Importance of early glycemic control in management of type 2 diabetes Prof. Khalifa M. Abdallah Professor of Internal Medicine Unit of Diabetes & Metabolic Diseases Alexandria Faculty of Medicine

Overview The importance of early and sustained glycemic control The rationale for early insulinization Advantages of basal insulin therapy Take home message

Diabetes Mellitus A Constellation of Complications Gastropathy Autonomic Neuropathy Renal Disease Peripheral Neuropathy Retinopathy/ Macular Edema Hypertension Cardiovascular Disease Dyslipidemia Peripheral Vascular Disease Erectile Dysfunction Diabetes Leading cause of adult blindness Results in 2- to 4-fold increase in cardiovascular risk Nearly double the rates of diagnosed depression 1,2,3 3

- A1c & Microvascular Complications 60 – 70 % Reduction of Complications Retinopathy 15 Nephropathy 13 11 9 Neuropathy Relative Risk 7 The relative risk of developing microvascular complications of diabetes (progression of retinopathy, progression to clinical neuropathy, progression to severe nonproliferative or proliferative retinopathy, or progression to microalbuminuria) was directly related to HbA1c level. In this representation of the relationship between the risk of complications and HbA1c, the relative risk of complications is set to 1 at an HbA1c of 6%. Reference Skyler J. Diabetic complications. The importance of glucose control. Endocrinol Metab Clin. 1996;25:243–254. 5 Microalbuminuria 3 1 6 7 8 9 10 11 12 HbA1c (%) Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.

Effects of reduction of A1c by 1.9% in intensively treated group Risk Reduction in DCCT Effects of reduction of A1c by 1.9% in intensively treated group Neuropathy Albuminuria Retinopathy 76% 54% 60% 39% Onset Progression 20 40 60 80 albuminuria Risk Reduction P=0.002 P=0.002 P=0.002 P=0.04 P=0.04 DCCT Research Group. N Engl J Med. 1993;329:977-986.

A1c : Myocardial Infarction and Microvascular Complication 80 Microvascular disease 60 Myocardial infarction Incidence per 1000 patient-years 40 20 Mean HbA1c (%) 5 6 7 8 9 10 11 UKPDS 35. BMJ 2000; 321: 405-12.

UKPDS: Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12% for any diabetes related endpoints p=0.029 25% for microvascular endpoints p=0.0099 16% for myocardial infarction p=0.052

UKPDS: Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12% for any diabetes related endpoints p=0.029 25% for microvascular endpoints p=0.0099 16% for myocardial infarction p=0.052

Causes of Death in People With Diabetes 50 65% of Diabetic Patients Deaths are from CV Causes Deaths (%) 40 40 30 20 15 13 13 10 10 4 5 All other Diabetes Malignant neoplasms Other heart disease Pneumonia/ influenza Ischemic heart disease Cerebrovascular disease WHO Report 1997. World Health Organisation. Geneva 1997

Can long-term glycemic control reduce the risk of cardiovascular disease?

Summary of ACCORD, ADVANCE and VADT No. of participants 10,251 11,140 1791 Participant age ,years 62 66 60 HbA1C at Baseline, % 8.1 7.5 9.4 Significant Effect on Macrovascular Outcomes? No Significant Effect on Microvascular Outcomes? NA Significant for nephropathy, not retinopathy Rosiglitazone use, (intensive vs. standard) 90% vs. 58% 17% vs. 11% 85% vs. 78% Duration of follow-up, years 3.4 5.0 6

ACCORD ADVANCE and VADT- No Significant Effect on Macro or Micro Vascular Outcomes No. of participants 10,251 11,140 1791 Participant age ,years 62 66 60 Duration of diabetes at study entry, years 10 8 11.5 HbA1C at Baseline, % 8.1 7.5 9.4 Participants with prior cardiovascular event, % 35 32 40 Duration of follow-up, years 3.4 5.0 6

DCCT / EDIC: majority of patients receive intensive therapy and HbA1C levels converge Conventional Conventional Conventional Conventional group Conventional group Conventional group 11 11 encouraged to switch encouraged to switch encouraged to switch to intensive to intensive to intensive 10 10 treatment treatment treatment (%) (%) 9 9 c c 1 1 8 8 HbA HbA During DCCT, intensive insulin therapy in people with type 1 diabetes significantly reduced HbA1c relative to those receiving conventional treatment. The intensively-treated group achieved a mean HbA1c of 7.1%, while the conventionally-treated patients had HbA1c of approximately 9.0%. During the EDIC (Epidemiology of Diabetes Intervention and Complications research group) follow-up of the DCCT cohort, all patients were encouraged to adopt intensive insulin therapy. During this time, HbA1c stablised to a similar level (just over 8%) in both treatment groups. 7 7 6 6 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 DCCT DCCT 1 1 1 2 2 2 3 3 3 4 4 4 5 5 5 6 6 6 7 7 7 DCCT DCCT end end EDIC EDIC EDIC Year Year DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653

