Logistic model of glucose-regulated C-peptide secretion: hysteresis pathway disruption in impaired fasting glycemia.

The present analysis tests the hypothesis that quantifiable disruption of the glucose-stimulated insulin-secretion dose-response pathway mediates impaired fasting glycemia (IFG) and type 2 diabetes mellitus (DM). To this end, adults with normal and impaired fasting glycemia (NFG, n = 30), IFG (n = 32), and DM (n = 14) were given a mixed meal containing 75 g glucose. C-peptide and glucose were measured over 4 h, 13 times in NFG and IFG and 16 times in DM (age range 50-57 yr, body mass index 28-32 kg/m(2)). Wavelet-based deconvolution analysis was used to estimate time-varying C-peptide secretion rates. Logistic dose-response functions were constructed analytically of the sensitivity, potency, and efficacy (in the pharmacological sense of slope, one-half maximal stimulation, and maximal effect) of glucose's stimulation of prehepatic insulin (C-peptide) secretion. A hysteresis changepoint time, demarcating unequal glucose potencies for onset and recovery pathways, was estimated simultaneously. According to this methodology, NFG subjects exhibited distinct onset and recovery potencies of glucose in stimulating C-peptide secretion (6.5 and 8.5 mM), thereby defining in vivo hysteresis (potency shift -2.0 mM). IFG patients manifested reduced glucose onset potency (8.6 mM), and diminished C-peptide hysteretic shift (-0.80 mM). DM patients had markedly decreased glucose potency (18.8 mM), reversal of C-peptide's hysteretic shift (+4.5 mM), and 30% lower C-peptide sensitivity to glucose stimulation. From these data, we conclude that a dynamic dose-response model of glucose-dependent control of C-peptide secretion can identify disruption of in vivo hysteresis in patients with IFG and DM. Pathway-defined analytic models of this kind may aid in the search for prediabetes biomarkers.

Microdialysis--a versatile technology to perform metabolic monitoring in diabetes and critically ill patients.

Continuous subcutaneous glucose monitoring has been tested in type 1 diabetes (T1D). Since in critically ill patients vascular access is granted vascular microdialysis may be preferential. To test this hypothesis comparative accuracy data for microdialysis applied for peripheral venous and subcutaneous glucose monitoring was obtained in experiments in T1D patients. Twelve T1D patients were investigated for up to 30 h. Extracorporeal vascular (MDv) and subcutaneous microdialysis (MDs) was performed. Microdialysis samples were collected in 15-60 min intervals, analyzed for glucose and calibrated to reference. MDv and MDs glucose levels were compared against reference. Median absolute relative difference was 14.0 (5.0; 28.0)% (MDv) and 9.2 (4.4; 18.4)% (MDs). Clarke Error Grid analysis showed that 100% (MDv) and 98.8% (MDv) were within zones A and B. Extracorporeal vascular and standard subcutaneous microdialysis indicated similar performance in T1D. We suggest microdialysis as a versatile technology for metabolite monitoring in subcutaneous tissue and whole blood.

The effect of vitamin D supplementation on peripheral regulatory T cells and ß cell function in healthy humans: a randomized controlled trial.

BACKGROUND: Increasing evidence supports the role of vitamin D (vitD) in modifying the risk to develop type 1 diabetes (T1D) and other autoimmune diseases. VitD3 might stimulate regulatory T cells (Tregs), a central player in the maintenance of self-tolerance. In addition, direct effects of vitD on ß-cell function are postulated. The aim of our study was to evaluate the effect of a high dose vitD supplementation on Tregs frequency (%Tregs) and ß-cell function assessed by a mixed meal tolerance test (MMTT) in healthy humans. METHODS: A double-blind, placebo controlled trial was performed in 59 healthy adult subjects (49% females). Subjects received oral vitD3 (140,000 IU monthly) or placebo for 3 months. %Tregs within 20,000 CD4+ T cells of peripheral blood was determined by multi-parametric FACS-analysis. A liquid MMTT was carried out before and after treatment. RESULTS: %Tregs increased significantly in the vitD group, but remained unchanged in the placebo group. Fasting C-peptide concentrations did not change significantly in either group. Similarly, the mean AUC for C-peptide after 3 months and the change in mean values from baseline to the end of the treatment were comparable in both groups. CONCLUSIONS: A short time high dose vitD3 supplementation significantly increased the frequency of Tregs, but did not further improve ß-cell function in apparently healthy subjects. The immunomodulatory potential of vitD might be an important mechanistic link for the association of vitD and T1D.

