OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0% (<53 mmol/mol). RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA1c <7.0% (50%, 57%, and 43%) and significantly more weight loss (–3.2, –3.9, and –1.9 kg [–3.5%, –4.2%, and –2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis– and volume depletion–related AEs) was higher in the CANA arms (0.4–4.4%) versus MET (0–0.8%). AE-related discontinuation rates were 1.3–3.0% across groups. The incidence of hypoglycemia was 3.0–5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.

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Relaxation of spontaneously contracting single rat cardiac cells with an effective sarcoplasmic reticulum was shown to be sensitive to load, as previously described for intact mammalian ventricular cardiac muscle. Caffeine and tetanic stimulation could modify load-dependent relaxation in intact papillary muscle from cat or rat into a load-insensitive relaxation. Although such load dependence was demonstrated to be normally absent in frog ventricular cardiac muscle, in the present study it could also be made moderately manifest under specific conditions, e.g., high calcium, low sodium, or ouabain. The appearance of load dependence during relaxation in cardiac muscle thus emphasizes the presence of an effective sarcoplasmic reticulum.

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SUMMARY The present study evaluated potential mechanisms for the slow length-dependent change in myocardial contractile state. Using 40 isolated right ventricular cat papillary muscles, we found that 10 mM caffeine reversed the subsequent slow change in myocardial performance following a change in muscle length. Since caffeine acts both at the sarcolemma and the sarcoplasmic reticulum, we attenuated the sarcolemmal influx of calcium with verapamil, manganese, and low external calcium concentration. None of these interventions altered the caffeine reversal of the length-dependent effect. It thus appears that the length-dependent alteration of contractile state is of intracellular origin, and probably related to altered calcium handling by the sarcoplasmic reticulum. Circ Res 47: 592-598, 1980 THE relationship between muscle length and cardiac performance has been described by the FrankStarling relationship. After an increase in end-diastolic fiber length along the ascending limb of this relationship, there is an increase in cardiac performance. At any given length, positive inotropic agents can further increase cardiac performance. Thus, the traditional view was that these two mechanisms for altering cardiac performance were independent of each other. The Frank-Starling relationship was explained by a variation in the number of crossbridges formed between the contractile proteins (Gordon et al., 1966). The positive inotropic response was explained by an increase in the rate of interaction of these cross-bridges (Katz, 1970).Contrary to the traditional belief that these two mechanisms for altering cardiac performance were separate from one another, we reported a slow length-dependent change in myocardial contractile state (Parmley and Chuck, 1973). In isolated cat papillary muscles, the immediate response to an increase of muscle length was followed by a slow additional increase in performance. Thus, in addition to the instantaneous length, the length history becomes an important determinant of the "FrankStarling" response. Subsequent studies have suggested that the immediate increase in force along the ascending limb is due not so much to myofilament and cross-bridge overlap, but to a lengthdependent alteration in the amount of calcium activating these cross-bridges (Allen et al., 1974;Jewell, 1977;Lakatta and Jewell, 1977;Fabiato and Fabiato, 1975 Received June 4, 1979; accepted for publication May 27,1980. tions the traditional separation between alterations in performance due to length and contractility. In our early attempts to identify a mechanism for the slow time-dependent coupling between muscle length and contractile state, we ruled out crosssectional area, release of stored catecholamines, temperature effects (24°-37°C), or series viscous elements as mechanisms for this observation (Parmley and Chuck, 1973). We did find, however, that varying the external calcium concentration changed the magnitude of the slow response, suggesting a calcium-mediated mechanism. In this paper, we report additional s...

The present study was undertaken to reevaluate the effects of preload on maximum velocity of shortening at zero load, V max , relative to the lengthtension curve. Force-velocity relations were measured from afterloaded isotonic contractions and were calculated from isometric contractions of isolated cat papillary muscles. Results were interpreted in the light of three alternative mechanical models of muscle. V max was obtained by mathematical extrapolation of each force-velocity relation to zero load using a hyperbolic least-squares analysis performed on an IBM 360 computer. With the application of all three muscle models to isotonic force-velocity relations, V max was relatively constant at low preloads but was reduced substantially as muscle length approached L max (the length at the peak of the active length-tension curve). In force-velocity relations from isometric contractions, similar results were obtained with the two-element and Voigt models of muscle. With the Maxwell model, V max remained more nearly constant near L max . Peak developed force (isometric contraction), maximum dP/dt, peak calculated velocity of the contractile element (V CE ), and V max were compared in terms of their dependence on preload and length over the entire length-tension curve (using the Maxwell model). Peak V CE and V malc were similar and were less dependent on preload than maximum dP/dt or developed force. KEY WORDScontractile element series elastic element parallel elastic element Frank-Starling mechanism Voigt model Maxwell model cat papillary muscle preload contractile state• The classic studies of A. V. Hill (1) identified the hyperbolic relation between the velocity of shortening and force development as the most fundamental mechanical relation of skeletal muscle. The extension of this forcevelocity relation to cardiac muscle (2, 3) provided a precise means for quantifying the mechanical behavior of the myocardium. In particular, the extrapolated maximum velocityFrom the

The present study was undertaken to evaluate the effects of methoxamine on force development and adenyl cyclase activity in cat ventricular myocardium. Methoxamine produced a dose-related increase in force development of isometrically contracting cat papillary muscles. The positive inotropic effects of methoxamine were not altered by beta-adrenergic blockade (propranolol), or catecholamine depletion by prior reserpinization, but were completely prevented by alpha-adrenergic blockade (phentolamine or ergotamine). Neither ergotamine, phentolamine, nor methoxamine had any direct effects on adenyl cyclase activity. Phentolamine did not attenuate the increase in force development produced by paired electrical stimulation, suggesting that it does not block the entry of calcium into the muscle. In summary, methoxamine produced a dose-related increase in force development of the cat papillary muscle that was selectively blocked by alpha-adrenergic receptors in ventricular myocardium.

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