DCCT / EDIC – incidence of all predefined cardiovascular outcome Patients previously receiving intensive treatment in the DCCT study had a 57% reduced incidence of nonfatal myocardial infarction, stroke or death from cardiovascular disease DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653

UKPDS: Post-Trial Changes in HbA1c Mean (95%CI) UKPDS results presented UKPDS 80. N Eng J Med 2008; 359

UKPDS: Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank N Eng J Med 2008

Can long-term glycemic control reduce the risk of cardiovascular disease? Yes If early and sustained glycemic control started before atherosclerosis is established

At present, The question is not whether to intensively treat people with type 2 diabetes at onset of the disease to prevent long-term complications. The question rather is how to intensively treat patients with type 2 diabetes to consistently keep A1c < 7% all through the course of the disease

ADA: Position statement: Need for early treatment “Patients with shorter duration of Type 2 diabetes and without established atherosclerosis might reap cardiovascular benefits from intensive glycaemic control”1 Skyler JS, et al. J Am Coll Cardiol. 2009;53(3):298-304.

Glycemic control & A1c Target AACE ADA <6.5 <7 A1c (%) <110 80-120 Preprandial (mg/dl) <140 140-180 Postprandial (mg/dl) 100-140 Bedtime (mg/dl) ADA: American Diabetes Association AACE: American Association of Clinical Endocrinologists

Two-thirds of Type 2 Patients are not Achieving Glycemic Control R19/p19/C1/P1/L1-4 NHANES1 44.5% 35.8% A1c <7% R1/p3/L1-2 1988-1994 N=1215 1999-2000 N=372 AACE survey 2003-20042 Only about one-third of Americans with type 2 diabetes meet either the ADA or AACE standards for glycemic control. Recent statistics reveal that the majority of patients with diabetes are not achieving adequate glycemic control. The National Health and Nutrition Examination Survey (NHANES) is conducted periodically on a nationwide scale in the United States to gather health and nutritional data. Results from the 1988-1994 survey revealed that 44.5% of patients with type 2 diabetes had an A1c level of 7% or lower. NHANES data gathered during 1999-2000 are even more disappointing: just over one-third of patients reported having an A1c level of 7% or lower. The NHANES findings are corroborated by data gathered during 2003-2004 by the American Association of Clinical Endocrinologists (AACE). In a survey of 157,000 patients with type 2 diabetes across 39 states in the US, two-thirds of respondents were failing to achieve an A1c goal of 6.5% or below. References: Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults with type 2 diabetes. Diabetes Care 2004;27:17-20. American Association of Clinical Endocrinologists. “State of Diabetes in America,” 2003-2004. Available at: http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmerica Report.pdf. Accessed January 6, 2006. 33% R19/p19/C1/P1/L1-4 A1c 6.5% N=157,000 type 2 patients 39 US states included R1/p3/L1-2 NHANES = National Health and Nutrition Examination Survey. 1Koro et al. Diabetes Care. 2004;27:17-20; 2 “State of Diabetes in America,” American Association of Clinical Endocrinologists, 2003-2004. Available at: http://www.aace.com/public/awareness/stateofdiabetes/ DiabetesAmericaReport.pdf. Accessed January 6, 2006.

Traditional Type 2 Diabetes Management: A “Treat-to-Fail Approach” Published Conceptual Approach Mean HbA1c of patients 1/Del Prato p.1349 Figure 2A 2/Campbell p.626 Figure 1 OAD + multiple daily insulin injections Diet and exercise OAD monotherapy OAD up-titration OAD combination OAD + basal insulin 10 9 8 HbA1c Goal 7 6 Duration of Diabetes Conventional stepwise treatment approach OAD=oral antihyperglycemic agent. Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

Delays often occur between stepping up from monotherapy to combination therapy Length of time between first monotherapy HbA1c > 8.0% and switch/addition in therapy (months) 25 20.5 months 20 14.5 months 15 Months 10 Initial improvements in glycemic control seen with conventional antidiabetic agents in monotherapy are usually not maintained long term, and most patients ultimately require combination therapy to achieve good glycemic control.1 In practice, there is often a considerable delay between the loss of glycemic control with monotherapy and the introduction of another antidiabetic agent. Analysis of data from the Kaiser Permanente Northwest database (1994–2002)2 found that the average time from when the HbA1c action point of 8% was exceeded and the introduction of an additional or alternative oral antidiabetic agent was: 14.5 months for those on metformin monotherapy 20.5 months for those on sulfonylurea monotherapy. Earlier introduction of combination therapy could reduce exposure of patients to the risk of diabetes-related complications associated with periods of hyperglycemia.2 1Turner RC, et al. JAMA 1999; 281:2005–2012. 2Brown, JB et al. Diabetes Care 2004; 27:1535–1540. 5 Metformin only Sulfonylurea only n = 513 n = 3394 Brown, JB et al. Diabetes Care 2004; 27:1535–1540.

Clinical Inertia: Failure to Advance Therapy When Required Percentage of subjects advancing when A1C >7% < 8% At insulin initiation, the average patient had: 100 5 years with A1C > 8% 10 years with A1C > 7% 80 66.6% 60 44.6% % of Subjects 35.3% 40 18.6% 20 Diet Sulfonylurea Metformin Combination Brown JB et al. Diabetes Care 2004;27:1535-1540.

Lifestyle Intervention + Metformin Diagnosis Lifestyle Intervention + Metformin No HbA1c ≥7% Yes Add Basal Insulin Add Sulfonylurea Add Glitazone Add DPP-4 inhibitor ADA-EASD-Consensus 2006

Consensus Algorithm Update 2009 Tier 1: Well-validated core therapies Lifestyle + Metformin plus Basal Insulin At diagnosis: Lifestyle + Metformin Lifestyle + Metformin plus Intensive Insulin Lifestyle + Metformin plus Sulfonylureaa Step 1 Step 2 Step 3 Tier 2: Less well-validated therapies Check A1C every 3 months until <7%. Change treatment if A1C is ≥7% Lifestyle + Metformin plus Pioglitazone No hypoglyceamia Oedema / CHF Bone Loss Lifestyle + Metformin plus Pioglitazone plus Sulfonylurea Lifestyle + Metformin plus GLP-1 agonist No hypoglyceamia Weight loss Nausea / vomiting Lifestyle + Metformin plus Basal Insulin Nathan DM et al. Diabetes Care 2009;32:193-203..

Sulphonylureas failed to maintain glycemic control Glyburide 1 Glimpiride Glyburide Glibenclamide Gliclazide Glyburide Hanefeld (n=250) HBA1c % Reduction -1 Tan (n=297) Chicago (n=230) -2 Periscope (n=181) ADOPT (n=1441) UKPDS (n=1573) 1 2 3 4 5 10 Time (years)

UKPDS: Islet -cell function and the progressive nature of diabetes Time of diagnosis 100 80 60 (% of normal by HOMA) Islet -cell function Pancreatic function = 50% of normal 40 20 10 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 Years HOMA = homeostasis model assessment Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25; UKPDS. Diabetes. 1995;44:1249-1258

Advantages of insulin It lowers mean blood glucose in a predictable dose-dependent manner Can be tailored to individual needs on a unit-to-unit basis It has the longest experience than any other drug (90 years) No contraindications to its use

Advantages of insulin Insulin is the only drug that directly reduces lipolysis and free fatty acid concentrations in blood, thus reducing lipotoxicity Insulin improves lipoprotein metabolism, decreases LDL cholesterol and triglycerides, and increases HDL cholesterol Insulin improves endothelial dysfunction

thoughts/concerns about starting insulin Common Fears: Needles Hypoglycemia Weight gain Common Beliefs: Insulin is the last option Insulin causes complications Insulin is a personal failure Adverse impact on relationships/lifestyle 32

What should I tell people with Type 2 diabetes about insulin? ‘Most people with Type 2 diabetes eventually need insulin because their own production of insulin falls off with time and they therefore inevitably become insulin deficient’

What should I tell people with Type 2 diabetes about insulin? ‘If you need insulin, it doesn’t mean you failed. Tablets cannot control blood glucose forever, because they don’t stop the problem of your own declining insulin production getting worse’ Islet -cell dysfunction worsens over time, regardless of therapy

What should I tell the person with Type 2 diabetes who needs insulin, but doesn’t want to take it? ‘Insulin will not make your diabetes worse. In fact, it will help control your glucose, so you’ll have fewer complications and you’ll feel better.’ Strict glycaemic control reduces the risks of both microvascular and macrovascular complications

Insulin Regimens 1. Basal insulin ( NPH or long-acting insulin analogue) + OAD 2. Total insulin replacement therapy - Premixed insulins - Basal-bolus

