Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E
McGill Nutrition and Food Science Centre, McGill University, Montreal Quebec, Diabet. Med. 2006 Jul;23(7):736-42.

Insulin is generally withheld until people with Type 2 diabetes are unresponsive to other therapies. However, its potential advantages suggest that it could be added earlier to achieve glycaemic goals; this possibility was tested in a clinical trial. Consenting adults aged 18-80 years with Type 2 diabetes for at least 6 months, HbA(1c) of 7.5-11%, and on 0, 1 or 2 oral agents, were randomized to one of two therapeutic approaches for 24 weeks: evening insulin glargine plus self-titration by 1 unit/day if the fasting plasma glucose (FPG) was > 5.5 mmol/l; or conventional therapy with physician adjustment of oral glucose-lowering agents if capillary FPG levels were > 5.5 mmol/l. The primary outcome was the first achievement of two consecutive HbA(1c) levels ≤ 6.5%. Two hundred and six participants were allocated to glargine and 199 to oral agents. Compared with control subjects, participants receiving glargine: (i) were 1.68 times more likely to achieve two consecutive HbA(1c) levels ≤ 6.5% (95% CI 1.00-2.83; P = 0.049); (ii) reduced their HbA(1c) by 1.55 vs. 1.25% (P = 0.005), achieving adjusted means of 7.0 vs. 7.2% (P = 0.0007);
(iii) had lower FPG (P = 0.0001), non-high-density lipoprotein (HDL) cholesterol (P = 0.02) and triglycerides
(P = 0.02); (iv) had greater increases in treatment satisfaction (P = 0.045); and (v) had a 1.9-kg greater increase in weight (P < 0.0001). No differences in hypoglycaemia were noted. Adding insulin glargine is more likely to achieve a lower HbA(1c) level than conventional therapy with oral agents.

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Comparison of Basal insulin added to oral agents
versus twice-daily premixed insulin
as initial insulin therapy for type 2 diabetes.

Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Jarvinen H.
Zentralkrankenhaus, Bremen-Nord, II Medizinische Abteilung, Hammersbecker Str. 228, 28755 Bremen, Germany. hans.janka@klinikum-bremen-nord.de.
Diabetes Care. 2005 Feb;28(2):254-9

Objective:
To compare the efficacy and safety of adding once-daily basal insulin versus switching to twice-daily premixed insulin in type 2 diabetic patients insufficiently controlled by oral antidiabetic agents (OADs).

Research Design and Methods:
In a 24-week, multinational, multicenter, open, parallel group clinical trial, 371 insulin-naive patients with poor glycemic control (fasting blood glucose [FBG] ≥120 mg/dl, HbA(1c) 7.5-10.5%) on OADs (sulfonylurea plus metformin) were randomized to once-daily morning insulin glargine plus glimepiride and metformin (glargine plus OAD) or to 30% regular/70% human NPH insulin (70/30) twice daily without OADs. Insulin dosage was titrated to target FBG ≤100 mg/dl (both insulins) and predinner blood glucose ≤100 mg/dl (70/30 only) using a weekly forced-titration algorithm.

Results:
Mean HbA(1c) decrease from baseline was significantly more pronounced (-1.64 vs. -1.31%, P = 0.0003), and more patients reached HbA(1c) ≤7.0% without confirmed nocturnal hypoglycemia (45.5 vs. 28.6%, P = 0.0013) with glargine plus OAD than with 70/30. Similarly, FBG decrease was greater with glargine plus OAD (adjusted mean difference -17 mg/dl [-0.9 mmol/l], P < 0.0001), and more patients reached target FBG ≤100 mg/dl with glargine plus OAD than with 70/30 (31.6 vs. 15.0%, P = 0.0001). Glargine plus OAD patients had fewer confirmed hypoglycemic episodes than 70/30 patients (mean 4.07 vs. 9.87/patient-year, P < 0.0001).

Conclusions:
Initiating insulin treatment by adding basal insulin glargine once daily to glimepiride plus metformin treatment was safer and more effective than beginning twice-daily injections of 70/30 and discontinuing OADs in type 2 diabetic patients inadequately controlled with OADs.

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Adiponectin levels in women with polycystic ovary syndrome
and severe insulin resistance.

