Management of Patients with Newly Diagnosed Diabetic Mellitus: Ophthalmologic Outcomes in Intensive versus Conventional Glycemic Control

Figures & data

Figure 1 PRISMA chart, curation process for studies identified. Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.⁵²

Table 1 Summary of Articles Review on the Effect of Intensive Glycemic Control on Diabetic Retinopathy

Studies	Age of Participants	Study Type	Participants	Diabetes Type	Baseline Retinopathy Status	Interventions	Study Arms	Duration	Ocular Efficacy Outcome	Significant Findings	Limitations
Diabetic retinopathy after two years of intensified insulin treatment. Follow-up of the Kroc Collaborative Study. The Kroc Collaborative Study Group (1988, North America and England)^Citation18	N/A	Multicenter RCT	68 patients	IDDM	Mild to moderate	Receiving either intensified diabetic control with continuous subcutaneous insulin infusion (CSII) or unchanged conventional insulin treatment (CIT)	i. CSII ii. CIT	2 years	Mean retinopathy level (MRL) and the score keyed to the worse eye (Worse Eye Score) based on ETDRS protocol	With tightened control of diabetes in patients with mild to moderate nonproliferative retinopathy, no initiation of vasproliferative deterioration in retinopathy was found.	Small sample size
Early Worsening of Diabetic Retinopathy in the Diabetes Control and Complications Trial (1998)^Citation21	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	3–9 years follow-up	Retinopathy grading based on ETDRS protocol	Intensive insulin treatment provides patient with long term benefits and outweight the risks of worsening in early phrase.	N/A
Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group (1994)^Citation26	13 to 39 years old	Multicenter RCT	195 patients	IDDM	125 (no), 70 (mild)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	4–9 years follow-up	Retinopathy grading based on ETDRS protocol	The progression of diabetic retinopathy in adolescent patients became slower with intensive therapy	N/A
Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group (1995)^Citation20	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	3–9 years follow-up	Retinopathy grading based on ETDRS protocol	After receiving 3 years of Intensive insulin therapy, a reduction in the need of laser treatment and prevention of blindness is found in patients with mild to moderate diabetic retinopathy	N/A
The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial (1995)^Citation19	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	3–9 years follow-up	Retinopathy grading based on ETDRS protocol	Intensive therapy is found to be able to decrease the progression of retinopathy after 8.5 years in diabetic patients with or without diabetic retinopathy.	N/A
Aiello (2015)^Citation22	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	Follow up of patients from 1983–1989 until 2015	Self report of ocular surgical procedures annually	A reduction in the risk of ocular surgery was reported in type 1 diabetes patients who received intensive therapy.	Ocular operations based on patients’ self report only
Azad (2014)^Citation13	60 ± 9 years old	Multicenter RCT	858 patients	NIDDM	263 (no), 595 (yes but not specified)	Receiving either intensive or standard glycemic control	i. intensive insulin/drug treatment ii: standard insulin/drug treatment	5 years	Retinopathy grading based on ETDRS protocol	Intensive insulin therapy was found to be related with lowering of diabetic retinopathy in young patients but increasing risk in older patients.	Participants are mostly men with advanced NIDDM, no investigator blinding
Brinchmann-Hansen (1992)^Citation23	Male: 26 (18–36) years old Female: 13 (6–23) years old	RCT	45 patients	IDDM	Mean count of microaneurysms and hemorrhages=17	Receiving insulin pumps (continuous subcutaneous insulin infusion), multiple injections (four to six times daily), and conventional insulin treatment (twice daily)	i. insulin pumps; ii. multiple injections; iii. conventional insulin treatment	7 years	Retinopathy score based on the number of microaneurysms and haemorrhages	Non proliferative retinopathy is beneficial by lowering glycated haemoglobin in long term.	Small sample size
Chew (2010)^Citation24	26 (18–36) years old	Multicenter RCT	2856 patients	NIDDM	N/A	Receiving intensive glycemic/lipid/BP control or standard therapy	i. intensive glycemic control (target HbA1c <6.0%) ii.standard therapy (target HbA1c7.0 to 7.9%); i. intensive lipid control by fibrate and statin ii.: standard lipid control by statin only; i. intensive BP control (SBP<150mmHg) ii. standard BP control (SBP< 180mmHg)	4 years	Retinopathy grading based on ETDRS protocol, development of proliferative diabetic retinopathy necessitating photocoagulation therapy or vitrectomy.	The rate of progression of diabetic retinopathy can be reduced by the use of intensive glycaemic control and intensive treatment of dyslipidemia	Retinopathy data collected only every 2 year
Crofford (1995)^Citation25	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	3–9 years follow-up	Retinopathy grading based on ETDRS protocol	Intensive treatment is probably recommended to most patients with IDDM, though the implementation is difficult.	N/A
Davis (1998)^Citation33	18–69 years old	Multicenter RCT	3680 patients	Both IDDM and NIDDM	From mild NPDR to moderate PDR	Receiving either aspirin or placebo/early photocoagulation on one eye and deferral of photocoagulation unless high-risk PDR on the other eye	i. aspirin ii. placebo; i. early photocoagulation ii. photocoagulation unless high risk PDR	5 years	Development of high-risk PDR and of severe visual loss or vitrectomy (SVLV)	Better glycemic control can reduce retinopathy progression in both diabetes types, in all age groups and in all retinopathy stages including the severe nonproliferative and early proliferative stages	N/A
Emanuele (1996)^Citation34	40–69 years old	Multicenter RCT	153 patients	NIDDM	38% had no retinopathy, 5 of them had PDR	Receiving either intensive diabetic control (target HbA1c 4.0–6.1%) or standard insulin treatment (1injection per day)	i. 4-step intensive glycemic control ii: standard insulin injection	2 years	Retinopathy grading based on ETDRS protocol	Intensive control did not cause transient worsening of retinopathy, though no improvement was seen in one-year time	Only men included, short follow-up time
Henricsson (1999)^Citation35	Progression of retinopathy ≤ 2 level: 61.4 ±7.6 years old Progression of retinopathy ≥ 3 level: 64 ± 6.3 years old	Prospective observational study	45 patients	NIDDM	21 (no), 17 (mild NPDR), 5 (moderate NPDR)	Receiving insulin therapy	i. diabetic retinopathy progression <2 levels after intervention ii. diabetic retinopathy progression > 3 years after intervention	24 months	Change of retinopathy level, change in HbA1c, hemostatic variables and IGF-1	In type 2 diabetes, the improvement in glycosylated hemoglobin is associated with the reduced retinopathy progression in 2-year time	Small sample size
Kayashima (1995)^Citation37	Insulin withdrawal cases without shift to oral hypoglycemic agents: 55.3± 11.9 insulin withdrawal cases with shift to oral hypoglycemic agents: 57.0 ± 7.6	Prospective study	171 patients	NIDDM	N/A	Receiving obseration period for 2–5 days, insulin therapy with strict diet therapy. Insulin therapy was discontinued in patients with excellent level of glycemic control for more than 7 days. Patients with blood glucose concentrion more than 180 mg/dL within 7 days after after withdrawal of insulin therapy was given oral hypoglycaemic agents.	i. Insulin withdrawal cases without shift to oral hypoglycemix agents ii. insulin withdrawal cases with shift to oral hypoglycaemic agent iii. cases continuing with insulin	1 year	Glycaemic control in terms of HbA1c, FBG, PPG, MDBG	Insulin therapy is advised to commence at the early stage in NIDDM patients without retinopathy.	N/A
Kilpatrick (2012)^Citation29	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensive or conventional blood glucose management	i. intensive glycaemic control ii. conventional glycaemic control	3–9 years follow-up	Retinopathy grading based on ETDRS protocol	The frequency of exposure to severe hypoglycaemia was not predictive of the risk of developing retinopathy at any given HbA1c	N/A
Lachin (2000)^Citation30	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	4 years	Retinopathy grading based on ETDRS protocol assessed by fundus photography, number of patients received panretinal scatter photocoagulation therapy during DCCT	In type 1 diabetes, intensive therapy resulted in reduced risk of progressive retinopathy despite increased incidence of hyperglycemia.	N/A
Molyneaux (1998)^Citation36	57.5 (50.0–64.6) years old	Observational study	963 patients	NIDDM	Without any retinopathy	Receiving diet modification, oral agent and insulin treatment	i. type 2 diabetic patients ii. type 1 diabetic patients in DCCT	7 years	Retinal findings of direct fundoscopy	In type 2 diabetes, the development of retinopathy is associated with the magnitude of hypoglycaemia although the association is weaker than that of type 1 diabetes	N/A
Nathan (1993)^Citation31	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	3–9 years follow-up	Retinopathy grading by seven field stereoscopic fundus photographs	Intensive therapy was useful in delaying the onset and slowing the progression of retinopathy	N/A
Nathan (2014)^Citation12	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	DCCT (1982–1993); EDIC (1994–2012)	Retinopathy grading based on ETDRS protocol	Intensive glycemia control can reduce the long-term complications of diabetes.	N/A
Pettitt (2005)^Citation1	Intervention group: 55.0±11.6 Control group: 55.5 ±12.9	Multicenter RCT	200 patients	NIDDM	110 (no), 76 (mild), 14 (severe)	Receiving either intensive diabetes management in addition to standard care or standard care	i. intensive management ii. standard treatment	2 years	Effects and progression of diabetic retinopathy by retinal photographs	Starting intensive treatment before clinically significant retinopathy develops can reduce the risk of retinopathy progression in type 2 diabetes.	N/A
Service (2001)^Citation32	13 to 39 years old	Multicenter RCT	565 patients	IDDM	268 (no), 265 (mild NPDR), 32 (moderate NPDR)	Receiving wither intensive therapy or conventional therapy	i. intensive therapy ii. conventional therapy	4 years	Retinopathy grading based on ETDRS protocol in patients with seven point capillary glucose data	The major risk for progression of retinopathy is conveyed by updated mean blood glucose especially above 8.3 mmol/L	N/A
White (2008)^Citation28	13 to 39 years old	Multicenter RCT	1441 patients	IDDM	726 (no), 715 (mild to moderate)	Receiving either intensified diabetic control (at least 3 injections per day) or conventional insulin treatment (1 or 2 injections per day)	i. intensive insulin injection ii: conventional insulin injection	10 years	Retinopathy status and progression assessed by 7 field sterofundus photography	The benefits of intensive therapy on retinopathy progression continues for at least 10 years	N/A

Abbreviations: RCT, randomized controlled trials; IDDM, insulin-dependent diabetes; CSII, continuous subcutaneous insulin infusion; CIT, conventional insulin treatment; ETDRS, Early Treatment Diabetic Retinopathy; NIDDM, non-insulin-dependent diabetes; NPDR, non proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; DCCT, Diabetes Control and Complications Trial.

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