Lipid-heparin infusion suppresses the IL-10 response to trauma in subcutaneous adipose tissue in humans.

An imbalance between pro- and anti-inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low-grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18-gauge open-flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid-heparin infusion to elevate circulating NEFA levels or saline over a period of 28 h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) levels increased during the study period but were not affected by lipid-heparin infusion. In contrast, the level of IL-10, an anti-inflammatory cytokine, was significantly reduced during the final hour of lipid-heparin infusion (saline: 449.2 ± 105.9 vs. lipid-heparin: 65.4 ± 15.4 pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.

Hospital glucose control: safe and reliable glycemic control using enhanced model predictive control algorithm in medical intensive care unit patients.

BACKGROUND: The aim of this study was to investigate the performance of the enhanced Model Predictive Control (eMPC) algorithm for glycemic control in medical critically ill patients for the whole length of intensive care unit (ICU) stay. METHODS: The trial was designed as a single-center, open, noncontrolled clinical investigation in a nine-bed medical ICU in a tertiary teaching hospital. In 20 patients, blood glucose (BG) was controlled with a laptop-based bedside version of the eMPC. Efficacy was assessed by percentage of time within the target range (4.4-6.1 mM; primary end point), mean BG, and BG sampling interval. Safety was assessed by the number of severe hypoglycemic episodes (<2.2 mM). RESULTS: Twenty patients (69 +/- 11 years old; body mass index, 27.4 +/- 4.5 kg/m(2); APACHE II, 25.5 +/- 5.2) were included for a period of 7.3 days (median; interquartile range, 4.4-10.2 days) in the study. Time within target range was 58.12 +/- 10.05% (mean +/- SD). For all patients with at least 7 days in the ICU, there was no statistically significant difference between the daily mean percentage of times in target range in respect of the averages. Mean arterial BG was 5.8 +/- 0.5 mM, insulin requirement was 101.3 +/- 50.7 IU/day, and mean carbohydrate intake (enteral and parenteral nutrition) was 176.4 +/- 61.9 g/day. Three hypoglycemic episodes occurred in three subjects, corresponding to a rate of 0.02 per treatment day. CONCLUSIONS: In our single-center, noncontrolled study the eMPC algorithm was a safe and reliable method to control BG in critically medical ICU patients for the whole length of ICU stay.

The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose.

OBJECTIVE: Low glucagon-like peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain whether these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG. RESEARCH DESIGN AND METHODS: We studied 22 subjects with IFG using a double-blinded, placebo-controlled, parallel-group design. At the time of enrollment, subjects ate a standardized meal labelled with [1-(13)C]-glucose. Infused [6-(3)H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-(2)H(2)] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to 100 mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated. RESULTS: As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1 +/- 0.7 vs 17.6 +/- 0.8 micromol/kg per min, P = 0.53), Rd (55.6 +/- 4.3 vs 58.9 +/- 3.3 micromol/kg per min, P = 0.47) and MRa (6639 +/- 377 vs 6581 +/- 316 micromol/kg per 6 h, P = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion. CONCLUSIONS: DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.

Dipeptidyl peptidase-4 inhibition by vildagliptin and the effect on insulin secretion and action in response to meal ingestion in type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS: We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S(I)), glucose effectiveness, and beta-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously. RESULTS: Vildagliptin reduced postprandial glucose concentrations (905 +/- 94 vs. 1,008 +/- 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net S(I) (7.71 +/- 1.28 vs. 6.41 +/- 0.84 10(-4) dl x kg(-1) x min(-1) x muU(-1) x ml(-1), P = 0.13) or glucose effectiveness (0.019 +/- 0.002 vs. 0.018 +/- 0.002 dl x kg(-1) x min(-1), P = 0.65). However, the net beta-cell responsivity index was increased (35.7 +/- 5.2 vs. 28.9 +/- 5.2 10(-9) min(-1), P = 0.03) as was total disposition index (381 +/- 48 vs. 261 +/- 35 10(-14) dl x kg(-1) x min(-2) x pmol(-1) x l(-1), P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 +/- 1.1 vs. 29.7 +/- 1.5 microg x l(-1) x 6 h(-1), P = 0.03), especially after administration of exogenous insulin (81.5 +/- 6.4 vs. 99.3 +/- 5.6 ng/l, P = 0.02). CONCLUSIONS: Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters alpha-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

The effect of dipeptidyl peptidase-4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double-blind, placebo-controlled crossover study.

OBJECTIVES: The incretin hormone glucagon-like peptide-1 (GLP-1) retards gastric emptying and decreases caloric intake. It is unclear whether increased GLP-1 concentrations achieved by inhibition of the inactivating enzyme dipeptidyl peptidase-4 (DPP-4) alter gastric volumes and satiation in people with type 2 diabetes. METHODS: In a double-blind, placebo-controlled crossover design, 14 subjects with type 2 diabetes received vildagliptin (50 mg bid) or placebo for 10 days in random order separated by a 2-week washout. On day 7, fasting and postmeal gastric volumes were measured by a (99m)Tc single-photon emission computed tomography (SPECT) method. On day 8, a liquid Ensure meal was consumed at 30 ml/min, and maximum tolerated volume (MTV) and symptoms 30 min later were measured using a visual analogue scale (VAS) to assess effects on satiation. On day 10, subjects ingested water until maximum satiation was achieved. The volume ingested was recorded and symptoms similarly measured using a VAS. RESULTS: Vildagliptin raised plasma GLP-1 concentrations. However, fasting (248 +/- 21 vs. 247 +/- 19 ml, P = 0.98) and fed (746 +/- 28 vs. 772 +/- 26 ml, P = 0.54) gastric volumes did not differ when subjects received vildagliptin or placebo. Treatment with vildagliptin did not alter the MTV of Ensure (1657 +/- 308 vs. 1389 +/- 197 ml, P = 0.15) or water compared to placebo (1371 +/- 141 vs. 1172 +/- 156 ml, P = 0.23). Vildagliptin was associated with decreased peptide YY (PYY) concentrations 60 min after initiation of the meal (166 +/- 27 vs. 229 +/- 34 pmol/l, P = 0.01). CONCLUSIONS: Vildagliptin does not alter satiation or gastric volume in people with type 2 diabetes despite elevated GLP-1 concentrations. Compensatory changes in enteroendocrine secretion could account for the lack of gastrointestinal symptoms.

Evidence that processes other than gluconeogenesis may influence the ratio of deuterium on the fifth and third carbons of glucose: implications for the use of 2H2O to measure gluconeogenesis in humans.

OBJECTIVE: The deuterated water method uses the ratio of deuterium on carbons 5 and 2 (C5/C2) or 3 and 2 (C3/C2) to estimate the fraction of glucose derived from gluconeogenesis. The current studies determined whether C3 and C5 glucose enrichment is influenced by processes other than gluconeogenesis. RESEARCH DESIGN AND METHODS: Six nondiabetic subjects were infused with [3,5-(2)H(2)]glucose and insulin while glucose was clamped at approximately 5 mmol/l; the C5-to-C3 ratio was measured in the in UDP-glucose pool using nuclear magnetic resonance and the acetaminophen glucuronide method. RESULTS: Whereas the C5-to-C3 ratio of the infusate was 1.07, the ratio in UDP-glucose was <1.0 in all subjects both before (0.75 +/- 0.07) and during (0.67 +/- 0.05) the insulin infusion. CONCLUSIONS: These data indicate that the deuterium on C5 of glucose is lost more rapidly relative to the deuterium on C3. The decrease in the C5-to-C3 ratio could result from exchange of the lower three carbons of fructose-6-phosphate with unlabeled three-carbon precursors via the transaldolase reaction and/or selective retention of the C3 deuterium at the level of triosephosphate isomerase due to a kinetic isotope effect. After ingestion of (2)H(2)O, these processes would increase the enrichment of C5 and decrease the enrichment of C3, respectively, with the former causing an overestimation of gluconeogenesis using the C2-to-C5 ratio and the latter an underestimation using the C3-to-C2 ratio. Future studies will be required to determine whether the impact of these processes on the measurement of gluconeogenesis differs among the disease states being evaluated (e.g., diabetes or obesity).

Contribution of hepatic and extrahepatic insulin resistance to the pathogenesis of impaired fasting glucose: role of increased rates of gluconeogenesis.

OBJECTIVE: To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (approximately 80 pmol/l, "preprandial") or within 30 min of eating (approximately 300 pmol/l, "prandial"). RESULTS: Despite higher (P < 0.001) insulin and C-peptide concentrations and visceral fat (P < 0.05), fasting EGP and glucose disposal did not differ between IFG and NFG subjects, implying hepatic and extrahepatic insulin resistance. This was confirmed during preprandial insulin infusion when glucose disposal was lower (P < 0.05) and EGP higher (P < 0.05) in IFG than in NFG subjects. Higher EGP was due to increased (P < 0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during prandial insulin infusion, indicating that hepatic insulin resistance was mild. Glucose disposal remained lower (P < 0.01) in IFG than in NFG subjects. CONCLUSIONS: Hepatic and extrahepatic insulin resistance contribute to fasting hyperglycemia in IFG with the former being due at least in part to impaired insulin-induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near-maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within 30 min of eating, extrahepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia.

Effects of nonglucose nutrients on insulin secretion and action in people with pre-diabetes.

To determine whether nonglucose nutrient-induced insulin secretion is impaired in pre-diabetes, subjects with impaired or normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite comparable glucose areas above basal, glucose-induced insulin secretion was higher (P < 0.05) and insulin action lower (P < 0.05) during the meal than the oral glucose tolerance test (OGTT) in all subgroups regardless of whether they had abnormal or normal glucose tolerance (NGT). However, the nutrient-induced delta (meal minus OGTT) in insulin secretion and glucagon concentrations did not differ among groups. Furthermore, the decrease in insulin action after meal ingestion was compensated in all groups by an appropriate increase in insulin secretion resulting in disposition indexes during meals that were equal to or greater than those present during the OGTT. In contrast, disposition indexes were reduced (P < 0.01) during the OGTT in the impaired glucose tolerance groups, indicating that reduced glucose induced insulin secretion. We conclude that, whereas glucose-induced insulin secretion is impaired in people with abnormal glucose tolerance, nonglucose nutrient-induced secretion is intact, suggesting that a glucose-specific defect in the insulin secretory pathway is an early event in the evolution of type 2 diabetes.

Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes.

OBJECTIVE: We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS: We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. RESULTS: Fasting (7.3 +/- 0.5 vs. 7.9 +/- 0.5 mmol/l) and peak postprandial (14.1 +/- 0.6 vs. 15.9 +/- 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 +/- 1.6 vs. 23.7 +/- 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 +/- 270 vs. 1,277 +/- 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. CONCLUSIONS: Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.

Prediction of postprandial glycemic exposure: utility of fasting and 2-h glucose measurements alone and in combination with assessment of body composition, fitness, and strength.

OBJECTIVE: To determine the best predictors of total postprandial glycemic exposure and peak glucose concentrations in nondiabetic humans. RESEARCH DESIGN AND METHODS: Data from 203 nondiabetic volunteers who ingested a carbohydrate-containing mixed meal were analyzed. RESULTS: Fasting glucose and insulin concentrations were poor predictors of postprandial glucose area above basal (R2 = approximately 0.07, P < 0.001). The correlation was stronger for 2-h glucose concentration (R2 = 0.55, P < 0.001) and improved slightly but significantly (P < 0.001) with the addition of fasting glucose, insulin, age, sex, and body weight to the model (r2 = 0.58). The 2-h glucose concentration also predicted the peak glucose concentration (R2 = 0.37, P < 0.001) with strength of the prediction increasing (P < 0.001) modestly with the addition of fasting glucose, insulin, age, sex, and body weight to the model (R2 = 0.48, P < 0.001). On the other hand, addition of measures of body function and composition did not improve prediction of total glycemic exposure or peak glucose concentration. CONCLUSIONS: Isolated measures of fasting or 2-h glucose concentrations alone or in combination with more complex measures of body composition and function are poor predictors of postprandial glycemic exposure or peak glucose concentration. This may explain, at least in part, the weak and at times inconsistent relationship between these parameters and cardiovascular risk.

Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance.

Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R(d)) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S(i)) and insulin-stimulated glucose disposal (S(i)*) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R(d) since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG.

[Drug treatment of type 2 diabetes]. / Medikamentöse Behandlung des Typ 2 Diabetes.

Diabetes mellitus and its complications constitute a major health problem in modern societies. The disease affects approximately 5% of the adult population in western countries. The underlying process of the metabolic disorder is a defect in insulin secretion, insulin action, or both. Weight reduction, calorie restriction and patient education remain the cornerstones of the management of type 2 diabetes. When lifestyle modification fails to maintain adequate glycaemic control, insulin or oral hypoglycemic agents are typically used to manage the disease. The currently available five classes of oral agents differ in mechanism and duration of action, the degree to which they lower blood glucose and their side-effect profile. For most of these antiglycaemic agents, there is a lack of evidence on the effects on long-term complications. Only metformin has clearly proved that it can reduce mortality in obese patients with type 2 diabetes. Human insulin reduces acute and long-term mortality in patients with CVD. Furthermore, intensive treatment either with insulin or sulfonylurea has proved that it can prevent microvascular complications in type 2 diabetes. Additional randomized controlled trails assessing hard clinical endpoints are needed to better inform patients and enable physicians to establish optimal treatment strategies.