Sepilian V, Nagamani M.
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility,
University of Texas Medical Branch, Galveston, Texas.
J Soc Gynecol Investig. 2005 Feb;12(2):129-34.

Objective
Adiponectin is an adipokine that is decreased in obesity and type 2 diabetes. Women with polycystic ovarian syndrome (PCOS) are obese and are at risk for type 2 diabetes. The objective of the current study was to investigate the relationship of adiponectin to obesity and insulin resistance in women with PCOS and severe insulin resistance.

Methods
Thirty women with PCOS and acanthosis nigricans indicating severe insulin resistance were included in the study. Eleven body mass index (BMI)-matched women with normal ovulatory cycles served as controls. Fasting glucose, insulin, and adiponectin levels were measured, and a standard oral glucose tolerance test (OGTT) with insulin levels was performed. To further investigate the role of insulin sensitivity on adiponectin levels, 10 women with PCOS were treated with 4 mg rosiglitazone daily for 6 months and adiponectin levels were measured before and after treatment.

Results
Fasting insulin levels (33.5 +/- 3.8 muU/mL; P <.001) and insulin area under the curve (AUC) during OGTT (536.2 +/- 70.5 muU/mL; P <.01) were higher in women with PCOS, while glucose levels were similar to controls. Adiponectin levels were lower (P <.01) in women with PCOS (5.6 +/- 2.6 mug/mL) compared with controls (8.5 +/- 3.9 mug/mL). There was a significant negative correlation between adiponectin levels and fasting insulin levels (r = -0.40, P = .02), insulin AUC during OGTT (r = -0.47, P = .008), fasting glucose levels (r = -0.45, P = .01), and glucose AUC during OGTT (r = -0.51, P = .003). There was no correlation between BMI and serum adiponectin (r = -0.12, P = .508) in women with PCOS, while there was a negative correlation (r = -0.746, P = .013) in controls. There was a significant (P <.01) increase in adiponectin levels when treated with rosiglitazone, despite unchanged BMI.

Conclusions
These results indicate that in women with PCOS and severe insulin resistance, insulin sensitivity appears to be the major determinant of adiponectin levels rather than adiposity. Low adiponectin levels may predict women with PCOS who are at high risk for developing type 2 diabetes.

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Initiating Insulin Therapy in Type 2 Diabetes:
A comparison of biphasic and basal insulin analogs.

Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA, Hu P, Bode B, Garber A.
Department of Internal Medicine, Southwestern Medical Center at Dallas, Dallas, TX 75390-8858. philip.raskin@utsouthwestern.edu.
Diabetes Care. 2005 Feb;28(2):260-5.

Objective
Safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 70/30, prebreakfast and presupper) were compared with once-daily insulin glargine in type 2 diabetic subjects inadequately controlled on oral antidiabetic drugs (OADs).

Research Design and Methods
This 28-week parallel-group study randomized 233 insulin-naive patients with HbA(1c) values >/=8.0% on >1,000 mg/day metformin alone or in combination with other OADs. Metformin was adjusted up to 2,550 mg/day before insulin therapy was initiated with 5-6 units BIAsp 70/30 twice daily or 10-12 units glargine at bedtime and titrated to target blood glucose (80-110 mg/dl) by algorithm-directed titration.

Results
A total of 209 subjects completed the study. At study end, the mean HbA(1c) value was lower in the BIAsp 70/30 group than in the glargine group (6.91 ± 1.17 vs. 7.41 ± 1.24%, P < 0.01). The HbA(1c) reduction was greater in the BIAsp 70/30 group than in the glargine group (-2.79 ± 0.11 vs. -2.36 ± 0.11%, respectively; P < 0.01), especially for subjects with baseline HbA(1c) >8.5% (-3.13 ± 1.63 vs. -2.60 ± 1.50%, respectively; P < 0.05). More BIAsp 70/30-treated subjects reached target HbA(1c) values than glargine-treated subjects (HbA(1c) ≤6.5%: 42 vs. 28%, P < 0.05; HbA(1c) <7.0%: 66 vs. 40%, P < 0.001). Minor hypoglycemia (episodes/year) was greater in the BIAsp 70/30 group than in the glargine group (3.4 ± 6.6 and 0.7 ± 2.0, respectively; P < 0.05). Weight gain and daily insulin dose at study end were greater for BIAsp 70/30-treated subjects than for glargine-treated subjects (weight gain: 5.4 ± 4.8 vs. 3.5 ± 4.5 kg, P < 0.01; insulin dose: 78.5 ± 39.5 and 51.3 ± 26.7 units/day, respectively).