24-hour Plasma Glucose Curve: Rationale for Adding Basal Insulin Slide 1-22 400 Diabetes 300 Glucose (mg/dL) 200 Normal 100 0600 1000 1400 1800 2200 0200 0600 Time of Day Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

24-hour Plasma Glucose Curve: Rationale for Adding Basal Insulin Slide 1-22 400 300 Diabetic Glucose (mg/dL) 200 100 Normal 0600 1000 1400 1800 2200 0200 0600 Time of Day Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Starting With Basal Insulin in DM 2 – Advantages 1 injection with no mixing Insulin pens for increased acceptance Slow, safe, simple titration Low dosage Effective improvement in glycemic control Limited weight gain Slide 6-37 INSULIN TACTICS Starting With Basal Insulin Advantages Patients who no longer respond adequately to oral agents will benefit from combination therapy that consists of maintaining the use of oral antidiabetic agents together with insulin therapy. The advantages of adding basal insulin to prior treatment with oral agents include the following: (1) only one insulin injection may be required each day, with no need for mixing different types of insulin; (2) the use of insulin pens can enhance patient acceptance of the treatment; (3) titration can be accomplished in a slow, safe, simple fashion; and (4) eventually combination therapy requires a lower total dose of insulin. The result is effective improvement in glycemic control while causing only limited weight gain.

Insulin Glargine vs. NPH Insulin Added to Oral Therapy Mean A1C Levels During Study 9 Insulin glargine NPH insulin 8 Mean A1C (%) 7 Target A1C (%) 6 4 8 12 16 20 24 Time (weeks) Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

Less Hypoglycemia with Insulin Glargine vs NPH 3500 3000 2500 2000 1500 1000 NPH Insulin glargine Hypoglycemia events per 100 patient-years T1DM p=0.004 between treatments 6 7 8 9 10 HbA1c 200 150 100 50 Hypoglycemia events per 100 patient-years T2DM p=0.021 between treatments 6 7 8 9 10 HbA1c Mullins P et al. Clin Ther 2007;29:1607−19.

Insulin Glargine vs. NPH Insulin Added to Oral Therapy Symptomatic Hypoglycemia by Time of Day Glargine NPH insulin Basal insulin 1.4 * * 1.2 * * 1.0 * * 0.8 * Events per Patient-Year 0.6 0.4 0.2 Similar trends were observed when the overall number of symptomatic hypoglycemic episodes occurring over time were analyzed. Between midnight and 8 am, and breakfast time, there were fewer episodes of symptomatic hypoglycemia in the insulin glargine group compared with the NPH insulin group At other times of day, the number of episodes of symptomatic hypoglycemia were similar in both treatment groups ROSENSTOCK Abstract OBJECTIVE: To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS: A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n = 259) or NPH insulin once or twice daily in = 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose <6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS: The treatment groups showed similar improvements in A1C from baseline to end point on intent-to-treat analysis. The mean change (means +/- SD) in A1C from baseline to end point was similar in the insulin glargine group (-0.41 +/- 0.1%) and the NPH group (-0.59 +/- 0.1%) after patients began with an average baseline A1C of approximately 8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.%) However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase(26.5 vs. 35.5%, P = 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P < 0.0007). CONCLUSIONS: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine demonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin. 20 22 24 2 4 6 8 10 12 14 16 18 Time of Day (hour) Hypoglycemia defined as PG  72 mg/dL, by hour *P < 0.05 vs. glargine. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

Insulin Glargine Trials Showing Effective Reduction in HbA1c 10 9 8 7 6 5 9.5 8.85 8.80 8.71 8.80 8.61 HbA1c (%) 7.14 7.15 7.14 6.96 6.96 6.80 Treat-To-Target LANMET APOLLO LAPTOP Triple Therapy INITIATE Baseline Study endpoint

Insulin Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Insulin Treatment Regimen Target: FPG 100 mg/dL Subjects (n=364) were randomly assigned to: Insulin glargine once daily + continued OADs OADs* Premixed human insulin 70/30 BID 0 24 Time (wk) Baseline End Point *Sulfonylurea + metformin OAD=oral antidiabetic drug Janka HU, et al. Diabetes Care. 2005;28:254-259.

Insulin Glargine Plus OADs vs Twice-daily Premixed Human Insulin Change in A1C from Baseline to Study End Point* P=0.0003 Baseline 24 week A1C At 24 weeks, superior reduction was achieved with insulin glargine plus OADs compared with twice-daily pre-mixed insulin. *Intent-to-treat analysis OAD=oral antidiabetic drug Janka HU, et al. Diabetes Care. 2005;28:254-259. Janka H, Plewe G, Kliebe-Frisch C, et al. Starting insulin for type 2 diabetes with insulin glargine added to oral agents vs twice-daily premixed insulin alone. Presented at: American Diabetes Association 64th Scientific Sessions; June 4-8, 2004; Orlando, Fla.

LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures N=371 insulin-naïve patients Insulin glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks Twice-daily premixed insulin Insulin glargine + OADs p=0.0003 9 5 5.7 1.3% 1.7% 4 8 p=0.0009 3 7.5% Hypoglycaemia* (events/patient year) HbA1c (%) 7 7.2% 2.6 2 6 1 5 *Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l]) Janka H et al. Diabetes Care 2005;28:254−259.

Documented Hypoglycemic Episodes Per Patient-Year Less Hypoglycemia With Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Insulin Documented Hypoglycemic Episodes Per Patient-Year P<0.0001 10 9.9 8 # of Episodes Per Patient-Year 6 4 4.1 At 24 weeks, less hypoglycemia was documented with insulin glargine plus oral anti-diabetic drugs versus twice-daily pre-mixed insulin. 2 Insulin Glargine + OAD Premixed Average dose = 28.2 IU with G + OAD vs 64.5 IU with premixed insulin Weight Gain: 1.4 ± 3.4 kg with G + OAD vs 2.1 ± 4.2 kg with pre mixed insulin Janka HU, et al. Diabetes Care. 2005;28:254-259. Janka H, Plewe G, Kliebe-Frisch C, et al. Starting insulin for type 2 diabetes with insulin glargine added to oral agents vs twice-daily premixed insulin alone. Presented at: American Diabetes Association 64th Scientific Sessions; June 4-8, 2004; Orlando, Fla.

Conclusions Due to declining -cell function, insulin therapy will be necessary for most patients with Type 2 diabetes Insulin therapy should be initiated early when glycemic control exceeds the recommended targets Insulin effectively lowers HbA1c, thereby reducing the risks of both micro- and macrovascular complications

Relative Contributions of Fasting and Postprandial Glycemia(%) to The Overall Diurnal Hyperglycemia Over Quintiles of A1C PPG FPG 100 80 70 70 Contribution % 60 40 30 30 20 A1c <7% A1c 8% A1c 9% A1c >10% Diabetes Care 2003, 26:881-885

Conclusions-cont. Insulin glargine when used as a basal insulin has the following advantages: It effectively lowers fasting and mean blood glucose Easily initiated and titrated Low risk of hypoglycemia

Thank You

Insulin glargine provides superior long term efficacy vs. NPH. Insulin glargine offers long-term efficacy without the need for intensification Key points Insulin is normally added to oral glucose-lowering drugs in people with type 2 diabetes when glycaemic control becomes suboptimal. Outcomes in people starting insulin therapy with neutral protamine Hagedorn (NPH), detemir, glargine or premixed insulins were evluated Insulin-naive people with type 2 diabetes (n = 8009), ‡ 35 years old, HbA1c ‡ 6.5% and begun on NPH (n = 1463), detemir (n = 357), glargine (n = 2197) or premix (n = 3992), were identified from a UK database of primary care records (The Health Improvement Network) Unadjusted and multivariate-adjusted analyses were conducted, with persistence of insulin therapy assessed by survival analysis. In the study population (n = 4337), baseline HbA1c was 9.5 ± 1.6%, falling to 8.4 ± 1.5% over 12 months (change )1.1 ± 1.8%, p < 0.001) Compared with NPH, people taking detemir, glargine and premix had an adjusted reduction in HbA1c from baseline, of 0.00% (p = 0.99), 0.19% (p < 0.001) and 0.03% (p = 0.51). Body weight increased by 2.8 kg overall (p < 0.001), and by 2.3, 1.7, 1.9, and 3.3 kg on NPH, detemir, glargine and premix (p < 0.001 for all groups) Insulin dose at 12 months was 0.70 (overall), 0.64, 0.61, 0.56 and 0.76 U ⁄ kg ⁄ day After 36 months, 57% of people on NPH, 67% on glargine and 83% on premix remained on their initially prescribed insulin In routine clinical practice, people with type 2 diabetes commenced on NPH experienced a modest disadvantage in glycaemic control after 12 months compared with other insulins. When comparing the insulins, glargine achieved best HbA1c reduction, while premix showed greatest weight gain and the highest dose requirement, but had the best persistence of therapy Insulin glargine provides superior long term efficacy vs. NPH. Gordon J, et al. Int J Clin Pract. 2010;64(12):1609-18.   52 52