCT study group/1993, 1995(5; 6)	Abnormal neurological examination plus abnormal NCS in at least 2 peripheral nerves	N =1441 Mean age 26 years	INT N=711 either external insulin pump or by three or more daily insulin injections guided by frequent blood glucose monitoring CON N=730 one or two daily insulin injections	6.5 years	Baseline INT : 9.1 % CON: 9.1 % End of DCCT INT : 7.2 % CON: 9. 1 %	Prevalence of DSP INT : 6.8 % CON : 5.6 % INT : 9.3 % CON:17.51 % P <0.002
Epidemiology of Diabetes Interventions and Complications (EDIC) Albers et al./2010(11)	Abnormal neurological examination plus abnormal NCS in at least 2 peripheral nerves	N=1186 Mean age 34 years	N/A Former INT N=603 Former CON N=583	13/14 years	EDIC year 13/14 INT : 8.0 % CON: 8. 0 %	Prevalence of DSP INT : 23.6 % CON:32.7 % P <0.05
Type 2 Diabetes Observational Studies
Study Name Author/year	DSP Measures	Study Population N/age	Intervention	Follow-up	HbA1c	Outcomes
San Luis Valley Diabetes Study Sands et al./ 1997(48)	Two or more of the following: bilateral paresthesia in legs or feet; bilateral decreased or absent ankle reflexes; and/or bilateral decreased or absent cold temperature discrimination in feet to an iced tuning fork	N=231 Age 20–74 years	N/A	4.7 years	Baseline DSP + : 11.2 % DSP − : 10.2 % Subgroups: HbA1c <9.0 % HbA1c =9.0 %	Unadjusted incidence rate (IR) : 6.1 /100 person-yrs Adjusted IR 4.71 /100 person/yrs 5.60 /100 person/yrs P=NS
Taiwan Study Chao et al./2007(46)	Neuropathy Symptom Score, Neuropathy Disability Score, Total Neuropathy Score	N=498 Mean age 62 years	N/A	N/A	DSP + : 8.2 % DSP – : 7.8 %	Significant correlations between A1c and warm/ cold thresholds. (r=0.451 and r=0.380 respectively, P <0.0001)
Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) study Klein R et al. 1996(39)	Loss of tactile sensation or temperature sensitivity	N=1780 Mean age 65 years	N/A	4 years	Baseline : 10.2 % Follow-up : 9.7 %	2 % change in A1c from baseline to 4 years resulted in 23 % decrease in the 10-year incidence of loss of tactile sensation P <0.005
Perkins et al./2010(63)	NCS median sensory nerve, bilateral sural nerve.	N=110 Mean age 56 years	N/A Placebo cohort analysis	1 year	Baseline 8.3 %	Improvement in A1c by −0.8 % associated with 2.9 m/s improvement in NCS A1c worsening by +1 % associated with decrease of −2.6 m/s NCS P =0.02
Randomized Controlled Trials
Study Name Author/year	DSP Measures	Study Population N/age	Intervention	Follow-up	HbA1c	Outcomes
KUMAMOTO Trial Ohkubo et al./1995(12)	NCS and VPT	N=110 Mean age 49 years	INT N=50 3 or more injections of insulin daily CON N =52 1or 2 daily injections of insulin	6 years	Baseline INT: ~9.2 % CON: ~9 % Follow-up INT: 7.1 % CON : 9.4 %	Median Motor NCS
							Baseline	6 years
						INT	50.8 m/s	53.2 m/s
						CON	51.6 m/s	50.2 m/s
						P <0.05
United Kingdome Prospective Diabetes Study (UKPDS) UKPDS group/1998(22)	Either one of loss of knee/ ankle reflexes or abnormal VPT	N=3867 Mean age 54 years	INT N=2729 Oral agents or with insulin CON N=1138 Diet or oral agents or with insulin	10–15 years	Baseline INT : 7.05 % CON : 7.09 % Follow-up INT : 7.0 % CON : 7.9 %	Prevalence of abnormal VPT INT : 30.2 % CON : 51.7 % P =0.005 Prevalence of absent ankle reflexes INT : 35 % CON : 37 % P=NS
VA Cooperative Study on Type II Diabetes Mellitus (VA CSDM) Azad et al./1999(18)	Symptoms and signs of DSP by cranial neuropathy, muscle strength, deep tendon reflexes, touch sensation, prickling sensation, vibratory sensation, proprioceptive sensation	N =153 Mean age 60 years	INT N=75 four-step plan, daily self- monitoring CON N=78 1 morning injection/ day	2 years	Baseline INT: 9.3 % CON: 9.5 % Follow-up INT=7.3 % CON=9.5 %	Prevalence of DSP INT : 48 % CON : 53 % Prevalence of DSP INT : 64 % CON : 69 % P=NS
Veteran Affairs Diabetes Trial (VADT) Duckworth et al. /2009(24)	Self -reported radiculoneuropathy, polyneuropathy, diabetic amyotrophy, or neuropathic ulcer.	N =1791 Mean age 60 years	INT N=892 started on oral drugs, then insulin if HbA1c not<6 % CON N=899 started on half the maximal doses, insulin if HbA1c not less than 9 %	5.6 years	Baseline INT: 9.4 % CON: 9.4 % Follow-up INT: 6.9 % CON: 8.4 %	Incidence of DSP at follow-up INT: 38.4 % CON: 40 % P=NS
ADDITION Denmark Study (ADDITION) Charles et al./2011(17)	Either one abnormality in the following: vibration detection threshold and light touch sensation, and the MNSI	N=1,533 Mean age 60 years	INT N=702 Glucose target-driven intervention using multiple medications and lifestyle interventions CON N=459 Standard of care for diabetes at the time in Denmark	6 years	Baseline INT : 6.4 % CON: 6.4 % Follow-up INT: 6.4 % CON: 6.4 %	Prevalence of DSP at follow-up INT : 30.1 % CON: 34.8 % P=NS
Action to Control Cardiovascular Risk in Diabetes (ACCORD) Ismail-Beigi et al./2010(15)	MNSI>2, vibratory sensation, ankle reflex, monofilament test	N=10,251 Mean age 62 years	INT N=5128 intensive glycemic therapy target HbA1c<6 % CON N=5123 Standard glycemic therapy target HbA1c 7–7.9 %	5 years	Baseline INT: 8.1 % CON: 8.1 % Follow- up INT: 6.3 % CON: 7.6 %	Prevalence of DSP at follow-up MNSI>2 INT:55·6 % CON: 58·6 % HR=0.92 CI (0.86–0.99) ; P=0.02 Loss of ankle jerk INT : 45.7 % CON: 49.3 % HR=0.90 CI (0.84–0.97); P=0.005 Loss of light touch INT: 12·1 % CON: 14·1 % HR=0·85 CI (0.76–0.95); P=0.004
STENO 2 Gaede et al./2003 (23)	VPT	N =160 Mean age 55 years	INT N=80 stepwise behavior modification and pharmacologic therapy targeting glucose and other risk factors CON N =80 Denmark national guidelines	7.8 years	Baseline INT: 8.4 % CON: 8.8 % Follow-up INT :7.9 % CON: 8.6 %	Relative Risk of DSP with intervention 1.09 (0.54–2.22) P=NS
Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI2D Pop-Busui et al./ 2013(16)	MNSI clinical examination score>2	N=2159 DSP - IS =530 IP=545 DSP + IS=550 IP=534 Mean age 62 years	IS: metformin, thiazolidinedies (TZDs), or both IP :sulfonylureas/ meglitinides, insulin or both	4 years	Baseline DSP + IS =7.7 % IP =7.8 % DSP - IS =7.6 % IP =7.6 % Follow-up IS=7.1 % IP=7.6 %	4-year cumulative incidence rate of DSP in subjects free of DSP at baseline IS=66 % IP=72 % P <0.05

Footnotes: NCS: nerve conduction studies, INT-intensive treatment, CON-conventional treatment, DSP-distal symmetrical sensorimotor polyneuropathy, CAN- cardiovascular autonomic neuropathy, RCT-randomized control trial, VPT-vibration perception threshold, OR-odds ratio, N-number, MNSI- Michigan Neuropathy Screening Instrument, IS-insulin sensitizing, IP-insulin providing, N/A-not applicable, HR-hazard ratio, CI-confident interval, NS-non significant