Conclusions
In subjects with type 2 diabetes poorly controlled on OADs, initiating insulin therapy with twice-daily BIAsp 70/30 was more effective in achieving HbA(1c) targets than once-daily glargine, especially in subjects with HbA(1c) >8.5%.

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Oral antidiabetic agents : current role in type 2 diabetes mellitus.

Krentz AJ, Bailey CJ.
Southampton University Hospitals NHS Trust, Southampton, UK.
Drugs. 2005;65(3):385-411.

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance.Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones).The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis - beyond expected effects on glycaemic control - is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited.The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option.Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA(1c)) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA(1c)), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations.Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive.Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.

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Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes.

Choi D, Kim SK, Choi SH, Ko YG, Ahn CW, Jang Y, Lim SK, Lee HC, Cha BS.
Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-Dong,
Seodaemoon-Ku, Seoul 120-749, Korea. bscha@yumc.yonsei.ac.kr.
Diabetes Care. 2004 Nov; 27(11):2654-60

Objective
Despite the popularity of coronary stenting in coronary artery disease (CAD), restenosis remains a challenging clinical problem. This study evaluated the efficacy of rosiglitazone for preventing in-stent restenosis in type 2 diabetic patients.

Research Design and Methods
We conducted a prospective, randomized, case-controlled trial involving 95 diabetic patients with CAD who were randomly assigned to either the control or rosiglitazone group (48 and 47 patients, respectively). Quantitative coronary angiography (QCA) was performed at study entry and again at 6-month follow-up. The primary end point was the restenosis rate, which was determined by QCA.

Results
Eighty-three patients (45 patients with 55 lesions in the control group and 38 patients with 51 lesions in the rosiglitazone group) completed follow-up angiography. Rosiglitazone treatment for 6 months reduced fasting insulin concentration. The high-sensitivity C-reactive protein concentration was significantly reduced in the rosiglitazone group compared with that in the control group (from 2.92 ± 1.98 to 0.62 ± 0.44 mg/l, P < 0.001 vs. from 2.01 ± 1.33 to 1.79 ± 1.22 mg/l, P = NS). However, the baseline and follow-up glucose and lipid concentrations were not different between two groups. The rate of in-stent restenosis was significantly reduced in the rosiglitazone group compared with the control group (for stent lesions: 17.6 vs. 38.2%, P = 0.030). The rosiglitazone group had a significantly lower degree of diameter stenosis (23.0 ± 23.4% vs. 40.9 ± 31.9%, P = 0.004) compared with the control group.

Conclusions
We demonstrated that treatment with rosiglitazone significantly reduces in-stent restenosis in diabetic patients with CAD who underwent coronary stent implantation.

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Rosiglitazone improves glomerular hyperfiltration,
renal endothelial dysfunction, and microalbuminuria
of incipient diabetic nephropathy in patients.

Pistrosch F, Herbrig K, Kindel B, Passauer J, Fischer S, Gross P.
Department of Medicine, Nephrology, University Hospital "Carl Gustav Carus," Fetscherstrasse 74, 01307 Dresden, Germany. frankpistrosch@hotmail.com.
Diabetes. 2005 Jul;54(7):2206-11.

Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-l-arginine-acetate (l-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 ± 9.8 vs. 119.6 +/- 8.7 ml/min; filtration fraction: 23.2 ± 1.7 vs. 20.5 ± 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 ± 8.6 ml/min, filtration fraction 20.4 ± 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of l-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 ± 31 to 40.4 ± 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria.

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A randomized multicentre trial of insulin glargine compared
with NPH insulin in people with type 1 diabetes.

Home PD, Rosskamp R, Forjanic-Klapproth J, Dressler A.
Newcastle Diabetes Centre and University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
Diabetes Metab Res Rev. 2005 Jul 15;

Background
To compare insulin glargine with NPH human insulin for basal insulin supply in adults with type 1 diabetes.

Methods
People with type 1 diabetes (n = 585), aged 17-77 years, were randomized to insulin glargine once daily at bedtime or NPH insulin either once- (at bedtime) or twice-daily (in the morning and at bedtime) according to their prior treatment regimen and followed for 28 weeks in an open-label, multicentre study. Both groups continued with pre-meal unmodified human insulin.

Results
There was no significant difference between the two insulins in change in glycated haemoglobin from baseline to endpoint (insulin glargine 0.21 ± 0.05% (mean ± standard error), NPH insulin 0.10 ± 0.05%). At endpoint, self-monitored fasting blood glucose (FBG) had decreased similarly in each group (insulin glargine -1.17 ± 0.12 mmol/L, NPH insulin -0.89 ± 0.12 mmol/L; p = 0.07). However, people on >1 basal insulin injection per day prior to the study had a clinically relevant decrease in FBG on insulin glargine versus NPH insulin (insulin glargine -1.38 ± 0.15 mmol/L, NPH insulin -0.72 ± 0.15 mmol/L; p < 0.01). No significant differences in the number of people reporting ≥1 hypoglycaemic episode were found between the two groups, including severe and nocturnal hypoglycaemia. Insulin glargine was well tolerated, with a similar rate of local injection and systemic adverse events versus NPH insulin.

Conclusions
A single, bedtime, subcutaneous dose of insulin glargine provided a level of glycaemic control at least as effective as NPH insulin, without an increased risk of hypoglycaemia.

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Thiazolidinediones May Cut Myocardial Infarction Risk in Type 2 Diabetics

By Jill Stein CHICAGO, IL -- November 20, 2002 --

The use of thiazolidinediones as a strategy for blood glucose lowering in type 2 diabetics may be associated with a reduced risk of myocardial infarction (MI). The findings were presented by Dr. William H. Sauer and co-workers at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania, United States, at the 2002 Scientific Sessions of the American Heart Association (AHA).
The researchers conducted a case-control study of myocardial infarction (MI) in the Philadelphia metropolitan area to examine the effects of prescription and over-the-counter drug exposure and the risk of MI. Cases were type 2 diabetics aged 40 through 75 with a first MI who were hospitalized at one of 36 acute care hospitals from May, 1998 through April, 2001 in a five- county region. Controls were subjects meeting the same above inclusion and exclusion criteria, and they were selected using random digit dialing. Detailed information regarding medication use and other clinical and demographic data were obtained by telephone interview. There were 50 thiazolidinedione users among 462 type 2 diabetics. After adjustment for all confounders including age, sex, race, beta-blocker or insulin use, and a history of hypertension or hypercholesterolemia, the odds ratio for MI among current thiazolidinedione users compared with other diabetics was 0.40 (< 0.01). There was no significant association between MI risk and the use of insulin, metformin, sulfonylurea, or other hypoglycemic drug use. Dr. Sauer said that the results are consistent with the previously observed association between metformin use and reduced risk of MI, suggesting that insulin sensitization is the mechanism for the prevention of macrovascular complications of diabetes. Recall bias is unlikely because there was no association observed between users of other hypoglycemic agent (who would be expected to have the same bias) and MI prevention. The potential benefit of thiazolidinediones over diet or other specific oral hypoglycemic drugs could not be assessed because there were too few subjects who used thiazolidinediones as a single agent.

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Rosiglitazone RECORD study: glucose control outcomes at 18 months

Home PD. Jones NP, Pocock SJ et al; for the RECORD Study Group.
Diabet Med2007 Jun;24(6):626-34

Aims
To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes.

Methods
RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA(1c) of 7.1-9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA(1c) was managed to </= 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA(1c) of 0.4%.

Results
At 18 months, HbA(1c) reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI -0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (-0.09, 0.20)%]. At 6 months, the effect on HbA(1c) was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea -0.36 (-0.74, 0.02) mmol/l, rosiglitazone vs. metformin -0.34 (-0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P </= 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001].

Conclusions
In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA(1c) over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain.